Abstract
Targeting synthetic lethal interactions has emerged as a promising strategy for cancer therapeutics, particularly by exploiting DNA damage response (DDR) pathways. A well-known example of this are PARP inhibitors, that selectively kill cancer cells compromised by mutations in DDR genes like BRCA1/2, while sparing normal cells with functional homologous recombination repair. These compounds have substantially improved clinical outcomes, especially in BRCA1/2-mutated ovarian cancer, enhancing both survival rates and quality of life. Their great clinical impact has been constrained by the appearance of resistance and safety concerns. New generation PARP inhibitors are being developed with enhanced selectivity and reduced side effects. Beyond PARP inhibition, several other drugs inhibiting key DDR components, such as ATR, ATM and DNA-PK, have progressed to clinical trials. These DDR inhibitors are being studied alone or in combination with chemotherapy, radiotherapy, immunotherapy or other targeted therapy, increasing efficacy and improving outcomes in resistant and advanced cancers. While most synthetic lethality-based clinical trials in oncology target DDR, an increasing trend in the preclinical and clinical setting is focused on inhibiting non-DDR pathways (e.g., PRMT5 and SMARCA4/2). However, challenges remain in determining the most effective combinations, identifying which patient populations will benefit the most from these therapies and overcoming resistance. Continued research is also essential to fully understand the intricate network of synthetic lethality and maximize the therapeutic potential of synthetic lethality-based therapies. Nonetheless, targeting synthetic lethal interactions with inhibitors represents an exciting frontier in precision oncology, offering the potential for more tailored, effective and less toxic cancer treatments.
Subject terms: Drug development, Drug development
Introduction
Cells are constantly exposed to endogenous and exogenous sources of DNA damage that, if unrepaired, compromise cell viability. To overcome this, they rely on an intricate network of DNA damage response (DDR) pathways responsible for maintaining genomic stability by detecting DNA lesions, controlling the cell cycle and promoting accurate DNA repair. The dysregutlation of these pathways can lead to tumorigenesis. In fact, DDR pathway gene alterations are amongst the most common genomic events observed in human cancers, making DDR components attractive targets for cancer treatment.
Despite the involvement of DDR defects in promoting cancer development, the dysfunction of these pathways also represents a specific vulnerability that can be exploited therapeutically. A promising approach gaining attention for cancer therapeutics in this context is synthetic lethality (SL), where the inhibition of a specific gene or pathway becomes toxic in cancer cells harboring mutations or deficiencies in other genes. By selectively killing cancer cells while sparing normal tissues, this strategy offers the potential for more precise and less toxic cancer treatments. This is exemplified by the success of Poly (ADP-ribose) Polymerase inhibitors (PARPi) in treating BRCA1/2-deficient tumors. BRCA1/2-deficient cells are impaired in homologous recombination repair (HRR), a high-fidelity mechanism for processing DNA double-strandtabl breaks (DSBs). The inhibition of PARP enzymes in these cells, which are involved in the repair of single-strand breaks (SSBs) by base excision repair (BER), results in the accumulation of DNA lesions that cannot be effectively repaired by HRR due to non-functional BRCA1/2 proteins, ultimately leading to cancer cell death. The discovery of novel SL interactions within other DDR genes, coupled with the benefits of PARPi for cancer treatment and the advances in functional genomics, has led to extensive research into targeting other DDR components, such as the three primary phosphatidylinositol 3-kinase-like protein kinases ATR, ATM and DNA-PK, and their downstream effectors, CHK1/2. These proteins participate in the detection of DNA damage and the coordination of cell cycle progression in response to replication stress or DNA damage. Some other DDR targets that are being clinically explored are other cell cycle control kinases (WEE1, PKMYT1, CDKs and PLK1); proteins involved in DSB repair such as the polymerase POLQ (non-homologous end-joining) and the recombinase RAD51 (HRR); USP1, which deubiquitinates FANCD2/FANCI (FA/BRCA pathway) and PCNA (translesion synthesis); the WRN helicase, that mediates the choice between different DSB repair pathways; and APE1, an endonuclease involved in BER. Based on this, cancer cells containing high levels of replication stress or DNA damage often exhibit high dependency on these pathways, making them attractive targets for SL-based therapies.
In addition to monotherapy approaches, combining DDR inhibitors (DDRi) with conventional therapies, such as chemotherapy (CTx) and radiotherapy (RT), has shown promise in enhancing treatment efficacy and overcoming cancer drug resistance by exacerbating DNA damage beyond the repair capacity of cancer cells. Moreover, as DDRi are also able to modulate the tumor microenvironment (TME), increasing the tumor mutational burden and promoting immunogenic cell death, multiple clinical trials are testing their combination with immune checkpoint inhibitors (ICIs). Furthermore, DDR-targeting drugs are also being clinically associated with other targeted therapies, such as with the VEGF inhibitor bevacizumab, and with other DDRi featuring different mechanisms of action.
Although the vast majority of clinically advanced drugs targeting SL in oncology are DDRi, non-DDR agents, including metabolic enzymes (e.g., PRMT5, MAT2A), epigenetic regulators (e.g., SMARCA4, SMARCA2 and ALC1) and RNA helicases (e.g., DHX9), can also induce SL and some of them are undergoing preclinical and clinical evaluation, highlighting the broader applicability of SL across diverse cancer types and molecular contexts.
Based on these considerations, this review aims to provide a comprehensive overview of the mechanisms of SL in DDR and non-DDR pathways, focusing on the clinical development of novel therapeutic targets exploiting SL interactions in oncology. By integrating mechanistic insights with emerging clinical evidence, we discuss the opportunities and challenges associated with the translation of SL into effective cancer treatments, and we draw future directions for the rational design of targeted therapeutic strategies.
Synthetic lethality (SL)
The term synthetic lethality (SL), coined by Theodor Dobzhansky in 1946,1 refers to the genetic interaction between two or more genes wherein their simultaneous alteration leads to severe loss of cell viability and death, while each of them is non-lethal alone2 (Fig. 1). This phenomenon had been previously described at the beginning of the 20th century by Calvin Bridges, who noticed that certain combinations of gene mutations in Drosophila melanogaster were lethal, while the homozygous parents were viable.3
Fig. 1.
Overcoming cancer drug resistance using a double-synthetic lethality approach. In the presence of a normal or cancer cell with 2 functional synthetic lethal genes (genes A and B), if only one of the genes is inhibited (gene B), cells remain viable. However, if this cancer cell has already a mutation on one of the genes (gene A) that impairs its function and the other gene is inhibited this results in cancer cell death. When cancer resistance appears due to for example the mutation or over-expression of an additional gene (gene C), it may be possible to overcome this resistance by designing an inhibitor that targets gene C, thereby restoring cancer cell lethality through this double-SL approach. Figure created with BioRender
Although SL interactions have most commonly been associated with loss-of-function (LOF) alleles, an alternative SL situation, also called synthetic dosage lethality, may involve gain-of-function (GOF) alleles. In this case, a GOF mutation may be lethal only in the presence of a second-site mutation.4 This concept may also be extended to the so-called “synthetic sick” interactions where the combination of mutations in two genes results in non-lethal impairment of cellular fitness more than mutation of either gene alone.5 Combinations of other types of perturbations may also result in SL, including the action of chemical compounds or changes in the TME.6,7
Cancer is considered a disease of the genome. Recent advances in genome sequencing and the use of large-scale genetic CRISPR screens have allowed the rapid identification of genetic and epigenetic changes that distinguish tumor cells from non-tumor cells, revealing vulnerabilities that may be exploited to selectively target the tumor with therapeutics.8,9 In the cancer therapy context, SL has been used as an innovative strategy to design drugs that inhibit one gene product that is lethal in the presence of a mutation in another specific gene, often occurring in tumors.10 A well-known case of drugs targeting SL interactions is PARPi, used for the treatment of HRR-deficient (HRD) tumors. Furthermore, the term SL has not only been used in cancer therapeutics to target LOF alterations in cancer cells via inhibition of a gene product, but also for GOF alterations that may not be targeted directly, such as the case of KRAS-targeted therapies.11 There are additional factors that influence drug-induced SL, such as the TME, metabolic networks, the control of the cell cycle, epigenetic regulation and the DDR pathways.12 Therefore, SL increases selectivity towards the killing of tumor cells that harbor mutations in ‘undruggable’ proteins, including LOF mutations, hence enhancing the therapeutic index between the tumor and normal tissue. Moreover, combination therapy with these drugs might not only increase the efficacy of conventional therapies, allowing to decrease doses and, consequently, adverse effects, but also to overcome drug resistance13 (Fig. 1).
DNA damage response (DDR) as anticancer target
Cells are constantly exposed to a variety of endogenous and exogenous sources of DNA damage. To mitigate these threats, they rely on different mechanisms to repair DNA damage, maintain genomic stability and promote cell survival (Fig. 2). SSBs are mainly repaired by BER, DNA replication errors by MMR, DNA adducts and covalent crosslinks between bases in the same DNA strand are repaired by NER, and the correction of abasic sites and damaged bases and the removal of uracil are performed by BER. The pathway that cells use to process DSBs depends on multiple variables, including the cell cycle stage during which they are generated, whether the DSB itself is one-ended or two-ended and chemically “clean” or “dirty”.14 Eukaryotic cells utilize two main mechanisms for DSB repair: error-prone non-homologous end-joining (NHEJ) and error-free HRR. The NHEJ pathway may be divided into canonical non-homologous end joining (c-NHEJ) or the alternative pathway for non-homologous end joining (alt-NHEJ), which is also termed as microhomology-mediated end-joining (MMEJ). These last two pathways, as the name end-joining indicates, involve the direct ligation of two-ended DSB ends with little or no sequence homology required. Since no repair template is required, it may occur at any phase of the cell cycle. Both c-NHEJ and alt-NHEJ typically cause short deletions or insertions at the DSB site, and besides, they may generate large deletions or chromosomal rearrangements.15,16 In contrast, HRR requires a homologous sequence as a template, which allows the recombination machinery to accurately restore any missing genetic information in the vicinity of the break site.17 Therefore, HRR may only take place in cell cycle stages with an available sister chromatid, which includes the S and G2 phases, and hence a strict control mechanism is needed.16 Another important type of DNA damage vital for cells are interstrand crosslinks (ICLs). ICLs result extremely toxic because they covalently link both DNA strands, preventing their separation during replication and transcription, and if left unrepaired, activate cell apoptosis.18 A well-reported class of ICL-inducers is chemotherapeutic agents such as mitomycin C, cisplatin, nitrogen mustard, nitrosourea, and their derivatives. In non-proliferating cells or during G1 phase of the cell cycle, ICLs are recognized and removed by the NER pathway, followed by excision by XPF-ERCC1 and translesion synthesis (TLS).19,20 In contrast, in replicating cells, the DNA replication machinery serves as a sensor for ICLs, triggering DNA damage checkpoint activation, transient G2 arrest and DNA damage repair by the Fanconi anemia/BRCA (FA/BRCA) pathway.21 The resulting DNA duplex with a DSB may be finally repaired by multiple DSB repair sub-pathways, with HRR the preferential one, thanks to the readily available HRR-compatible template that occurs at ICL sites.21
Fig. 2.
Major DNA repair pathways that are being targeted clinically using the SL approach. Cells rely on multiple mechanisms to repair DNA damage. DNA replication errors are repaired by MMR and DNA adducts and pyrimidine dimers resulting from UV and polycyclic aromatic hydrocarbons (PAHs) by NER. The repair of abasic sites and damaged bases and the removal of uracil as well as SSBs, caused by radiation, alkylating agents or reactive oxygen species (ROS), are performed by BER. DSBs that can arise from X-rays, antitumor agents or replication fork collapse are repaired by error-prone non-homologous end-joining (NHEJ) and error-free homologous recombination repair (HRR). The NHEJ pathways may be divided into canonical non-homologous end joining (c-NHEJ) or the alternative pathway for non-homologous end joining (alt-NHEJ). ICLs, which can be caused by chemotherapeutic agents (e.g., MMC and cisplatin) amongst others, covalently link both DNA strands preventing their separation during replication and transcription. In non-proliferating cells or during G1-phase this type of damage is recognized and removed by the NER pathway, followed by excision by XPF-ERCC1 and TLS. In replicating cells, DNA damage checkpoint is activated and damage is repaired by the FA/BRCA pathway. The other DNA duplex with a DSB may be finally repaired by multiple sub-pathways, being HRR the preferential one. Colored in red are the proteins for which selective drug inhibitors have been identified and have progressed to clinical trials. Figure created with BioRender
Defects in these pathways may cause gene mutations and increase genomic instability that not only alter gene function but may also induce uncontrolled cellular growth and cancer,22,23 for example, by the activation of oncogenes or inactivation of tumor suppressor genes.23 Actually, many proteins involved in DDR, such as BRCA1/2, have been found altered in different tumor types and have been related to cancer initiation, development, metastasis and resistance to anticancer drugs.24–27 The disruption of a specific DDR pathway frequently enhances the dependency of cancer cells on compensatory pathways for their survival. As previously described, these compensatory pathways can be disrupted using the SL concept to specifically target tumors with lower toxicities than conventional therapies. Moreover, a large number of studies have shown that DDR inhibition leads to significantly enhanced sensitivity of cancer cells to CTx and RT.28–32 Dysfunction of several DDR pathways may also trigger the activation of the host’s immune system,33 contributing to the sensitization of tumors to ICIs. This finding suggested a potential treatment strategy for combining DDR-targeting agents with ICIs.34 Preliminary results from different clinical trials have shown that combining DDR-targeting drugs with ICIs represents a promising therapeutic strategy for cancer therapy.35,36 Consequently, accurate recognition and repair of DNA damage is essential to maintain genomic integrity and prevent genomic instability and tumorigenesis. Additionally, the identification of specific alterations in DDR genes in tumors can serve as a biomarker for the selection of the most suitable DDR-targeting drug to treat specifically these tumors, exemplified by the use of PARPi in tumors with BRCA1/2 mutations. To add even more complexity, the reported sensitization effect of DDRi to conventional CTx and RT, and the reported link between DDR pathways and immunotherapy, encourages the study and design of DDRi-based combination treatments to circumvent cancer drug resistance.
The case of PARP inhibitors (PARPi)
Mechanism of action of PARPi
The success of PARPi as anticancer agents for BRCA1/2-deficient tumors provided a proof-of-principle example of the substantial promise of SL for cancer treatment. The discovery in 2005 of a SL interaction between the inhibition of PARP and mutations in BRCA1 or BRCA2 marked a milestone in cancer therapeutics.37,38 BRCA1 and BRCA2 are tumor suppressor genes that confer a higher risk of cancer in mutation carriers, including breast, ovarian, pancreatic and prostate cancer.39,40 Functional BRCA1/2 proteins are crucial to repair DSBs by HRR. When cells acquire HRR deficiency (HRD), driven by defects in BRCA1, BRCA2 or other pathway components, such as PALB2, ATM or ATR,41,42 non-conservative forms of DNA repair, like NHEJ, predominate. These other processes either fuse broken DNA ends at the DSB without using a homologous DNA sequence as a template or fuse regions of DNA close to the site of damage that display short regions of DNA sequence homology, deleting the intervening DNA sequence. The lack of use of homologous sequences as repair templates leads to error-prone repair, which causes DNA alterations and, in turn, cancer initiation or progression43,44; this explains in part the increase in cancer risk related to BRCA1/2 mutations.45 These tumors have frequently arisen in individuals with a germline (g) BRCA1/2 mutation that have developed a somatic LOF aberration in the wild-type BRCA1/2 allele.46
Upon DNA damage, members of the PARP family bind the DNA lesion and modify several proteins with ADP-ribose using NAD+ as a substrate, rapidly recruiting other DNA repair factors.47 PARP1 or 2 and tankyrase 1 (PARP5A) or 2 (PARP5B) generate PARylation, while other PARP members instead attach mono-ADP-ribose onto target proteins and seem to have cancer-relevant functions, being possible future targets for cancer therapy.48,49 However, evidence to date suggests that only PARP1, 2 and 3 are activated by DNA breaks and catalyze ADP-ribosylation after DNA damage, with PARP1 responsible for 80–90% of the global PAR synthesis following DSBs.48,50 PARP1 is the best-characterized member of the PARP family, and apart from regulating cell proliferation and differentiation by repairing SSBs and DSBs, it also participates in the stabilization of DNA replication forks and the modification of chromatin structure.51 Its structure comprises three zinc finger domains for DNA binding, a BRCA-C-terminal domain, a catalytic domain containing a conserved ADP-ribosyl transferase fold, and a WGR (Trp-Gly-Arg) domain, which participates in DNA interaction and regulates the catalytic activity in response to DNA damage.52 Binding to damaged DNA leads to an increase of the PARylation activity and the binding of NAD+ stabilizes the catalytic domain in its unfolded conformation and strengthens the interaction between the regulatory domains and DNA.53 Short base lesions and SSBs that maintain DNA structure are mainly repaired by BER (Fig. 3). Damaged sites are first cleaved by glycosylase and APE1 and create a single-stranded DNA (ssDNA) nick. This is recognized as a SSB by members of the PARP family, being PARP1 the most relevant. PARP proteins generate PARylation of target proteins and themselves, using NAD+ as a substrate.47 Auto-PARylated PARP1 recruits downstream BER components, such as Polβ, XRCC1 and DNA ligase III to the DNA damage site.54,55
Fig. 3.
Base excision repair (BER) pathway. BER is the major DNA damage repair pathway for correcting non-bulky forms of DNA damage (e.g., deamination, base oxidation or alkylation) that do not significantly distort the DNA helix. This process is performed in a series of successive reactions. A damage specific DNA glycosylase initially detects the lesion and excises the damaged base creating an abasic site (AP site), that is then cleaved by APE1 creating a SSB with 3′-hydroxyl (OH) and 5′-dRP ends. Alternatively, the NEIL1-3 glycosylase generates a 1-nucleotide (nt) gap through βδ-elimination flanked by 3′- and 5′-phosphate ends. The 3′ phosphate is removed by PNKP to produce a 3′-OH end. These DNA ends are processed by one of two sub-pathways: short-patch (single-nucleotide) or long-patch (more than one nucleotide) repair, during which a DNA polymerase fills the gap with the correct nucleotides and the repair mechanism is completed with the sealing of the nick by a DNA ligase. More concretely, the ssDNA nick is recognized by PARP1, which upon auto-PARylation, recruits downstream BER components. In short-patch BER, Polβ excises the dRP and fills the gap with a new nucleotide. The nick is then ligated by XRCC1-LIG3. In long-patch BER, Polδ/ε fill the gap with 2-11 nucleotides, creating a 5’-flap that is excised by FEN1 and finally ligated by LIG1 in a PCNA-dependent manner. Figure created with BioRender
PARPi compete with NAD+ for binding and are mostly selective for PARP1 and PARP2. Once bound, they prevent auto-PARylation of PARP and, therefore, its dissociation from the broken DNA. This causes the stabilization and trapping of PARP on the DNA and leads to DSB formation by stalling and collapsing replication forks56,57 or by increasing the speed of fork elongation, what should be correctly repaired by HRR in the S/G2-phase.58 In cells with non-functional HRR, due to, for example, homozygous BRCA1/2 mutations, the PARP1-dependent BER pathway compensates for the damaged DNA not repaired by HRR. Thus, in these cells, the pharmacological inhibition of PARP1 by PARPi causes the accumulation of SSBs, which during DNA replication form DSBs, leading to genomic instability, mitotic damage and cell death59,60 (Fig. 4). Additionally, PARP1 seems to be essential for managing transcription-replication conflicts. Therefore, when it is inhibited, the head-on collision between transcription and replication machineries is left unresolved, creating a source of endogenous DNA stress that must be repaired by HRR.61 Although it was long thought that the main mechanism for the hypersensitivity of BRCA1/2-deficient tumors to PARPi was the formation of unrepaired DSBs, recent findings suggest that ssDNA replication gaps are fundamental to the cytotoxicity of these agents. This hypothesis is based on the fact that BRCA1/2-deficient cells fail to restrain DNA replication in response to genotoxic stress and in consequence, accumulate ssDNA gaps. When these gaps are suppressed by either restored fork slowing or gap filling, these cells acquire chemoresistance. This suggests that the critical lesion that determines drug sensitivity to genotoxic chemotherapies, such as PARPi and cisplatin, are these ssDNA gaps instead of DSB.62,63
Fig. 4.
Synthetic lethality in tumors from BRCA1/2 mutation carriers treated with PARPi. PARPi induce PARP trapping and BER inhibition on sites with SSBs. SSBs in the cells are recognized by PARP1, that recruits downstream BER components to repair the damage. If the BER pathway is inhibited by PARPi in cells with heterozygous mutations in BRCA1/2 (BRCA1/2+/−), PARP1 becomes trapped on the DNA. This causes the stalling and collapse of replication forks and the formation of DSBs, that should be repaired by HRR using the functional BRCA1/2 copy. The same happens in BRCA1/2+/− cancer cells, resulting in cancer cell survival and drug resistance. However, these cancer cells often lose the wild-type copy of BRCA1/2 by loss of heterozygosity (LOH) and, in this case, when exposed to PARPi they can no longer repair the DSBs, leading to cancer cell death by SL between PARP1 (BER) and BRCA1/2 (HRR). Figure created with BioRender
PARPi approved or in clinical trials
Six PARPi have been approved for cancer treatment: olaparib (FDA 2014, EMA 2014; Lynparza® from AstraZeneca), niraparib (FDA 2017, EMA 2017; Zejula® from GlaxoSmithKline), rucaparib (FDA 2016, EMA 2018; Rubraca® from Pharmaand GmbH), talazoparib (FDA 2018, EMA 2019; Talzenna® from Pfizer), and only in China, fuzuloparib (NMPA 2020; AiRuiYi® from Jiangsu Hengrui Pharmaceuticals) and pamiparib (NMPA 2021; Partruvix® from BeiGene). The different PARPi display large variable levels of cytotoxicity by causing distinct degrees of PARP trapping: talazoparib » niraparib > olaparib = rucaparib » veliparib57,64 (Fig. 5). Although the trapping ability of PARPi depends on catalytic inhibition and the resulting dissociation rates, other factors such as reverse allosteric effects may also play a significant role.65,66
Fig. 5.
PARPi approved for marketing. Six PARPi have been approved for cancer treatment: olaparib (Lynparza® from AstraZeneca), niraparib (Zejula® from GlaxoSmithKline), rucaparib (Rubraca® from Pharmaand GmbH), talazoparib (Talzenna® from Pfizer), and only in China, fuzuloparib (AiRuiYi® from Jiangsu Hengrui Pharmaceuticals) and pamiparib (Partruvix® from BeiGene). These drugs, except fuzuloparib and pamiparib, are currently approved by the FDA and the EMA for treating cancers such as breast, ovarian, prostate and pancreatic cancer. Fuzuloparib (formerly fluzoparib) received approval in 2021 by the NMPA for the treatment of ovarian cancer (including fallopian tube cancer or primary peritoneal cancer). Also in 2021, pamiparib was approved by the NMPA for gBRCA1/2m recurrent advanced ovarian, fallopian tube or primary peritoneal cancer previously treated with two or more lines of chemotherapy. Several clinical trials of these drugs directed to the expansion of their indications are ongoing. The different PARPi display distinct degrees of PARP trapping: talazoparib » niraparib > olaparib = rucaparib. Although backed by less evidence, fuzuloparib harbors similar trapping capacity compared to olaparib, and pamiparib similar or higher level. Figure created with BioRender
The clinical journey of PARPi began in 2003 with the introduction of rucaparib (then under the name AG014699) into human trials in combination with the chemotherapeutic agent temozolomide.67 This milestone opened a new chapter in oncology, which was soon followed by a breakthrough Phase I trial for olaparib in BRCA1/2-carriers with advanced solid tumors. This study revealed that 63% of these patients experienced antitumor response with less side effects than conventional CTx (NCT0051637368). Soon afterwards, a Phase II trial showed that olaparib as maintenance treatment (MT) significantly improved median progression-free survival (mPFS) among patients with PtS recurrent ovarian cancer with a BRCA1/2m (NCT0075354569). This led to the approval of olaparib (Lynparza®) in 2014 by the EMA and the FDA for advanced BRCA1/2m ovarian carcinoma. This drug had been developed and taken into the first clinical trials by the UK-based biotech, KuDOS Pharmaceuticals, which was acquired by AstraZeneca in 2006. Subsequently, in 2017, the PARPi niraparib (Zejula®), originally developed by Tesaro and later acquired by GlaxoSmithKline, was approved as MT for recurrent ovarian cancer in complete/partial response (CR/PR) to Pt irrespective of BRCA1/2m status, based on data from the NOVA trial (NCT01847274). This trial found significantly longer mPFS in patients with PtS recurrent ovarian cancer treated with niraparib compared to those receiving placebo, regardless of the gBRCA1/2 mutation or HRD status.70 Following results from the Phase II QUADRA trial (NCT0235458671), niraparib also won approval in 2019 by the FDA as monotherapy for HRD relapsed ovarian cancer treated with three or more prior CTx regimens. Consequently, the therapeutic scope of PARPi expanded beyond BRCA1/2m tumors, requiring the improvement of the available tests for determining HRD in order to correctly identify eligible patients.
Thanks to the significant PFS benefit shown in the OlympiAD trial (NCT0200062272), the indications of olaparib were further expanded in 2018 (FDA) and 2019 (EMA) for gBRCA1/2m HER2- metastatic breast cancer previously treated with an anthracycline and a taxane (in the (neo)adjuvant or metastatic setting). Talazoparib (Talzenna®), another PARPi originally discovered by BioMarin Pharmaceutical, followed by acquisition by Medivation and subsequently acquired in 2016 by Pfizer, also received approval by the FDA (2018) and EMA (2019) for locally advanced or metastatic gBRCA1/2m HER2- breast cancer. This was based on the Phase III EMBRACA study (NCT01945775), where talazoparib as a single agent provided significant benefit in terms of PFS compared to standard CTx.73 Similar to what happened with olaparib in the OlympiAD trial for breast cancer,74 final overall survival (OS) data from the EMBRACA study did not show a significant improvement with talazoparib compared with CTx, although authors considered this lack of OS significance was likely confounded by high rates of post-progression crossover.75
Furthermore, the PARPi developed by Clovis Oncology and afterwards sold to Pharmaand GmbH, rucaparib (Rubraca®), received accelerated approval by the FDA in 2016 and conditional approval by the EMA in 2018 for g/sBRCA1/2m ovarian cancer progressed after 2 or more prior CTx lines, based on the better PFS data observed in patients with BRCA1/2 mutation in the ARIEL 2 trial (NCT0189134476). In addition, following outcomes of the Phase III ARIEL3 trial (NCT01968213), rucaparib was also approved in 2018 by the FDA and the EMA for MT of recurrent ovarian cancer in CR/PR to Pt. This trial documented a statistically significant improvement in mPFS for patients with recurrent PtS ovarian cancer receiving MT with rucaparib vs placebo.77 This was confirmed in subsequent exploratory analyzes (median follow-up of more than 2 years) showing that MT with rucaparib provided a meaningful delay in starting further therapy, without negatively impacting the efficacy of subsequent treatments administered after the first progression event.78 After reviewing the final data provided by the ARIEL4 study (NCT0285594479) in 2024, both the EMA and the FDA considered that rucaparib was not as effective as CTx at prolonging patients’ lives for g/sBRCA1/2m ovarian cancer that progressed after 2 or more prior CTx lines. Consequently, the agencies revoked the initial accelerated/conditional approvals granted to rucaparib, while the MT indication remains unaffected.
As soon as the benefits of PARPi in recurrent disease became clear, especially by increasing PFS,69,80–82 clinical research focus shifted toward preventing recurrence through first-line MT. The SOLO1 study, which tested olaparib as MT for BRCA1/2m advanced ovarian cancer, detected an improvement in mPFS of around 42 months compared to the placebo group (NCT0184498683). Based on these findings, both the FDA (2018) and the EMA (2019) approved olaparib for MT of BRCA1/2m ovarian cancer in CR/PR to first-line Pt. However, after the approval, results from the final analysis of the SOLO1 study were published and reported a clinically meaningful, albeit not statistically significant, improvement in OS.84 With the goal to broaden these benefits, in the following step researchers investigated in three clinical trials whether MT of PARPi alone or in combination could be beneficial as first-line treatment of newly diagnosed ovarian cancer irrespective of BRCA1/2 status. PAOLA1 (NCT02477644), which was the first of these trials, showed that olaparib combined with the antiangiogenic agent bevacizumab provided continued PFS benefit for ovarian cancer beyond first progression, especially in patients with HRD-positive tumors.85 This was translated to a clinically meaningful OS in patients with HRD-positive ovarian cancer86 and led to the approval in 2020 of the combination of olaparib and bevacizumab as MT treatment for advanced HRD ovarian cancer in CR/PR to Pt by both the EMA and the FDA. Moreover, the PRIMA trial (NCT02655016) studied niraparib in newly diagnosed patients with advanced ovarian cancer in response to Pt. This study reported that those receiving niraparib exhibited significantly longer PFS, regardless of the HRR status,87 although no differences in OS were found between the niraparib and placebo arm in the final analysis.88 However, niraparib was approved by the EMA and FDA in 2020 for MT of advanced ovarian cancer in CR/PR to first-line Pt, regardless of the biomarker status. Finally, the VELIA trial (NCT02470585) tested veliparib plus CTx (carboplatin and paclitaxel) followed by MT with veliparib in ovarian cancer patients. This approach led to significantly longer PFS than carboplatin and paclitaxel induction therapy alone,89 although benefit in OS was also not detected in the final analysis.90 This trial also found that veliparib had a lower incidence of toxic effects, such as anemia and thrombocytopenia, than the other PARPi,89 allowing a better safety profile when combined with CTx, which itself has a myelosuppressive effect. However, as described previously, veliparib displays markedly less trapping ability than the other PARPi, which may cause lower efficacy, especially in monotherapy91 and has not been approved to date. Other side effects of PARPi reported in clinical trials include fatigue, nausea and hypertension.89,92,93 In addition, the 5-year follow-up SOLO2 trial (NCT01874353), which tested oral MT with olaparib in recurrent disease, found a high risk for developing myelodysplastic syndrome or acute myeloid leukemia (AML). This association between olaparib and blood cancers is being further explored in an additional long-term follow-up of the patients.94
All these studies (SOLO1, PAOLA1, PRIMA and VELIA) showed a significant improvement in PFS of MT with a PARPi. However, all patients did not manifest the same magnitude of response: people with BRCA1/2m tumors benefited the most, followed by those with cancers with HRD not related to BRCA1/2 mutations, and finally those that did not harbor any kind of HRD. Only the PRIMA trial with niraparib demonstrated significant benefit in the last group, although it was just beyond 3 months.87 Moreover, the incongruency found in several trials exploring MT with PARPi (SOLO1, PRIMA and VELIA) between the PFS and the final OS results should be interpreted with caution and may be due to different factors, such as the long follow-up required, the subsequent lines of anticancer therapies (including PARPi) that receive these patients in the broad post-progression survival period and also the impact of prior treatments that can lead to PARPi and/or Pt resistance,95 amongst others. Finally, the results from the OReO/ENGOT-Ov-38 Phase IIIB trial (NCT03106987) evaluating olaparib as MT in patients with relapsed ovarian carcinoma previously treated with a PARPi and at least two lines of Pt have recently been published. This trial assessed patients who relapsed after ending the initial treatment with a PARPi, but not those whose cancer relapsed during the treatment because of PARPi resistance. MT with olaparib provided these patients a modest significant improvement in mPFS over placebo of around 2 months regardless of BRCA1/2m status, with a proportion of them remaining progression-free at 1 year. The accelerated disease progression in a subset of patients from this trial suggests that they may have acquired PARPi resistance during prior MT with PARPi.96 Therefore, this study was the first to demonstrate that maintenance olaparib rechallenge in heavily pretreated ovarian cancer patients may improve, albeit modestly, PFS, regardless of BRCA1/2m status.
Another great advance in the adjuvant setting was the approval in 2022 by both the EMA and the FDA of olaparib as adjuvant treatment of patients with deleterious or suspected deleterious gBRCA1/2m HER2- high-risk early breast cancer previously treated with neoadjuvant or adjuvant CTx. This was based on the international OlympiA Phase III trial (NCT02032823) studying 1836 patients with high-risk gBRCA1/2m HER2- early breast cancer receiving 1 year of adjuvant olaparib after completion of definitive local treatment and neoadjuvant or adjuvant CTx. Results showed that patients treated with olaparib exhibited significantly longer distant disease–free survival than those with placebo.97 In 2024, the first PARPi/immunotherapy combination was approved in the EU: olaparib associated with durvalumab for MT of primary advanced or recurrent MMR-proficient endometrial cancer not progressed on first-line treatment with durvalumab plus carboplatin and paclitaxel. This approval was based on the results from the Phase III DUO-E/GOG-3041/ENGOT-EN10 trial (NCT04269200). In this study, the combination of carboplatin/paclitaxel plus durvalumab followed by durvalumab MT with olaparib demonstrated a significant PFS benefit in advanced or recurrent endometrial cancer patients.98
Apart from the different approvals for ovarian, breast and endometrial cancers (Fig. 6), the therapeutic landscape with PARPi has continued to expand into new indications and combinations. In the realm of metastatic castration-resistant prostate cancer (mCRPC), olaparib was approved in 2020 by the FDA for g/sHRD mCRPC and by the EMA for g/sBRCA1/2m mCRPC progressed to prior treatment with enzalutamide or abiraterone. This was based on the PROfound clinical trial (NCT02987543) that studied men with mCRPC harboring at least one alteration in BRCA1/2 or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent. In this study, patients initially assigned to the olaparib group displayed significantly longer OS than those receiving enzalutamide or abiraterone plus prednisone as control therapy, despite substantial crossover from control therapy to olaparib.99 Also in 2020, the FDA granted accelerated approval to rucaparib for g/sBRCA1/2m mCRPC previously treated with androgen receptor (AR)-directed therapy and a taxane-based CTx, thanks to the antitumor activity reported in the Phase II TRITON2 trial (NCT02952534100). In 2025, thanks to the efficacy data from the Phase III TRITON3 trial (NCT02975934) showing significantly longer duration of imaging-based PFS with rucaparib than with control medication in BRCA1/2m patients,101 rucaparib received regular approval for g/sBRCA1/2m mCRPC previously treated with AR-directed therapy. Furthermore, the combinations olaparib/niraparib plus abiraterone and talazoparib plus enzalutamide have established new standards for treating mCRPC. This started in 2022 when the EMA extended the indication of olaparib to its combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with mCRPC in whom CTx is not clinically indicated, based on the results of the Phase III PROpel study (NCT03732820). This trial evaluated the efficacy and safety of olaparib plus abiraterone in the first-line mCRPC setting and found significantly prolonged imaging-based PFS compared with abiraterone and placebo irrespective of HRR mutation status.102 This was followed by approval in 2023 of this same combination by the FDA for patients with deleterious or suspected deleterious BRCA1/2m mCRPC, thanks to an exploratory subgroup analysis suggesting that the benefit was higher in patients with BRCA1/2 mutations.103 Also in 2023, the FDA approved the fixed-dose combination of niraparib and abiraterone acetate, with prednisone, for patients with deleterious or suspected deleterious BRCA1/2m mCRPC, as determined by an FDA-approved companion diagnostic, based on results from the MAGNITUDE trial (NCT03748641). This study showed a significant improvement in radiographic PFS (rPFS)104 and a trend toward longer OS with this combination in the HRD population and the BRCA1/2 subgroup.105 In the case of talazoparib, both the EMA and FDA extended its indications in the same year to the combination with enzalutamide for HRD mCRPC based on results from the TALAPRO-2 (NCT03395197) trial. This study detected a clinically meaningful and statistically significant improvement in rPFS with talazoparib plus enzalutamide versus standard-of-care (SOC) in men with HRD mCRPC.106 This benefit has been further supported by the clinically meaningful improvement in OS observed in the final analysis results.107 Finally, a new indication for olaparib was added as MT for metastatic gBRCA1/2m pancreatic cancer after receiving more than 16 weeks of Pt, by both the FDA (2019) and EMA (2020). This was based on the longer PFS with olaparib than with placebo reported in the Phase III POLO trial (NCT02184195108), although final OS results did not reach statistical significance.109
Fig. 6.
Timeline of PARPi approvals by the EMA and FDA. Olaparib (Lynparza®) was the first PARPi to receive regular approval by both agencies in 2014 for ovarian cancer, followed by niraparib (Zejula®) in 2017. In 2018, olaparib’s indications expanded to breast cancer (FDA), while talazoparib (Talzenna®) and rucaparib (Rubraca®) received approvals for breast and ovarian cancer, respectively. Subsequent years saw a rapid expansion of indications: olaparib for pancreatic cancer (FDA, 2019; EMA, 2020) and the first approvals for metastatic castration-resistant prostate cancer (mCRPC) for both olaparib (FDA and EMA) and rucaparib (FDA) in 2020. Notably, the timeline reflects a recent shift toward combination therapies, including olaparib with bevacizumab for ovarian cancer (FDA and EMA, 2020) and multiple PARPi combinations with androgen receptor-signaling inhibitors (abiraterone, enzalutamide) for mCRPC (2022–2023). Most recently, in 2024, olaparib was approved in combination with durvalumab for endometrial cancer (EMA), highlighting the ongoing integration of PARPi into immuno-oncology regimens. Figure created with BioRender
The role of PARPi is also expanding into earlier treatment settings. Historically, PARPi were reserved for recurrent disease, where acquired Pt resistance, frequently associated with secondary mutations restoring HRR function, often confers cross-resistance to PARP inhibition.110,111 To circumvent these resistance mechanisms and maximize therapeutic impact, recent clinical trials have explored PARPi in the neoadjuvant setting. For instance, a Phase II trial (NCT02624973) testing olaparib monotherapy in primary treatment-naïve triple-negative breast cancer (TNBC) found high response rates in tumors with HRD, particularly in gBRCA1/2m tumors, but also in those with gPALB2 or somatic ATRX, BRCA1, EMSY, MEN1, PTEN and SETD2 mutations.112 The high pathological CR rates from olaparib, alone or in combination with durvalumab in the Phase II OlympiaN trial (NCT05498155) provided additional encouraging evidence supporting further investigation of olaparib in the neoadjuvant setting for early-stage BRCA1/2m breast cancer.113 These same outcomes were not observed in the PARTNER trial (NCT03150576) exploring neoadjuvant olaparib added to CTx in patients with TNBC cancer without gBRCA1/2m. Although these results need further confirmation in larger cohorts, they indicate that olaparib monotherapy could be useful to debulk big HRD early-stage breast cancer before surgery or treatment with CTx.114
PARPi are continuously included in novel clinical trials alone or associated with different chemo- or radiotherapeutic regimens, immunotherapy or targeted therapy (Table 1). PARP inhibition increases the collapse of replication forks after ionizing radiation (IR), generating persistent DNA DSBs that should be repaired by HRR.115 Preclinical studies suggested that PARPi can act as radiosensitizers to improve the therapeutic outcomes of RT, especially in BRCA1/2m tumors.28,31,116 Several clinical trials have explored this combination together with other agents for solid tumors (e.g., NCT04037254 and NCT01908478) with inconsistent results.117–119 PARPi are also being clinically explored in combination with several ICIs, such as durvalumab (NCT04269200), camrelizumab (NCT06533384) and tislelizumab (NCT04164199), with positive results.35,98 This is due to recent studies that have reported that PARPi mitigate resistance and enhance the efficacy of ICIs by increasing immune priming and TME modification.120 In fact, PARP inhibition in BRCA1/2-defficient TNBC cells reduced DDR and induced neoantigens and cytosolic DNA, activating the IFN pathway via STING, resulting in the tumors’ sensitization to ICIs.121 Moreover, as PARPi cause the upregulation of PD-L1 expression, the combination of PARPi and anti-PD-L1 antibodies sensitized cancer cells to PD-L1 blockade.122 Based on preclinical findings suggesting the potentiation of PARPi effects by VEGFRi,123 the synergy between these drugs is also being clinically analyzed in ovarian cancer with promising results (e.g., NCT02477644). Regarding CDK4/6i, the association of the CDK4/6i, dalpiciclib, with the estrogen receptor (ER) antagonist fulvestrant demonstrated significant clinical benefit in HR+ and HER2- advanced breast cancer (NCT03927456124). This combination is being studied in a Phase III trial associated with fuzuloparib (NCT06612814). Talazoparib is also being evaluated in a Phase I trial in association with the CDK4/6i palbociclib (NCT04693468). Preclinical data showed that abemaciclib and talazoparib synergistically suppressed the growth of TNBC cells and overcame talazoparib resistance through cell cycle arrest and apoptosis.125 This synergy was also demonstrated in non-small cell lung cancer (NSCLC) xenografts.126 Besides, the combination of talazoparib and palbociclib also reduced tumor growth in an in vitro bladder cancer model.127 Results from a bioinformatics analysis in osteosarcoma also revealed potential sensitivity to combination therapy with CDK4/6i and PARPi.128 PARPi are also included in clinical trials associated with: inhibitors of the PI3K/AKT/mTOR pathway, such as the α-selective PI3K inhibitor alpelisib (NCT04729387) or the pan-PI3K inhibitor buparlisib (NCT01623349), that are both being analyzed combined with olaparib; inhibitors of RAS/RAF/MEK, such as the MEK inhibitor selumetinib combined with olaparib (NCT03801369); the BET inhibitor ZEN003694 associated with talazoparib (NCT05071937 and NCT05327010); c-MET inhibitors, such as crizotinib, tested in combination with talazoparib (NCT04693468), and cabozantinib being combined with pamiparib (NCT05038839) and niraparib (NCT03425201); and drugs targeting EGFR/HER2, such as the dual EGFR/HER2 inhibitor, lapatinib, that was studied with the PARPi veliparib (not yet approved) in TNBC (NCT02158507) and the pan-EGFR inhibitor neratinib (NCT04502602), the EGFR inhibitor osimertinib (NCT03891615), the HER2-directed agent trastuzumab (NCT03368729 and NCT04508803 also adding the anti-PD-1 HX008) and the HER2-targeting antibody–drug conjugate comprised of trastuzumab bound to a linker drug containing duocarmycin, SYD985 (NCT04235101), that are all being clinically studied associated with niraparib.
Table 1.
Recent Phase I/II, II, III and/or IV clinical trials for approved PARP inhibitors: monotherapy and combination therapy
| Target | Agent | Intervention | Cancer type | Phase | Clinicaltrials.gov identifier |
|---|---|---|---|---|---|
| PARP | Olaparib | Olaparib | BRCA1/2m CRPC | IV | NCT05457257 |
| Optimal dosing of oral anticancer drugs (e.g., Olaparib) | Renal cell, ovarian, thyroid, breast and endometrial carcinoma | IV | NCT05949424 | ||
| Olaparib | Breast and ovarian cancer | IV | NCT04330040 | ||
| Olaparib (adjuvant) | HER2- BRCA1/2m breast cancer | III | NCT02032823 | ||
| Olaparib | HRD-mCRPC | III | NCT02987543 | ||
| Olaparib + Abiraterone | mCRPC | III | NCT03732820 | ||
| Olaparib (MT) | Ovarian cancer | III | |||
| Olaparib + Bevacizumab | Ovarian, fallopian tube or peritoneal cancer | III | NCT02477644 | ||
| Olaparib + Durvalumab | Proficient-MMR endometrial cancer | III | NCT04269200 | ||
| Olaparib + Alpelisib | PtR ovarian cancer | III | NCT04729387 | ||
| Niraparib | Niraparib (MT) | Ovarian cancer | IV | NCT05187208 NCT06412120 NCT03752216 NCT04861181 | |
| Niraparib (MT) | PtS ovarian cancer | III | NCT02655016 NCT01847274 NCT03705156 NCT03709316 | ||
| Niraparib vs Placebo | HER2- BRCA1/2m breast cancer or TNBC | III | NCT04915755 | ||
| RT vs Brachytherapy (vaginal) vs Observation vs Niraparib | Serous or TP53-mutated endometrial cancer | III | NCT04159155 | ||
| Niraparib or Temozolomide | Glioblastoma | III | NCT06388733 | ||
| Abiraterone + Prednisone ± Niraparib | HRD-CRPC | III | NCT04497844 NCT03748641 | ||
| Niraparib + CTx ± Bevacizumab | Ovarian cancer | III | NCT05009082 | ||
| Niraparib ± Pembrolizumab (MT) | NSCLC | III | NCT04475939 | ||
| Niraparib ± Dostarlimab vs CTx | Endometrial or ovarian carcinosarcoma | II/III | NCT03651206 | ||
| Niraparib + Dostarlimab vs CTx | Ovarian, fallopian tube or peritoneal cancer | III | NCT04679064 | ||
| SOC ± Niraparib ± Dostarlimab | Ovarian cancer | III | NCT03602859 | ||
| Carboplatin-Paclitaxel + Dostarlimab/Placebo ± Niraparib | Endometrial cancer | III | NCT03981796 | ||
| CTx + Niraparib ± Atezolizumab | Ovarian cancer | III | NCT03598270 | ||
| Molecular targeted therapy (e.g., Niraparib) vs CTx | Biliary cancer | III | NCT05615818 | ||
| Niraparib + Heated Intraperitoneal CTx | Ovarian, fallopian tube or peritoneal cancer | III | NCT05659381 | ||
| SOC vs SOC+3 treatments (SBRT, radioactive material or Niraparib) | Castration-sensitive prostate cancer | III | NCT06320067 | ||
| Biomarker-driven therapy (e.g., Niraparib + Abiraterone + Prednisone) vs SOC | Metastatic prostate cancer | III | NCT03903835 | ||
| Atezolizumab + other (e.g., Niraparib) | Rollover study | III | NCT03768063 | ||
| Rucaparib | Rucaparib (MT) | Rollover study | III | NCT04676334 | |
| Rucaparib (MT) | PtS ovarian, fallopian tube or peritoneal cancer | III | NCT01968213 | ||
| Rucaparib (MT) post-Bevacizumab | Ovarian, fallopian tube or peritoneal cancer and clear cell carcinoma | III | NCT04227522 | ||
| Rucaparib vs CTx | BRCA1/2m ovarian, fallopian tube or peritoneal cancer | III | NCT02855944 | ||
| Rucaparib vs Abiraterone or Enzalutamide or Docetaxel | HRD-mCRPC | III | NCT02975934 | ||
| Rucaparib + Nivolumab/Placebo (MT) | Ovarian cancer | III | NCT03522246 | ||
| Rucaparib/Placebo + Enzalutamide | mCRPC | III | NCT04455750 | ||
| Atezolizumab + other (e.g., Rucaparib) | Rollover study | III | NCT03768063 | ||
| Talazoparib | Talazoparib vs Capecitabine/Eribulin/Gemcitabine/ Vinorelbine | BRCA1/2m breast cancer | III | NCT01945775 | |
| Talazoparib + Enzalutamide vs Enzalutamide | mCRPC | III | NCT03395197 | ||
| Talazoparib + Enzalutamide vs Placebo | DDR-deficient castration-sensitive prostate cancer | III | NCT04821622 | ||
| Avelumab vs Avelumab + other (e.g., Talazoparib) | Solid tumors | III | NCT05059522 | ||
| Fuzuloparib | Fuzuloparib (MT) | Ovarian cancer | III | NCT03863860 | |
| Fuzuloparib + Abiraterone + Prednisone | CRPC | III | NCT04691804 | ||
| Fuzuloparib/Capecitabine + Camrelizumab | TNBC | III | NCT06533384 | ||
| Fuzuloparib ± Apatinib (MT) | Ovarian cancer | III | NCT06188455 NCT04229615 NCT06539091 | ||
| Fuzuloparib ± Apatinib vs CTx | BRCA1/2m HER2- breast cancer | III | NCT04296370 | ||
| Fuzuloparib + Apatinib vs CTx | HRD/HER2- breast cancer | III | NCT06255392 | ||
| Fuzuloparib + Dalpiciclib + Fulvestrant | HR+/HER2- breast cancer | III | NCT06612814 | ||
| Fuzuloparib + Endocrine therapy | HR+/HER2- SNF3- early breast cancer | III | NCT05891093 | ||
| Pamiparib | Pamiparib (MT) | Ovarian cancer | III | NCT03519230 | |
| Pamiparib + Tislelizumab or Temozolomide | Advanced malignancies | III | NCT04164199 | ||
| Pamiparib | SCLC | II | NCT05483543 | ||
| Pamiparib | Ovarian cancer | II | NCT05489926 | ||
| Pamiparib | HRD-mCRPC | II | NCT05327621 | ||
| Pamiparib | HER2- breast cancer | II | NCT03575065 | ||
| Pamiparib | Gastric cancer | II | NCT03427814 | ||
| Pamiparib | Rare tumors | II | NCT06692491 | ||
| Pamiparib + Surufatinib | Ovarian cancer | II | NCT05652283 | ||
| Pamiparib + Tamoxifen | Ovarian cancer | II | NCT05669768 | ||
| Pamiparib + Tislelizumab | HRD-advanced malignancies | II | NCT04985721 | ||
| Pamiparib + Abiraterone (neoadjuvant) | Prostate cancer | II | NCT05376722 | ||
| Rezvilutamide + Goserelin + Pamiparib | Prostate cancer | II | NCT06387056 | ||
| Pamiparib + Bevacizumab | Ovarian cancer | II | NCT05044871 | ||
| PARPi (e.g., Pamiparib) + Androgen deprivation therapy ± Abiraterone | Prostate cancer | II | NCT05406999 | ||
| Pamiparib | Ovarian cancer and TNBC | I/II | NCT03333915 | ||
| Pamiparib + Surufatinib | Ovarian cancer | I/II | NCT05494580 | ||
| Pamiparib + Temozolomide | IDH1/ 2-mutated gliomas | I/II | NCT03914742 |
Data extracted from clinicaltrials.gov up until November 2025
This global momentum for PARPi is further evidenced by the approval of new PARPi such as fuzuloparib and pamiparib in China, which are currently being tested in diverse combinations with VEGFR inhibitors and PD-1 blockers to tackle Pt-resistant cancers. Fuzuloparib (AiRuiYi®), formerly fluzoparib, is an oral small molecule being developed by Jiangsu Hengrui Pharmaceuticals that received first approval in 2020 by the China National Medical Products Administration (NMPA) for the treatment of gBRCA1/2m recurrent ovarian cancer in patients who have received two or more lines of chemotherapy. Its indications have since expanded to include MT for PtS advanced ovarian cancer regardless of BRCA1/2m status (2022), and treatment for gBRCA1/2m, HER2- metastatic breast cancer (2025). The efficacy of fuzuloparib as MT for PtS recurrent ovarian cancer was confirmed in the Phase III FZOCUS-2 study (NCT03863860). In this trial, MT with fuzuloparib demonstrated a statistically significant and clinically meaningful improvement in PFS in these patients regardless of gBRCA1/2 status, with a manageable safety profile.129 Preclinical data suggested that fuzuloparib in combination with the VEGFR inhibitor (VEGFRi) apatinib or with apatinib and paclitaxel could exhibit significant efficacy without additive toxicity.130 Based on these findings, several clinical trials exploring this combination in the maintenance setting are being conducted (e.g., NCT04229615 and NCT06539091). However, recent data from the Phase III FZOCUS-1 trial (NCT04229615) indicated that the addition of apatinib to fuzuloparib did not show an improvement in PFS compared to fuzuloparib alone, as first-line MT for newly diagnosed advanced ovarian cancer.131 In contrast, a Phase II study (NCT04517357) reported a trend toward improved overall response rate (ORR) with the combination in patients with Pt-resistant (PtR) ovarian cancer or those naïve to VEGFRi,132 suggesting that the benefit of the combination may be specific to later-line or resistant settings. Several other Phase II or III trials of fuzuloparib in combination with adjuvant endocrine therapy (NCT05891093), PD-1 inhibitors (NCT06533384) or abiraterone and prednisone (NCT04691804), amongst others, or as MT (NCT06188455) are ongoing.
In 2021, the China NMPA granted conditional approval to the PARPi pamiparib (Partruvix®) from Beigene for the treatment of gBRCA1/2 mutation-associated recurrent advanced ovarian cancer previously treated with two or more lines of CTx. This approval was supported by the pivotal Phase II portion of a Phase I/II trial in subjects with gBRCA1/2m epithelial ovarian cancer (NCT03333915133). Currently, Phase III clinical trials are evaluating pamiparib in combination with temozolomide or the PD-1 inhibitor tislelizumab for advanced malignancies (NCT04164199), alongside its use as MT for PtS recurrent ovarian cancer (NCT03519230). Beyond ovarian cancer, a Phase II study demonstrated promising efficacy and a tolerable safety profile for pamiparib in patients with advanced and metastatic BRCA1/2m HER2- breast cancer (NCT03575065134). Conversely, the Phase II PARALLEL-303 study (NCT03427814) failed to show a significant benefit from MT with pamiparib in patients with inoperable gastric cancer who responded to Pt.135 More recently, preliminary results from a prospective Phase II trial (Chinese Clinical Trial Register information number: CTR2200059119) indicated that the combination of pamiparib with neoadjuvant CTx and bevacizumab showed promising efficacy and acceptable toxicity for newly diagnosed advanced ovarian cancer.136 Beyond its primary indications, pamiparib is distinguished by its unique pharmacokinetic profile. Unlike several other PARPi, it is not a substrate for the P-glycoprotein (P-gp) efflux pump, suggesting a potential to overcome specific mechanisms of acquired resistance. Additionally, its high blood-brain barrier penetration has expanded its clinical investigation into CNS-involved malignancies.137 The Phase IB/II POST-PARPi trial (NCT05494580) demonstrated that pamiparib in combination with the multi-kinase inhibitor surufatinib, provides a potential therapeutic avenue for patients with heavily pre-treated PtR ovarian cancer previously treated with PARPi.138
BRCAness phenotype
When seeking additional SL uses besides BRCA1/2 for these PARPi, the concept “BRCAness” showed up. “BRCAness” is a term used to define a subset of tumors that lack gBRCA1/2 mutations but share other molecular features with BRCA1/2m tumors, such as HRD, effectively acting as phenocopies of BRCA1/2m tumors.139 Increasing preclinical and clinical evidence suggests that defects in specific tumor suppressor genes involved in HRR and/or associated DDR pathways, especially PALB2, but also ATM, ATR or CHK2, amongst others, also influence the sensitivity to PARPi.46,140 Genetic screens have shown that other defective genes in cancer, such as CDK12, RAD51B and RAD51C, might also cause a “BRCAness” phenotype, although solid clinical data have not yet been provided.141–143 Apart from alterations in key DDR factors, alterations in chromatin regulators, such as ARID1A144 and BAP1,145,146 have also been associated with in vitro increased sensitivity to olaparib.
Clinical data indicate that the efficacy of PARPi in tumors exhibiting BRCAness or HRD varies according to the specific gene alteration and the tissue of origin. As for advanced pancreatic cancer, two parallel nonrandomized Phase II clinical trials of olaparib monotherapy in patients with BRCAness phenotype and lack of the gBRCA1/2 variant, found significantly longer PFS and OS in those with PtS tumors harboring alterations in the following genes: ATM (n = 14, 50% germline and 50% somatic), gPALB2 (n = 2), ARID1A (n = 3), sBRCA (n = 1), PTEN (n = 1), RAD51 (n = 1), CCNE (n = 1), and FANCB (n = 2).147 Similarly, in a Phase II trial (NCT02401347), single-agent talazoparib also demonstrated treatment-associated tumor regression in all HER2- advanced breast cancer patients with gPALB2 mutations. Stable disease was detected in one patient with a gCHK2 mutation (testicular cancer), in one patient with a gATM mutation (colon cancer) and in three breast cancer patients with gPALB2, sATR or sPTEN mutations.148 In contrast, the Phase II TBCRC-048 (NCT02032823) trial that studied the efficacy of olaparib for HRD metastatic breast cancer found confirmed responses and improved survival only in patients with mutations in gPALB2 (ORR, 82%; mPFS, 13.3 months) and sBRCA1/2 (ORR, 50%; mPFS, 6.3 months). No responses were observed in patients with ATM or CHK2 mutations alone.149 Talazoparib also failed to show a sufficient level of efficacy in patients with advanced HRD (defined by deleterious mutations in genes such as ATM, ATR, BRCA1/2, BARD1, PALB2, amongst others) squamous cell lung cancer in another trial (NCT02154490).150
Concerning mCRPC, several clinical trials have shed more light to these biomarker-driven responses, especially in the case of ATM. The Phase II TOPARP trial (NCT01682772) evaluated the antitumor activity of olaparib in 2 serial parts, TOPARP-A and TOPARP-B, with the goal of identifying predictive biomarkers for response in this cancer type. In TOPARP-A, high response rates were found in patients with alterations in BRCA1/2, ATM (monoallelic mutations affecting the kinase catalytic domain), PALB2 (one biallelic and the other monoallelic) or HDAC2 (biallelic).151 In the TOPARP-B, the greatest antitumor response was found in patients with g/sBRCA1/2 alterations, but some antitumor activity was observed in other subgroups with DDR alterations, especially in the case of biallelic PALB2 (but not in monoallelic), and to a less extend in those with ATM (gATM and loss of ATM protein expression by immunohistochemistry), FANCA, or CHK2 mutations.152 The TRITON2 Phase II study that resulted in accelerated approval (FDA) of rucaparib for g/sBRCA1/2 mCRPC also observed responses in patients with alterations in PALB2, FANCA, BRIP1 (also known as FANCJ) and RAD51B, while no significant responses were detected in the ATM, CDK12, or CHK2 subgroups (NCT02952534153). The same outcome was reported in the TRITON3 Phase III trial, where PFS was significantly longer with rucaparib compared to control among patients who had BRCA1/2m mCRPC, but not in those with alterations in ATM (NCT02975934101). A small retrospective observational study of patients with mCRPC who were prescribed off-label single-agent olaparib and were not reliably tested for the mutation type also found that patients with ATM mutations did not respond to PARPi as well as those with BRCA1/2 mutations.154 In contrast, RAD51C and RAD51D alterations have emerged as strong predictors of rucaparib sensitivity in ovarian cancer based on the Phase II ARIEL2 (NCT01891344155) and Phase III ARIEL3 (NCT01968213156) studies. Finally, niraparib monotherapy provided some disease stability in a proportion of patients with refractory solid tumors with mutations in BAP1, ATM, CHEK2, PTEN, RAD50 and ARID1A in another Phase II trial (NCT03207347157). Promising activity with olaparib was also found in the Phase II ORCHID trial (NCT03786796) in metastatic renal cell carcinoma patients harboring BAP1 mutations.158
Furthermore, as described before, some other clinical trials have found benefit with neoadjuvant PARPi for HRD breast cancers, such as with olaparib monotherapy in TNBC with germline BRCA1/2m or PALB2 or somatic ATRX, BRCA1, EMSY, MEN1, PTEN and SETD2 mutations (NCT02624973112). High response rates were also found with olaparib, alone or in combination with durvalumab for early-stage BRCA1/2m breast cancer (NCT05498155113), while no responses were reported with neoadjuvant olaparib plus CTx in TNBC cancer patients without gBRCA1/2 mutations (NCT03150576114).
Altogether, these data indicate that factors such as the particular type of DDR gene alteration, whether it is somatic or germline, or monoallelic or biallelic and the Pt sensitivity status matter as biomarkers of response to PARPi. Additionally, it is worth noting that most of the studies lack significant numbers of individuals with mutations in specific DDR genes, especially in the less common ones, such as RAD51C, RAD51D, and BARD1, what limits their ability to adequately assess PARPi responses. Despite the need for further research in larger cohorts, these findings have opened new paths to broaden the indications of PARPi beyond BRCA1/2 mutations.
Novel PARPi in clinical trials
Many other PARPi have progressed to clinical trials but currently lack regulatory approval (Table 2, and Supplementary Fig. S1).
Table 2.
Clinical trials for novel PARP and PARG inhibitors: monotherapy and combination therapy
| Target | Agent | Intervention | Cancer type | Phase | Clinicaltrials.gov identifier |
|---|---|---|---|---|---|
| PARP | Veliparib | Veliparib + Carboplatin | TNBC | III | NCT02032277 |
| Veliparib + Carboplatin + Paclitaxel vs CTx | NSCLC | III | NCT02264990 | ||
| Veliparib + Carboplatin + Paclitaxel | HER2- BRCA1/2m breast cancer | III | NCT02163694 | ||
| Veliparib + Carboplatin + Paclitaxel | Ovarian cancer | III | NCT02470585 | ||
| Veliparib + Carboplatin + Paclitaxel | NSCLC | III | NCT02106546 | ||
| Veliparib + Temozolomide | Glioblastoma | II/III | NCT02152982 | ||
| Veliparib + Temozolomide | Breast cancer | II | NCT01009788 | ||
| Veliparib + Temozolomide | CRC | II | NCT01051596 | ||
| Veliparib + Temozolomide | Solid tumors | II | NCT01193140 | ||
| Veliparib + Temozolomide | Melanoma | II | NCT00804908 | ||
| Veliparib ± Temozolomide | SCLC | II | NCT01638546 | ||
| Veliparib + RT + Temozolomide | Glioma without H3 K27M or BRAFV600 mutations | II | NCT03581292 | ||
| Veliparib + Temozolomide/Carboplatin + Paclitaxel | BRCA1/2m breast cancer | II | NCT01506609 | ||
| Veliparib + Temozolomide vs Pegylated Liposomal Doxorubicin | Ovarian cancer | II | NCT01113957 | ||
| Veliparib + Gemcitabine + Carboplatin | Testicular germ cell cancer | II | NCT02860819 | ||
| Veliparib + Cyclophosphamide | BRCA1/2m breast, ovarian, primary peritoneal or fallopian tube cancer, TNBC or low-grade NHL | II | NCT01306032 | ||
| Veliparib | Ovarian, fallopian tube or primary peritoneal cancer | II | NCT01540565 | ||
| Veliparib ± Carboplatin ± Paclitaxel | NSCLC | II | NCT01560104 | ||
| Topotecan + Carboplatin ± Veliparib | Advanced myeloproliferative disorders, AML or CML | II | NCT03289910 | ||
| Veliparib ± whole brain RT | NSCLC with brain metastases | II | NCT01657799 | ||
| Veliparib ± Cisplatin | TNBC, BRCA1/2m breast cancer ± brain metastases | II | NCT02595905 | ||
| Veliparib ± FOLFIRI ± Bevacizumab | CRC | II | NCT02305758 | ||
| Veliparib + Temozolomide | Solid tumors | II | NCT01827384 | ||
| Abiraterone + Prednisone ± Veliparib | CRPC | II | NCT01576172 | ||
| Veliparib + Topotecan + Filgrastim | Cervical cancer | II | NCT01266447 | ||
| Veliparib ± Gemcitabine and Cisplatin | Pancreatic cancer | II | NCT01585805 | ||
| Veliparib ± FOLFIRI | Pancreatic cancer | II | NCT02890355 | ||
| Veliparib ± Carboplatin | Breast cancer | II | NCT01149083 | ||
| Veliparib + FOLFOX + RT ± Pembrolizumab | Rectal cancer | II | NCT02921256 | ||
| Veliparib | Breast cancer | II | NCT01042379 | ||
| Senaparib | Senaparib (MT) | Ovarian cancer | III | NCT04169997 | |
| Senaparib | BRCA1/2m recurrent PtS ovarian cancer | II | NCT04089189 | ||
| Senaparib | HRR-mutated CRPC | II | NCT04822961 | ||
| Senaparib + Temozolomide | Advanced solid tumors and SCLC | I/II | NCT04434482 | ||
| Venadaparib | Venadaparib + XELOX/Irinotecan | Gastric cancer | I/II | NCT04725994 | |
| Venadaparib | HRD solid tumors | I/II | NCT04174716 | ||
| Stenoparib | Stenoparib | Ovarian cancer | II | NCT03878849 | |
| Stenoparib | Breast cancer | II | NCT03562832 | ||
| Stenoparib + Temozolomide/Carboplatin + Paclitaxel | Solid tumors and B-cell malignancies | I/II | NCT01618136 | ||
| Saruparib | Saruparib ± Durvalumab | SCLC | II | NCT06769126 | |
| Saruparib + AZD5335 | Solid tumors | I/II | NCT05797168 | ||
| Saruparib + AZD8205 | Solid tumors | I/II | NCT05123482 | ||
| Saruparib + Ceralasertib | Solid tumors | I/II | NCT02264678 | ||
| AZD9574 | AZD9574 ± Temozolomide/Deruxtecan | Solid tumors | I/II | NCT05417594 | |
| SC10914 | SC10914 | Breast cancer | II | NCT04556292 | |
| SC10914 | Ovarian cancer | II | NCT04556539 | ||
| SC10914 | BRCA1/2m CRPC | I/II | NCT04486937 | ||
| SC10914 | Solid tumors | I | NCT02940132 | ||
| Nesuparib | Nesuparib | Ovarian cancer | II | NCT05475184 | |
| Nesuparib + FOLFIRINOX/Gemcitabine + Paclitaxel | Pancreatic ductal adenocarcinoma | I | NCT05257993 | ||
| Nesuparib | Solid tumors | I | NCT04335604 | ||
| TSL-1502 | TSL-1502 vs CTx | BRCA1/2m breast cancer | II | NCT05420779 | |
| AMXI-5001 | AMXI-5001 | Solid tumors | I/II | NCT04503265 | |
| NMS-03305293 | NMS-03305293 + Temozolomide | Glioblastoma | I/II | NCT04910022 | |
| Simmiparib | Simmiparib | Solid tumors | I | NCT02993913 | |
| RP12146 | RP12146 | Solid tumors | I | NCT05002868 | |
| HWH340 | HWH340 | Solid tumors | I | NCT03415659 | |
| TQB3823 | TQB3823 | Solid tumors | I | NCT05021367 | |
| ABT-767 | ABT-767 | BRCA1/2m ovarian, fallopian tube or primary peritoneal cancer | I | NCT01339650 | |
| PARG | IDE161 | IDE161 | Advanced solid tumors | I | NCT05787587 |
| ETX-19477 | ETX-19477 ± Pembrolizumab | Advanced solid tumors | I | NCT06395519 |
Data extracted from clinicaltrials.gov up until November 2025
Veliparib (AbbVie) has received several Orphan Drug Designations by the FDA for different cancers since 2008, but all of them were later withdrawn or revoked. This drug demonstrated the ability to potentiate CTx and RT in different preclinical tumor models.159,160 The randomized BrighTNess Phase III trial in TNBC (NCT02032277) suggested that the improvement observed in the pathological CR was due to carboplatin and not to veliparib, when adding veliparib to carboplatin and paclitaxel.161 In the Phase III trial BROCADE3 (NCT02163694), oral treatment with veliparib in combination with paclitaxel and carboplatin seemed to significantly increase median progression-free survival (mPFS) in patients with HER2- metastatic BRCA1/2m breast cancer.162 In contrast, OS was numerically but not significantly improved.163 As described before, something similar occurred in the VELIA trial (NCT02470585), which found a significant prolongation in the mPFS of ovarian cancer patients treated with induction therapy with carboplatin, paclitaxel and veliparib followed by MT with veliparib,89 but no improvement in median OS.90 Regarding lung cancer, a specific informatic classifier, named LP52, was developed using independently derived RNA-seq data from 120 tumors representing a diverse set of NSCLC subtypes. Results from a Phase III trial (NCT02106546) in smokers with advanced squamous NSCLC could not demonstrate therapeutic benefit of adding veliparib to first-line CTx, but the LP52 signature seemed to identify a subgroup of patients likely to derive benefit from this combination.164 Another Phase III study (NCT02264990) in patients with non-squamous NSCLC also employed this LP52 classifier. No significant improvement in OS was detected with veliparib + carboplatin/paclitaxel versus CTx alone, although a trend toward improved OS in the LP52-positive population suggested this subgroup may benefit from veliparib.165 Recently, veliparib added to adjuvant temozolomide did not significantly prolong OS in patients with newly diagnosed MGMT-hypermethylated glioblastoma in a Phase III clinical trial (NCT02152982166). The same outcome was reported in the Phase II VERTU trial testing veliparib and RT, followed by adjuvant veliparib and temozolomide for newly diagnosed MGMT-unmethylated glioblastoma.117 After failure of multiple late-stage clinical trials, the future of veliparib is uncertain and seems to have been removed from AbbVie’s recent pipeline.
The PARPi senaparib (IMP4297) from Impact Therapeutics was included in a Phase III trial (NCT04169997) as MT following first-line CTx in patients with advanced ovarian cancer. Maintenance senaparib was well tolerated and significantly improved PFS irrespective of BRCA1/2 mutation status.167 Senaparib also demonstrated meaningful antitumor activity in a Phase II trial (NCT04089189) in BRCA1/2m recurrent PtS ovarian cancer patients.168 In another Phase I/II study (NCT04434482), clinical survival benefit was observed for senaparib combined with intermittent low-dose temozolomide in relapsed small cell lung cancer (SCLC) patients with manageable hematological toxicity.
Venadaparib (IDX-1197) is a selective inhibitor of PARP1/2 developed by Idience Co. A Phase I/II study (NCT04725994) of this drug in advanced gastric cancer demonstrated promising efficacy in combination with irinotecan, particularly in those with HRD gene mutations.169 A basket trial (NCT04174716) with this compound in patients with HRD solid tumors found strong potency of venadaparib in g/sBRCA1/2m metastatic breast cancer170 and higher tumor response in pancreatic cancer patients with co-occurring ATM and ASXL1 mutations.171
Stenoparib (E7449, 2X-121) is a dual inhibitor of PARP1/2 and of the regulators of canonical Wnt/β-catenin signaling, tankyrase1/2.172 This compound originally developed by Eisai Co. and currently by Allarity Therapeutics is involved in two clinical trials: a Phase I/II as single agent for advanced solid tumors or B-cell malignancies and in combination with temozolomide or with carboplatin and paclitaxel for advanced solid tumors (NCT01618136), and a Phase II for advanced ovarian cancer selected by the 2X-121 DRP® biomarker of drug response (NCT03878849). Based on the clear clinical benefit detected in this last trial in terms of tumor shrinkage and long-term disease stability, Allarity Therapeutics has recently announced its early discontinuation to enable and accelerate the development of a follow-on trial with FDA regulatory purpose.173
AstraZeneca is developing two additional PARPi, saruparib (AZD5305) and AZD9574. Saruparib (AZD5305) is a selective non-trapping PARP2 inhibitor with strong PARP1 trapping ability that maintains the antitumor efficacy of first-generation PARPi with lower hematological toxicity, although it is not central nervous system (CNS)-penetrant.174 This compound is included in two Phase III trials: in mCRPC receiving physician’s choice new hormonal agents (NCT06120491) and associated with the ER antagonist camizestrant compared with CDK4/ 6i plus endocrine therapy or camizestrant in HR+, HER2-, BRCA1/2, or PALB2-mutated breast cancer (NCT06380751). Several Phase I/II clinical trials with saruparib for advanced solid tumors (e.g., NCT04644068 and NCT02264678) are ongoing and have shown a manageable safety profile and preliminary signs of efficacy.175,176 AZD9574 is a CNS-penetrant PARPi that shows >8000-fold selectivity for PARP1 versus PARP2 and other members of the PARP family (PARP2, PARP3, PARP5A and PARP6) in biochemical assays.174,177 The CNS profile makes it ideal for treating CNS malignancies or brain metastases that depend on PARP inhibition. A Phase I/II trial (NCT05417594) of AZD9574 as monotherapy and in combination with other anti-cancer agents for advanced solid malignancies is recruiting.
SC10914 is a compound from Jiangxi Qinfeng Pharmaceutical that, in a Phase I study in advanced solid tumors (NCT02940132), showed that it was safe and it was effective, particularly in gBRCA1/2m ovarian cancer participants.178 Phase II studies of this compound in gBRCA1/2m prostate cancer (NCT04486937), breast cancer (NCT04556292) or ovarian cancer (NCT04556539) are ongoing.
Nesuparib (JPI-547/OCN-201) is another dual PARP1/2 and tankyrase1/2 inhibitor179 developed by Jeil Pharmaceutical Co. in collaboration with Onconic Therapeutics. This drug is participating in a Phase II clinical trial for PtR advanced/relapsed ovarian cancer previously exposed to a PARPi (NCT05475184). Results from a Phase I trial (NCT04335604) suggested that nesuparib monotherapy was tolerable and effective in patients with advanced solid tumors harboring BRCA1/2 or HRR mutations.180 Also from Jeil Pharmaceutical Co. is amelparib (JPI-289 free base), a PARP1 inhibitor that, based on its neuroprotective effects,181 is being evaluated for the treatment of acute ischemic stroke (NCT03062397, NCT02396069 and NCT01983358).
TSL-1502 is another PARPi that has been designed as a pro-drug whose metabolite (TSL-1502M) has higher localized concentration at cancer sites and, consequently, higher potency than current FDA/EMA approved PARPi, according to its developers (Tasly Pharmaceutical Group).182 This drug showed preliminary anti-cancer activity in a Phase II trial (NCT05420779) for HER2- gBRCA1/2m breast cancer.183
AMXI-5001 is a dual PARP1/2 and microtubule polymerization inhibitor being studied in a Phase I/II (NCT04503265) sponsored by AtlasMedx for advanced malignancies.
The non-trapping, CNS-penetrant and selective PARP1 inhibitor from Nerviano Medical Sciences, NMS-03305293 (NMS-293), is included in a Phase I/II trial (NCT04910022) associated with temozolomide for glioblastoma, upon termination of another Phase I (NCT04182516) for solid tumors. Nerviano Medical Sciences has recently announced that the FDA has granted approval to proceed with two Phase I studies in the relapse setting for SCLC combined with temozolomide and for BRCA1/2 wild-type ovarian cancer combined with DNA topoisomerase I inhibitor (TOP1i) topotecan.184
Several other PARPi remain in Phase I trials. Simmiparib (SOMCL-9112) is an orally bioavailable inhibitor involved in a first-in-human (FIH) trial (NCT02993913) sponsored by Shanghai Acebright Pharmaceuticals for advanced solid tumors. The compound RP12146 from Rhizen Pharmaceuticals showed in a Phase I in solid tumors (NCT05002868) a differentiated safety profile in patients with mCRPC with limited hematological toxicities, as compared to first-generation PARPi, and with encouraging activity particularly in patients with BRCA2 mutation.185 HWH340, being developed by Hubei Biological Medicine Industrial Technology Institute is also being studied for BRCA1/2m or HRD advanced solid tumors (NCT03415659). Lerzeparib (TQB3823) is an orally available small molecule PARPi that was included in a Phase I/II study (NCT05405439) for prostate cancer that was prematurely terminated by the sponsor (Chia Tai Tianqing Pharmaceutical). Another Phase I (NCT05021367) for advanced solid tumors is ongoing. Finally, ABT-767 is another PARPi from AbbVie that exhibited an acceptable safety profile in a Phase I trial (NCT01339650) and a better efficacy in patients with BRCA1/2 mutations, HRD positivity and Pt sensitivity.186
Limitations of PARPi: resistance and safety concerns
Despite the good initial response to PARPi, patients frequently develop resistance to these agents, resulting in disease relapse. Acquired resistance to PARPi may occur due to three general mechanisms. The first one consists of effects related to the drug target, such as the upregulation of drug efflux pumps,187 mutations in PARP188 or in the protein that removes PAR chains from target proteins, PARG.189 Related to this, several PARG inhibitors (PARGi) are being developed and the compounds IDE161 from IDEAYA Biosciences and ETX-19477 from 858 Therapeutics (structures undisclosed) already entered clinical trials for advanced solid tumors (NCT05787587 and NCT06395519, respectively). A second mechanism of resistance may be the reactivation of HRR. This can be due to restoration of BRCA1/2 function by the appearance of reversion mutations or epigenetic alterations inducing the re-expression of BRCA1/2 wild-type proteins or resulting in hypomorphic variants,190–193 or owing to compensatory mutations (e.g., loss of the 53BP1-RIF1-REV7-shieldin anti-resection signaling pathway) that result in re-wiring of the DDR.192,194,195 And the last mechanism that may cause PARPi resistance is the loss of DNA end-protection and/or restoration of replication fork stability, and the subsequent suppression of lethal ssDNA gaps. While PRIMPOL initially creates these gaps to allow the replication fork to bypass trapped PARP-DNA complexes,196 resistant tumors mitigate their lethality either through the restoration of fork protection or active gap-filling. Concerning the restoration of fork protection, the loss of factors like 53BP1, PTIP, EZH2, or MED12 prevents nucleases (primarily MRE11) from widening these gaps into DSBs.197–199 Regarding gap-filling, the upregulation of POLQ allows the tumor to ‘patch’ the gaps created by PRIMPOL, effectively masking the HRD phenotype and allowing the cell to survive despite the presence of the PARPi.200
Further studies are required to develop therapeutic strategies that help to overcome acquired PARPi resistance and to determine the extent of cross-resistance between the different therapeutic options. In women with ovarian cancer, tumor debulking to remove or eliminate resistant clones may be one option.201 Other potential strategies include combination therapies with the goal to amplify the antitumoral efficacy of PARPi, targeting the acquired mechanisms of resistance and/or delaying the appearance of resistance through suppression of the mutator phenotype, which arises in BRCA1/2 m tumors.202 It is important to remark, that non-HRD tumors are usually also resistant to Pt.190,203,204
Several combinational strategies aimed at overcoming PARPi resistance are being discussed, depending especially on the HRD status of the tumor at the time of treatment (Fig. 7). In these cases, therapeutic options to improve the durability of the treatment may direct to attack alternative vulnerabilities of the tumor, and the combination with therapies that prevent the acquisition of these resistance mechanisms.205 PARPi-resistant tumors seem to accumulate high levels of replication stress, exemplified by, for instance, the acquisition of amplifications in the gene encoding the cyclin E protein, the CCNE1 gene. In fact, HRR pathway mutations, such as the BRCA1 mutation, and CCNE1 amplification are nearly mutually exclusive, as these alterations provide different selective advantages for tumor development.206–208 The CCNE1 gene has also been found to be overexpressed in ovarian tumors resistant to CTx,208,209 and therefore, these tumors exhibit high risk of treatment failure and represent an urgent unmet medical need. In cases of high replication stress, cells activate the replication stress response (RSR), rendering inhibitors of the key effector kinases of RSR (ATR, CHK1 and WEE1) promising candidates to treat these tumors.210,211 In fact, combinations of these compounds with PARPi have shown great efficacy in clinical trials.212,213 Because of the synergistic interaction between TOP1i and PARPi,214 combinations of TOP1i and PARPi should also be considered as a way to increase efficacy in earlier lines of treatment, independently of the HRD status. As detected in sequence analyzes, error-prone DNA repair pathways, such as c-NHEJ and alt-NHEJ, may also be important for the acquisition of reversion events. Thus, another therapeutic approach to avoid restoration of HRR activity could be to combine PARPi with the c-NHEJ/alt-NHEJ inhibitors that are currently in clinical trials, such as DNA-PK and POLQ inhibitors (DNA-PKi and POLQi).215,216 As previously described, beyond its role in alt-NHEJ, POLQ is essential for mitigating the lethality of ssDNA gaps, as it provides critical ‘gap-filling’ activity that masks the HRD phenotype.200 Indeed, POLQ was found upregulated in HRD tumors, and the knockdown of POLQ in these tumors resulted in cancer cell death,217,218 suggesting that POLQ could constitute a novel druggable target to treat HRD tumors. Besides, inactivating mutations in 53BP1-shieldin, which cause acquired PARPi resistance, result in high in vitro and in vivo sensitivity to POLQi.219 Moreover, in a patient-derived xenograft (PDX) model with a combined loss of TP53BP1 and BRCA1, which was isolated from a patient with acquired PARPi resistance, novobiocin, a specific POLQi, was able to substantially reduce tumor growth.220 Furthermore, the restored HRR functionality caused by 53BP1-shieldin loss in BRCA1-mutated tumors seems to rely on sustained signaling through the ATR kinase.205,221 This reinforces the evidence that combining PARPi with ATRi or POLQi could provide a comprehensive strategy to overcome multiple axes of resistance, by simultaneously disrupting the RSR, exhausting cell cycle checkpoints, and forcing the re-accumulation of lethal ssDNA gaps.
Fig. 7.
Combination therapy strategies with PARPi. SSBs generated by CTx or RT are repaired by the BER pathway. PARPi inhibit PARylation and induce PARP trapping and the formation of ssDNA gaps, that may result in DSBs, which may also be caused directly by CTx or RT or by DSBs derived from ICLs first repaired by the FA/BRCA pathway in cooperation with TLS. Cancer cells with deficient HRR due to for instance BRCA1/2 mutations, will repair these DSBs by the c-NHEJ pathway (as the alt-NHEJ will be inhibited by PARPi), resulting in incorrect DSB repair, the accumulation of genomic rearrangements and apoptosis. In contrast, cancer cells with proficient HRR will repair these DSBs leading to cancer cell survival and drug resistance. Moreover, alterations in other components of these involved pathways may allow cancer cells to repair DNA damage and become resistant to PARPi. In consequence, the combination with inhibitors of these altered components may resensitize cancer cells to PARPi. Figure created with BioRender
Concerning BRCA1/2m but HRR-proficient tumors, resistance is normally driven by BRCA1/2-hypomorphic expression or DDR rewiring events. In these cases, the use of a functional assay of HRD status, such as the RAD51 foci formation assay,222 may increase the understanding of the level of HRD left in these tumors and therefore may help to predict the probability of response to PARPi.223 However, this test is still being validated and, therefore, it is not yet available to be clinically implemented.224 Currently, HRD status is being determined in the clinical setting by the identification of mutations in HRR genes, mutational signatures and/or genomic scars, through different centralized and in-house commercial tests and custom panels. However, as the HRD phenotype is dynamic and these tests reflect genomic history rather than the HRD status at the time of treatment, functional assays should be improved and clinically implemented in order to provide more real-time data on HRD status for prediction of response to PARPi and Pt-based CTx.225
Apart from the emerging resistance, safety concerns related to PARPi have also been raised. The different approved PARPi share several common adverse effects, such as hematological and gastrointestinal toxicities,226 that may lead to treatment discontinuation and reduce combination possibilities with other drugs. PARP trapping on the DNA seems to contribute to PARPi cytotoxicity in healthy bone marrow and exhibits an inverse relationship with PARPi tolerability.227 This should be taken into consideration when establishing combination regimens of PARPi with drugs with well-known bone marrow toxicity. Besides, recent data suggested that the SL effect of PARPi in cancer cells with HRD is due to PARP1 enzymatic activity and not to their capacity to trap PARP on DNA.61 Moreover, the inhibition of PARP2 and tankyrase1/2 is believed to be associated with hematological228,229 and gastrointestinal toxicities,230 respectively. Overall, this makes it imperative that new-generation PARPi should be directed to the selective inhibition of PARP1 enzymatic activity without causing PARP trapping. The clinical emergence of highly selective PARP1i (e.g., saruparib) represents a promising step toward this goal, potentially allowing for the safer integration of the multi-axis combination strategies previously described.
Based on results obtained for PARPi, the implementation of successful SL-based therapies for cancer treatment should consider additional variables, apart from the resistance mechanisms. On the one hand, several features related to the altered gene should be analyzed, such as the zygosity of the target genetic alteration, the prevalence of its loss in a given cancer type or across cancers and whether this loss is essential for tumor promotion and/or maintenance. In fact, although GOF alterations in proto-oncogenes typically act dominantly, LOF alterations in tumor suppressor genes are usually recessive, requiring biallelic inactivation for tumorigenesis promotion, for instance via loss of heterozygosity (LOH).143 It is also important to remark that a subset of tumor suppressor genes is known to be haploinsufficient, requiring only a single allele.231 To add even more complexity, some other genes may be haploinsufficient for only specific related phenotypes, and some others (e.g., TP53) may harbor alleles with either LOF or dominant-negative activity depending on the specific mutation.232,233 In consequence, the development of biomarkers that accurately assess LOH and zygosity would be helpful for the success of SL-based therapies. On the other hand, characteristics of the target gene to be inhibited therapeutically, such as the expression of the cell lineage and/or cancer type of interest and the toxicity impact of its inhibition in healthy tissue, should also be considered. Finally, the SL interaction itself should also be studied, for instance by determining the magnitude of the therapeutic index in preclinical models (effect size) and the penetrance of the SL interaction.233 In fact, some SL interactions exhibit incomplete penetrance due to differential gene-regulatory and signaling networks across cell types and genetic and epigenetic heterogeneity within the tumor.234 For instance, the varied expression of backup polymerases like POLQ or repriming factors like PRIMPOL across different genetic backgrounds may dictate the ultimate penetrance of PARPi-induced lethality.196
Targeting SL interactions in DDR genes beyond PARP inhibition
The discovery of new SL interactions in DDR genes and the success observed for PARPi has resulted in an increasing amount of oncologic research directed to targeting other components of the DDR pathway using the SL approach (Table 3). Many tumors bypass genotoxic stress from CTx and RT by upregulating different DDR members, effectively ‘rewiring’ their signaling networks to enable DNA repair and checkpoint activation and ensure survival.
Table 3.
Recent clinical trials for ATR, ATM, DNA-PK, CHK1, CHK2, WEE1, PKMYT1, CDKs, PLK1, POLQ, USP1, RAD51, WRN and APE1 inhibitors: monotherapy and combination therapy
| Target | Agent | Intervention | Cancer type | Phase | Clinicaltrials.gov identifier |
|---|---|---|---|---|---|
| ATR | Ceralasertib | Ceralasertib + Durvalumab vs Docetaxel | NSCLC | III | NCT05450692 |
| Ceralasertib + Durvalumab | NSCLC | III | NCT06732401 | ||
| Ceralasertib | Advanced solid tumors | IIA | NCT04564027 | ||
| Ceralasertib | NSCLC | II | NCT03334617 | ||
| Ceralasertib + Olaparib | Gynecologic cancer | II | NCT04065269 | ||
| Ceralasertib + Olaparib | NSCLC | II | NCT02937818 | ||
| Ceralasertib + Olaparib | SCLC | II | NCT03428607 | ||
| Ceralasertib + Olaparib | Ovarian cancer | II | NCT03462342 | ||
| Ceralasertib ± Olaparib | Breast cancer | II | NCT03182634 | ||
| Ceralasertib ± Olaparib | TNBC | II | NCT03330847 | ||
| Ceralasertib + Durvalumab | Melanoma | II | NCT03780608 | ||
| Ceralasertib + Acalabrutinib | CLL | I/II | NCT03328273 | ||
|
Ceralasertib ± Olaparib/ Durvalumab/Saruparib/Carboplatin |
Advanced solid tumors | I/II | NCT02264678 | ||
| Berzosertib | Berzosertib + Topotecan | SCLC | II | NCT03896503 | |
| Berzosertib + Topotecan | SCLC | II | NCT04768296 | ||
| Berzosertib + Sacituzumab govitecan | SCLC, extra-pulmonary small cell neuroendocrine cancer and PARPi resistant HRD-cancers | II | NCT04826341 | ||
| Cisplatin + Gemcitabine ± Berzosertib | Urothelial cancer | II | NCT02567409 | ||
| Gemcitabine ± Berzosertib | Ovarian, primary peritoneal or fallopian tube cancer | II | NCT02595892 | ||
| Gemcitabine ± Berzosertib | Leiomyosarcoma | II | NCT04807816 | ||
| Berzosertib + Irinotecan | TP53-mutant gastric or gastroesophageal junction cancer | II | NCT03641313 | ||
| Berzosertib + Carboplatin + Docetaxel | Prostate cancer | II | NCT03517969 | ||
| Berzosertib + Avelumab | Advanced solid tumors | II | NCT04266912 | ||
| Pembrolizumab + Gemcitabine + Carboplatin ± Berzosertib | NSCLC | I/II | NCT04216316 | ||
| Berzosertib + Lurbinectedin | SCLC and high-grade neuroendocrine cancers | I/II | NCT04802174 | ||
| Berzosertib + Topotecan | SCLC and extrapulmonary small cell cancers | I/II | NCT02487095 | ||
| Elimusertib | Elimusertib | Advanced solid tumors | I/II | NCT05071209 | |
| Elimusertib | Advanced solid tumors and lymphoma | I | NCT03188965 | ||
| Elimusertib + SOC CTx | Advanced solid tumors | I | NCT04491942NCT04616534NCT04514497 | ||
| Elimusertib + FOLFIRI CTx | Advanced cancers of the stomach and intestines | I | NCT04535401 | ||
| Elimusertib + Niraparib | Ovarian cancer and solid tumors (excluding prostate) | I | NCT04267939 | ||
| Elimusertib + Pembrolizumab | Advanced solid tumors | I | NCT04095273 | ||
| Elimusertib + Pembrolizumab | HNSCC | I | NCT04576091 | ||
| Camonsertib | Camonsertib | Solid tumors with ATM and SETD2 LOF | II | NCT04589845 | |
| Lunresertib + Camonsertib | Advanced cancer | II | NCT05605509 | ||
| Lunresertib + Camonsertib | CDK4/ 6i resistant ER+/ HER2- breast cancer | II | NCT05601440 | ||
| Camonsertib ± Talazoparib/Gemcitabine | Advanced solid tumors | I/II | NCT04497116 | ||
| Atezolizumab + Camonsertib ± Bevacizumab | NSCLC | I/II | NCT03337698 | ||
| Gartisertib | Gartisertib + Carboplatin | Advanced solid tumors | I | NCT02278250 | |
| Tuvusertib | Tuvusertib | SPOP-mutant prostate cancer | II | NCT05828082 | |
| Tuvusertib + Avelumab | Merkel cell skin cancer | II | NCT05947500 | ||
| Tuvusertib ± Avelumab | ARID1A-mutated endometrial cancer | II | NCT06518564 | ||
| Tuvusertib + Cemiplimab | NSCLC | II | NCT05882734 | ||
| Tuvusertib + Niraparib/Lartesertib | Ovarian cancer | II | NCT06433219 | ||
| Tuvusertib + Temozolomide | Advanced solid tumors and hematologic malignancies | I/II | NCT05691491 | ||
| ART0380 | ART0380 | Advanced solid tumors | II | NCT05798611 | |
| ART0380 ± Gemcitabine ± Irinotecan | Advanced solid tumors | I/II | NCT04657068 | ||
| SC0245 | SC0245 + Irinotecan | SCLC | II | NCT05731518 | |
| ATM | AZD0156 | AZD0156 + Olaparib/Irinotecan/ Fluorouracil/Folinic Acid | Advanced solid tumors | I | NCT02588105 |
| AZD1390 | AZD1390 + RT | Brain cancer | I | NCT03423628 | |
| AZD1390 + RT ± Durvalumab | Soft tissue sarcoma | I | NCT05116254 | ||
| AZD1390 + SBRT | Advanced solid tumor | I | NCT05678010 | ||
| AZD1390 + RT | NSCLC | I | NCT04550104 | ||
| AZD1390 | Healthy volunteers | I | NCT03215381 | ||
| WSD0628 | WSD0628 + RT | Glioblastoma | I | NCT05917145 | |
| Lartesertib | Tuvusertib + Niraparib/Lartesertib | Ovarian cancer | II | NCT06433219 | |
| Lartesertib | Advanced solid tumors | I | NCT04882917 | ||
| Tuvusertib + Lartesertib/Avelumab | Advanced solid tumors | I | NCT05396833 | ||
| ATM/ DNA-PK | XRD-0394 | XRD-0394 + RT | Advanced solid tumors | I | NCT05002140 |
| DNA-PK | CC-115 | CC-115 | Advanced solid tumors | I | NCT01353625 |
| CC-115 + Enzalutamide | Prostate cancer | I | NCT02833883 | ||
| CC-115 + Temozolmide | Glioblastoma | II | NCT02977780 | ||
| Peposertib | Peposertib + RT | Pancreatic cancer | I/II | NCT04172532 | |
| Peposertib + Avelumab + RT | Advanced solid tumors and hepatobiliary malignancies | I/II | NCT04068194 | ||
| Peposertib + RT ± Avelumab | CRPC | I/II | NCT04071236 | ||
| Peposertib + Capecitabine | Rectal cancer | I/II | NCT03770689 | ||
| Peposertib + Avelumab + Temozolomide | Pediatric cancer | I/II | NCT02813135 | ||
| AZD7648 | AZD7648 + Doxorubicin | Advanced solid tumors | I/IIA | NCT03907969 | |
| M9831 | VX-984 | Advanced solid tumors | I | NCT02644278 | |
| BY101298 | BY101298 | Advanced solid tumors | I | NCT06462716 | |
| DNA-PK/ mTor | Samotolisib | Samotolisib | Pediatric TSC1/2 or PI3K/ MTOR-mutated advanced solid tumors, NHL or histiocytic disorders | II | NCT03213678NCT03155620 |
| CHK1 | Prexasertib | Prexasertib + Irinotecan | Desmoplastic small round cell tumor and rhabdomyosarcoma | I/II | NCT04095221 |
| Prexasetib | Ovarian cancer, endometrial adenocarcinoma and urothelial carcinoma | I/II | NCT05548296 | ||
| Prexasertib | SCLC | II | NCT02735980 | ||
| Prexasertib | Breast, ovarian and prostate cancer | II | NCT02203513 | ||
| Prexasertib | HRD-solid tumors or solid tumors with replicative stress | II | NCT02873975 | ||
| Prexasertib | Ovarian cancer | II | NCT03414047 | ||
| Prexasertib + low dose Gemcitabine | HNSCC | II | NCT06597565 | ||
| Prexasertib + LY3023414 | TNBC | II | NCT04032080 | ||
| SRA737 | SRA737 | Advanced solid tumors or NHL | I/II | NCT02797964 | |
| SRA737 + Gemcitabine + Cisplatin | Advanced solid tumors | I/II | NCT02797977 | ||
| BBI-355 | BBI-355 ± Erlotinib/Futibatinib | EGFR- and FGFR2- amplificated tumors | I | NCT05827614 | |
| LY2880070 | LY2880070 ± Gemcitabine | Ewing sarcoma | I | NCT05275426 | |
| LY2880070 + Gemcitabine | Advanced or metastatic solid tumors | I | NCT02632448 | ||
| PEP07 | PEP07 | Advanced or metastatic solid tumors | I | NCT05983523 | |
| PEP07 | AML and mantle cell lymphoma | I | NCT05659732 | ||
| SMP-3124LP | SMP-3124LP | Advanced solid tumors | I/II | NCT06526819 | |
| CHK2 | PHI-101 | PHI-101 | Ovarian cancer | IA | NCT04678102 |
| PHI-101 | AML | I | NCT04842370 | ||
| WEE1 | Adavosertib | Adavosertib | SETD2-amplificated advanced solid tumors | II | NCT03284385 |
| Adavosertib | CCNE1-amplificated advanced solid tumors | II | NCT03253679 | ||
| Adavosertib | BRCA1/2m advanced solid tumors and hematologic malignancies | II | NCT04439227 | ||
| Adavosertib | Uterine serous carcinoma or carcinosarcoma | II | NCT03668340 | ||
| Adavosertib | Uterine serous carcinoma | II | NCT04590248 | ||
| Adavosertib | Prostate cancer | II | NCT03385655 | ||
| Adavosertib | SCLC | II | NCT02593019 | ||
| Adavosertib | BRCA1/2m advanced solid tumors and hematologic malignancies | II | NCT02465060 | ||
| Adavosertib + Carboplatin | Advanced solid tumors | II | NCT01827384 | ||
| Adavosertib + Carboplatin | SCLC | II | NCT02937818 | ||
| Adavosertib + Carboplatin | TP53-mutated ovarian cancer | II | NCT01164995 | ||
| Adavosertib + Carboplatin + Paclitaxel | Squamous cell lung cancer | II | NCT02513563 | ||
| Carbolatin + Paclitaxel ± Adavosertib | TP53-mutated ovarian cancer | II | NCT01357161 | ||
| Adavosertib + Cisplatin | Breast cancer | II | NCT03012477 | ||
| Adavosertib + Gemcitabine/Paclitaxel/ Carboplatin/Doxorubicin | Ovarian, primary peritoneal and fallopian tube cancer | II | NCT02272790 | ||
| Adavosertib + Paclitaxel | TP53-mutated gastric adenocarcinoma | II | NCT02448329 | ||
| Gemcitabine ± Adavosertib | Ovarian, primary peritoneal and fallopian tube cancer | II | NCT02101775 | ||
| Cytarabine ± Adavosertib | AML and myelodysplastic syndrome | II | NCT02666950 | ||
| Adavosertib + Gemcitabine + RT | Pancreatic adenocarcinoma | II | NCT02037230 | ||
| Adavosertib ± Olaparib | Ovarian, primary peritoneal and fallopian tube cancer | II | NCT03579316 | ||
| Olaparib ± Adavosertib | TNBC | II | NCT03330847 | ||
| Adavosertib + Paclitaxel + Gemcitabine | Pancreatic cancer | I/II | NCT02194829 | ||
| Adavosertib + Irinotecan | Advanced solid tumors | I/II | NCT02095132 | ||
| Adavosertib + Carboplatin | Relapsed or refractory pediatric cancer | I/II | NCT02813135 | ||
| Azenosertib | Azenosertib | Ovarian, primary peritoneal and fallopian tube cancer | II | NCT05128825 | |
| Azenosertib | Uterine serous carcinoma | II | NCT06369155NCT04814108 | ||
| Azenosertib + Gemcitabine | Pancreatic cancer | II | NCT06015659 | ||
| Azenosertib + Gemcitabine | Osteosarcoma | I/II | NCT04833582 | ||
| Azenosertib + Carboplatin + Pembrolizumab | TNBC | I/II | NCT06351332 | ||
| Debio-0123 | Debio-0123 + Sacituzumab govitecan | TNBC and HR+/ HER2- advanced breast cancer | I/II | NCT06612203 | |
| Debio-0123 + Temozolomide + RT | Glioblastoma and astrocytoma | I/II | NCT05765812 | ||
| Potrasertib | IMP7068 | Advanced solid tumors | I | NCT04768868 | |
| SY-4835 | SY-4835 | Advanced solid tumors | I | NCT05291182 | |
| APR-1051 | APR-1051 | Advanced solid tumors | I | NCT06260514 | |
|
WEE1/ PKMYT1 |
ACR-2316 | ACR-2316 | Advanced solid tumors | I | NCT06667141 |
| PKMYT1 | Lunresertib | Lunresertib + Gemcitabine/Camonsertib | CDK4/ 6i resistant ER+/ HER2- breast cancer | II | NCT05601440 |
| Lunresertib + Gemcitabine/FOLFIRI/Trastuzumab/Camonsertib | TP53/FBXW7/PPP2R1A/KRAS-mutated or CCNE1-amplified advanced cancer | II | NCT05605509 | ||
| Lunresertib + Carboplatin + Paclitaxel | Recurrent TP53-mutated ovarian and uterine cancer | I | NCT06107868 | ||
| Lunresertib + XELOX | CCNE1-amplificated and FBXW7-mutant advanced gastrointestinal cancer | I | NCT05147350 | ||
| Lunresertib ± Camonsertib/Debio-0123 | Advanced solid tumors | I | NCT04855656 | ||
| CDK4/6 | Palbociclib | Palbociclib + Fulvestrant | HR+/HER2- breast cancer | III | NCT01942135 |
| Palbociclib | Chordoma with CDKN2A/B LOF or RB1-/CDK4/6-positive | II | NCT03110744 | ||
| Palbociclib | Advanced cancer with CDKN2A/B LOF or CDK4/6 amplifications | II | NCT02693535 | ||
| Palbociclib | RB1-positive anaplastic oligodendroglioma | II | NCT02530320 | ||
| Abemaciclib | Abemaciclib | RB1-positive TNBC | II | NCT03130439 | |
| Abemaciclib | Thyroid cancer | II | NCT04552769 | ||
| Abemaciclib | CDKN2A-deficient mesothelioma | II | NCT03654833 | ||
| Abemaciclib ± Samotolisib ± Gemcitabine/Capecitabine | Pancreatic ductal adenocarcinoma | II | NCT02981342 | ||
| Abemaciclib + Samotolisib + Fulvestrant vs Other | Metastatic breast cancer | IB | NCT02057133 | ||
| CDK2 | INCB123667 | INCB123667 vs CTx | PtR ovarian cancer with cyclin E1 overexpression | III | NCT07214779 |
| INCB123667 | PtR ovarian cancer with cyclin E1 overexpression | II | NCT07023627 | ||
| INCB123667 ± Palbociclib/Ribociclib±Fulvestrant/ Bevacizumab/Olaparib/Paclitaxel | Advanced solid tumors | I | NCT05238922 | ||
| PLK1 | Onvansertib | Onvansertib | Relapsed SCLC with TP53-mutation and YAP1- or MYC expression | II | NCT05450965 |
| Onvansertib ± FOLFIRI/FOLFOX+Bevacizumab | KRAS/NRAS-mutated mCRC (first line) | II | NCT06106308 | ||
| Onvansertib + FOLFIRI + Bevacizumab | KRAS-mutated mCRC (second line) | I | NCT03829410 | ||
| POLQ | ART4215 | ART4215 ± Talazoparib | Advanced solid tumors | I/IIA | NCT04991480 |
| ART6043 | ART6043 ± Olaparib/Niraparib | Advanced solid tumors | I/IIA | NCT05898399 | |
| GSK4524101 | GSK4524101 ± Niraparib | Solid tumors | I/II | NCT06077877 | |
| RP-3467 | RP-3467 ± Olaparib | Advanced solid tumors | I | NCT06560632 | |
| SYN818 | SYN818 | Advanced solid tumors | I | NCT06666270 | |
| Novobiocin | Novobiocin | Advanced solid tumors | I | NCT05687110 | |
| USP1 | KSQ-4279 | KSQ-4279 ± PARPi | Advanced solid tumors | I | NCT05240898 |
| XL309 | XL309 ± Olaparib | Advanced solid tumors | I | NCT05932862 | |
| RAD51 | Emzadirib | Emzadirib ± Gemcitabine/Capecitabine/ Rituximab and Bendamustine | B-cell malignancies and advanced solid tumors | I/II | NCT03997968 |
| WRN | GSK4418959 | GSK4418959 ± PD-1 inhibitor | MSI-H or MMR-deficient advanced solid tumors | I/II | NCT06710847 |
| HRO761 | HRO761 ± Pembrolizumab/Irinotecan | MSI-H or MMR-deficient advanced solid tumors | I | NCT05838768 | |
| RO7589831 | RO7589831 ± Pembrolizumab | MSI-H or MMR-deficient advanced solid tumors | I | NCT06004245 | |
| APE1 | APX3330 | APX3330 | Advanced solid tumors | I | NCT03375086 |
| TRC102 | TRC102 + Pemetrexed + Cisplatin | Advanced solid tumors or mesothelioma | I/II | NCT02535312 | |
| TRC102 + Temozolomide | Solid tumors and lymphomas | I/II | NCT01851369 |
Data extracted from clinicaltrials.gov up until November 2025
Some of the primary targets of DDRi are the phosphatidylinositol 3-kinase-like protein kinases (PI3KKs) ATR, ATM and DNA-PK because of their role as master regulators of the DDR.235–237 Inhibitors of the downstream targets of ATR and ATM, CHK1 and CHK2, are also being developed. One of the hallmarks of cancer is uncontrolled sustained cell proliferation. The accumulation of genetic errors during cell division is surveilled by two major checkpoint-associated pathways: ATM-CHK2 and ATR-CHK1, which control G1/S and G2/M transitions through the DNA damage checkpoint and RSR, respectively. Functionally, this translates into the prevention of DNA damage accumulation and propagation (ATM-CHK2 axis) and the prevention of replication stress-induced DNA damage during cell division (ATR-CHK1 axis). Based on this, mutations in ATM-CHK2 may participate in cancer promotion and in ATR-CHK1 in cancer prevention.238 Interestingly, while ATM gene is frequently mutated in cancer, what makes it appropriate for SL approaches, mutations in ATR and PRKDC (the gene that codes for DNA-PKcs) are only found in specific cases of cancer.239–241 Moreover, although ATM and DNA-PK mediate the response to DSBs and ATR to SSBs and regions generated at stalled replication forks,242 there is increasing evidence of crosstalk and functional redundancy between both pathways.243 SL relationships have been reported between ATM and DNA-PKcs244,245 and between ATM and ATR,246 but apparently not between ATR and DNA-PKcs.247 The inhibition of other DDR pathways such as the serine/threonine kinase WEE1 that leads to G2/M arrest is also being explored. In fact, WEE1 has been found to be overexpressed in various malignancies, conferring resistance to anticancer drugs.248–250 When combined with DNA-damaging CTx or RT, the inhibition of checkpoint-associated pathways results in the overwhelming of the repair capacity of resistant tumor cells and enhanced cytotoxicity and therapeutic sensitization.29,30,32,251,252 Some other key DDR players that are being clinically targeted are the cell cycle regulating kinase similar to WEE1, PKMYT1, cyclin-dependent kinases (CDKs), PLK1, POLQ, RAD51, USP1, WRN and APE1.
ATR inhibitors (ATRi)
In response to genotoxic stressors affecting DNA replication, cells activate the RSR pathway, with the ultimate goal of slowing DNA synthesis and replication and allowing time for DNA repair.23 ATR is a protein kinase from the family of the phosphoinositide-3-kinase-related kinases (PIKKs) that is a key player of the RSR pathway. LOF mutations in the ATR gene cause Seckel syndrome, characterized by severe growth retardation in utero, impaired intellectual delay, microcephaly and dwarfism. However, whereas hypomorphic ATR function is compatible with life,253 the complete loss of ATR is embryonic lethal, underscoring its role as an essential gene.254 This biological constraint requires a ‘transient inhibition’ strategy, through for instance small molecules, rather than the catastrophic consequences of permanent/complete loss that protein degraders or knockouts would cause.
ATR shares sequence and functional homology with two other DDR kinases, ATM and DNA-PK.255,256 In human cells, the vast majority of ATR exists in complex with ATRIP,257,258 and responds to different types of DNA damage and genotoxic stress259; many of them have in common a DNA structure formed at the replication fork that ATR can recognize. This structure consists of RPA-coated ssDNA that recruits ATR through binding to its partner, ATRIP.257,260 CHK1 is a critical regulator of the G2/M and intra-S cell cycle checkpoints that is phosphorylated by ATR.261 Many cancer cells suffer dysregulation of G1 checkpoints,262,263 thereby creating a dependency on the S and G2/M checkpoints and increased replication stress when entering S-phase.264 This vulnerability may be further amplified in ALT+ tumors that rely on ATR to manage inherent telomeric replication stress.265 In addition, CTx, RT and cancer-related inflammation also increase replication stress. Because ATR and CHK1 are S- and G2-phase regulators, they are attractive targets for cancer therapeutics. Indeed, inactivating the ATR/CHK1 pathway in cancer cells results in the inhibition of DNA damage-induced G2/M checkpoint arrest, leading to mitotic catastrophe and apoptosis. Moreover, the inhibition of the ATR/CHK1 axis causes the collapse of replication forks and renders cancer cells dependent on HRR to repair DSBs. Synergism between ATR, CHK1 and PARP inhibition has been reported in BRCA1/2 m tumors.266 Preclinical and clinical data have also shown that deficiency in the other cell cycle checkpoint kinase ATM sensitizes cancer cells to ATR inhibition.267–269
Clinical development of ATRi currently follows three primary axes: (i) SL in ATM-deficient or ALT+ tumors; (ii) potentiation of DNA-damaging CTx/RT; and (iii) reversal of resistance to PARPi or ICIs. Several ATRi progressed to clinical trials (Supplementary Fig. S2), with AstraZeneca’s ceralasertib (AZD6738) having undergone the most extensive development. Berzosertib (VX-970/M6620/VE-822), gartisertib (M4344 or VX-803) and tuvusertib (M1774) from Merck, elimusertib (BAY1895344) from Bayer, camonsertib (RP-3500) from Repare Therapeutics, alnodesertib (ART0380) from Artios Pharma and SC0245 from Biocity Biopharmaceutics. Other ATRi that are still in preclinical phases are: VE-821, developed by Vertex/Merck; schisandrin B (isolated from Schisandra chinensis), AD1058; NU6027; dactolisib (NVP-BEZ235), EPT-46464, torin-2, AZ20 and Novartis’ tetrahydropyrazolo[1,5-a] pyrazines lead and azabenzimidazole series lead.
Ceralasertib (AZD6738) is an orally bioavailable ATRi with antitumor activity demonstrated in several preclinical models.270 Various Phase II clinical trials studied ceralasertib associated with olaparib. This was based on the finding that in BRCA1/2m tumors with acquired PARPi resistance, the inhibition of the ATR/CHK1 axis reverses restored HRR and compromises replication fork stability.266 The CAPRI study (NCT03462342) in recurrent high-grade serous ovarian cancer showed good tolerability of this combination and a signal of activity in BRCA1m tumors.271 A more thorough study of PtS patients within this study demonstrated clinical activity with an ORR of 48.5% and a mPFS of 8.3 months (95% CI: 5.9, 10.7). Remarkably, in patients with germline HRR gene alterations, ORR was 100% and mPFS was not reached.272 The Phase II OLAPCO trial (NCT02576444) in patients with HRD relapsed or refractory cancers found preliminary activity in ATM-mutated tumors and in PARPi-resistant BRCA1/2m ovarian cancer.273 Another Phase II trial in TNBC patients (NCT03182634) did not observe sufficient evidence of efficacy with the combination of olaparib and ceralasertib, but identified some biomarkers of potential benefit, such as functional HRD by RAD51 foci, CCNE1 amplification (high cyclin E1 expression) and pathogenic mutations in HRR genes.274 This was in line with data observed in the randomized Phase II VIOLETTE study (NCT03330847), where ceralasertib plus olaparib did not improve PFS compared to olaparib monotherapy as 2nd or 3rd line for metastatic TNBC.275 The Phase II SUKSES-N2 trial (NCT03428607) in SCLC patients with predefined DDR gene alterations also showed that olaparib alone or combined with ceralasertib did not meet the predefined efficacy, although disease stabilization was more evident in the combination arm.276 In contrast, ceralasertib associated with durvalumab exhibited promising antitumor activity in a Phase II study (NCT03780608) in patients with metastatic melanoma who had failed anti-PD-1 therapy277 and with advanced gastric cancer refractory to CTx.278 Consistent with this, the Phase II umbrella HUDSON study (NCT03334617) evaluating rational combination regimens for advanced NSCLC following failure of anti-PD-L1 and Pt-doublet therapy observed the greatest clinical benefit with durvalumab plus ceralasertib, especially in ATM-altered patients. Moreover, biomarker analyzes suggested that anti-PD-L1/ATR inhibition stimulated immune-mediated antitumor activity.279 This synergy is likely driven by the accumulation of cytosolic DNA fragments following ATR inhibition, which activates the cGAS-STING pathway. This causes an increase in the production of Type I interferons and proinflammatory cytokines within the tumor, thereby enhancing T-cell recruitment and overcoming resistance to ICIs.280 These findings resulted in the initiation of the Phase III LATIFY study associating ceralasertib with durvalumab in comparison to docetaxel in patients with NSCLC whose disease progressed on or after prior anti-PD-L1 therapy and Pt (NCT05450692). Another Phase III study is analyzing ceralasertib in addition to anti-PD-L1 immunotherapy to increase time without cancer for patients with NSCLC (NCT06732401). In relation to ATM, another Phase IIA study (NCT04564027) is assessing ceralasertib monotherapy in previously treated patients with ATM-altered tumors. Preliminary results have shown limited responses to ceralasertib monotherapy in these tumors, despite reaching target plasma levels. Alternative patient selection and combination treatment strategies are being explored.281 Another Phase I/II trial is studying ceralasertib administered orally in combination with CTx and/or novel anti-cancer agents (olaparib, saruparib or durvalumab) to patients with advanced malignancies (NCT02264678). One of the combinations under study is ceralasertib and olaparib for ATM-proficient versus deficient gastric adenocarcinomas. Clinical activity from the Phase I part of this study was reported for ceralasertib and olaparib in HRD PtS relapsed ovarian cancer.282 It is also important to remark that resistance mechanisms to ceralasertib have also been published. For instance, resistance was detected in gastric cancer cells with loss of the nonsense-mediated decay factor UPF2283 and, as happens with PARPi,187 in cancer cells with overexpression of the ATP-binding cassette transporters P-gp and BCRP.284
Berzosertib, formerly M6620, VX-970 or VE-822, is another ATRi that resulted in selective sensitization of pancreatic tumors to RT.251 It also showed suppression of gastric cancer cells’ proliferation and migration ability.285 The structure of berzosertib is based on that of VE-821, which was identified by Vertex Pharmaceuticals during high-throughput screening.286 An early Phase I trial (NCT02487095) found remarkable activity from the combination of berzosertib and the TOP1i topotecan in Pt-refractory SCLC patients, which tend not to respond to topotecan alone.287 Meanwhile, in a Phase II trial (NCT03896503) in relapsed SCLC patients, it showed no effect on PFS compared to topotecan alone, but a significant improvement in OS.288 The association of these two drugs was also explored in relapsed PtR SCLC patients (NCT04768296). Another Phase I/ II study (NCT04826341) is studying the anti-TROP2 antibody hRS7 conjugated to a TOP1i, sacituzumab govitecan, plus berzosertib in SCLC, extra-pulmonary small cell neuroendocrine cancer and HRD cancers resistant to PARPi. Response was observed in two patients with neuroendocrine prostate cancer and a patient with EGFR-transformed SCLC, but not in the other patients.289 Another Phase I study (NCT03641547) showed good tolerability of berzosertib in combination with CTx and RT in esophageal cancer.290 Moreover, in a Phase I study (NCT02157792) combining berzosertib with gemcitabine with or without cisplatin for advanced solid tumors, good tolerability and preliminary efficacy signs were observed.291 In contrast, in a Phase II randomized clinical trial (NCT02567409) with metastatic urothelial cancer patients, the addition of berzosertib to cisplatin and gemcitabine did not prolong PFS and was associated with significantly higher hematologic toxicities.292 More recently, in a randomized Phase II trial (NCT02595892) clinical benefit was observed with the addition of berzosertib to gemcitabine in PtR ovarian cancer patients stratified into the Pt-free interval below 3 months subgroup and in patients with ATM-mutated tumors.293 In fact, ATM loss sensitized human prostate cancer lines to berzosertib,269 what had already been reported for VE-821.246 Another Phase II trial associating berzosertib with irinotecan in progressive, metastatic or unresectable TP53-mutant gastric or gastroesophageal junction cancer (NCT03641313) did not meet primary ORR endpoint, but the combination demonstrated anti-tumor activity compared to other agents (e.g., ramucirumab and paclitaxel or TAS-102).294 Finally, it is also being studied in other Phase II trials in combination with avelumab for DDR-deficient metastatic or unresectable solid tumors (NCT04266912), with gemcitabine for soft-tissue sarcomas (NCT04807816) and with carboplatin with or without docetaxel in mCRPC patients (NCT03517969). Preliminary results from this last trial showed fewer ORRs and more adverse events in patients treated with carboplatin and berzosertib, compared to those treated with carboplatin and docetaxel.295 Other Phase I/II studies are analyzing berzosertib added to CTx and pembrolizumab for advanced squamous cell NSCLC (NCT04216316), and to the DNA alkylating agent lurbinectedin for solid tumors, SCLC and high-grade neuroendocrine cancers (NCT04802174). Especially after not observing the expected results with berzosertib and topotecan in PtR SCLC, Merck has decided to switch focus to the other ATRi, tuvusertib (M1774).
Tuvusertib (M1774), a potent and selective orally administered ATRi, showed antitumoral activity as monotherapy and in combination with the PARPi niraparib in preclinical models with DDR pathway gene mutations.296,297 Preliminary results of an FIH study (NCT04170153) of tuvusertib as monotherapy in patients with advanced solid tumors demonstrated a manageable safety profile and exposure-related target engagement.298 Tuvusertib is also included in Phase I/II trials in combination with the anti-PD-1 cemiplimab in non-squamous NSCLC patients (NCT05882734) and with temozolomide for metastatic solid tumors (NCT05691491). Some other Phase II studies that are currently recruiting analyze oral tuvusertib combined with the anti-PD-L1 avelumab for ARID1A-mutated endometrial cancer (NCT06518564) or merkel cell skin cancer (NCT05947500), alone for refractory SPOP-mutated prostate cancer (NCT05828082) and in association with the PARPi niraparib or the ATM inhibitor (ATMi) lartesertib in ovarian cancer patients (NCT06433219).
Elimusertib (BAY-1895344) is a highly selective, orally bioavailable ATRi, which exhibited strong monotherapy efficacy in cancer CDXs carrying certain DDR deficiencies. This compound was developed by lead optimization efforts focusing on potency, selectivity, and oral bioavailability starting from quinoline 2 that harbored weak ATRi activity.299 When associated with certain DNA damage-inducing CTx, RT or other DDRi (PARP, ATM, CHK1, DNA-PK or WEE1 inhibitors), synergistic antitumoral activity was observed. Furthermore, elimusertib plus the next-generation nonsteroidal AR antagonist darolutamide significantly improved antitumoral efficacy compared with monotherapy in androgen-dependent prostate cancer models, and this efficacy was further enhanced when adding RT.300 A FIH clinical trial exploring elimusertib as a single agent in advanced solid tumors and non-Hodgkin’s lymphoma (NHL) detected antitumor activity against cancers with certain DDR defects, including deleterious ATM mutations (NCT03188965; EudraCT 2016-004484-39).268 The durable stable disease observed in one patient with a BRCA1 deleterious mutation provided the rationale for a Phase IB clinical trial associating elimusertib with niraparib in patients with advanced solid tumors and ovarian cancer (NCT04267939, EudraCT 2018-003930-34). However, this study was terminated due to lack of clinical benefit. This trial also found upregulation of PD-L1 expression in tumor tissues from patients treated with elimusertib. These findings, together with previous preclinical data indicating synergy between elimusertib and ICIs resulted in a Phase I trial (NCT04095273; EudraCT 2018-003420-36) assessing elimusertib in combination with pembrolizumab, which was recently completed. Several other Phase I studies testing in different solid cancers the combination of elimusertib and CTx or RT (e.g., NCT04616534, NCT04491942 and NCT04535401) are ongoing. A Phase I/II trial is also exploring oral monotherapy with elimusertib in patients with relapsed or refractory solid tumors (NCT05071209). Preliminary results from these trials showed that elimusertib-related toxicities were primarily hematologic.301 Synergistic myelotoxicity was found when combined with CTx,302 including the first case of AML.303 Although several clinical trials with this drug are ongoing, elimusertib has been removed from Bayer’s portfolio.
Camonsertib (RP-3500) is a selective oral inhibitor of ATR kinase with IC50 values of 1.0 and 0.33 nM in biochemical and cell-based assays, respectively.304 A Phase I/II (NCT04497116) trial of camonsertib alone or in combination with talazoparib or gemcitabine for advanced solid tumors with ATRi-sensitizing mutations was recently completed. Preliminary data from the Phase I part of this trial demonstrated better clinical benefit in ovarian cancers with LOF alterations in ATM and other DDR genes.305 A patient with alternative lengthening of telomeres-positive (ALT+) (driven by biallelic loss of ATRX) metastatic melanoma experienced clinical and molecular response with good oral tolerability upon treatment with camonsertib. This provides clinical evidence of SL between ATRX-deficient/ALT+ tumors and ATRi, probably due to the high replication stress and defects in genome maintenance present in these tumors.306 Camonsertib is currently being included in several Phase I/II trials, including for advanced solid tumors associated with niraparib or olaparib (NCT04972110) and for metastatic NSCLC together with multiple immunotherapy-based drugs (NCT03337698). Three other Phase II trials that analyze camonsertib monotherapy in tumors with ATM or SETD2 loss (NCT04589845), or in combination with the PKMYT1 inhibitor (PKMYT1i) lunresertib for CDK4/ 6i resistant ER+/ HER2- metastatic breast cancer (NCT05601440) or advanced cancer (NCT05605509) are recruiting. Following termination of its collaboration agreement with Roche, Repare Therapeutics has regained global rights to camonsertib.
Gartisertib (M4344 or VX-803), developed by Vertex and bought by Merck in 2017, is a potent inhibitor of ATR-driven CHK1 phosphorylation with an IC50 of 8 nM and good binding affinity (Ki < 150 pM). It displayed good antiproliferative activity in a selected set of cancer cell lines, showing synergy with several types of DDRi, including ATM, PARP and CHK1 inhibitors (CHK1i). For instance, synergy between gartisertib and the ATMi lartesertib was demonstrated in PDX models of TNBC.307 Gartisertib also provided good in vivo results as monotherapy in ALT+ tumors or in combination with talazoparib in TNBC xenografts.308,309 Another preclinical study also found that gartisertib enhanced the activity of TOP1i, gemcitabine, cisplatin, and talazoparib.252 These data supported the use of gartisertib in Phase I clinical trials as monotherapy or associated with carboplatin for advanced solid tumors (NCT02278250), and in combination with niraparib against PARPi-resistant ovarian cancer (NCT04149145) and advanced solid tumors (NCT04655183), although the last two trials were withdrawn based on portfolio prioritization. Results from the first trial (NCT02278250) with gartisertib as a single agent or associated with carboplatin for advanced solid tumors showed good tolerability at lower doses, but unexpected liver toxicity that prevented further dose escalation, and limited antitumoral activity, leading to the discontinuation of its development.310
Alnodesertib (ART0380) is an orally available ATRi that is being evaluated in the Phase I/II STELLA trial as monotherapy or in combination with gemcitabine or irinotecan in patients with ATM-deficient metastatic solid tumors (NCT04657068). Based on promising preliminary results from the STELLA study,311 alnodesertib has recently won FDA Fast Track status for ATM-negative CRC.312 Another Phase II basket study as monotherapy in patients with biologically selected advanced solid tumors was terminated (NCT05798611).
Finally, SC0245 is a novel ATRi that displayed potent activity for ATR/ATRIP with IC50 of 14 nM,313 and is being studied in a Phase IB/II trial in patients with relapsed SCLC associated with irinotecan (NCT05731518). Preliminary results showed favorable safety and pharmacokinetic characteristics and antitumor activity.314
The diverse clinical outcomes of these ATRi, ranging from dose-limiting toxicities to promising “unmasking” of HRD, underscore the necessity for more precise biomarker-driven patient selection and optimized intermittent dosing schedules. Beyond ATM and ATRX loss, identifying drivers of high replication stress, such as CCNE1 amplification, may further refine the target population. Furthermore, the ability of ATRi to trigger cytosolic DNA-sensing pathways (cGAS-STING) and induce ‘viral mimicry’ provides a robust mechanistic rationale for their continued development in combination with ICIs.
ATM inhibitors (ATMi)
ATM is an active serine/threonine kinase responsible for the regulation of checkpoints during the cell cycle in response to DNA DSBs. More concretely, ATM is an important initiator of the DDR via the MRN complex at DNA DSBs sites.315,316 Active ATM then uses its kinase activity to phosphorylate multiple downstream targets such as BRCA1, CHK2 and p53 that are essential for DDR, apoptosis, cell cycle arrest, and as cell-cycle checkpoints.317,318 For this reason, ATM is often considered a major tumor suppressor gene. Biallelic gATM mutations result in the development of ataxia telangiectasia, a rare hereditary autosomal recessive disorder characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity.319
Somatic mutations in ATM are commonly seen in cancer, especially in lymphoid malignancies.320,321 In addition, ATM LOH may arise through deletion of the long arm of chromosome 11, which often causes the co-deletion of other genes present on this site, such as MRE11, CHK1 and H2AX.322,323 Nevertheless, a key mechanism of ATM deficiency is the hypermethylation of the ATM promoter region.324 Mutations in the gene downstream from the ATM/CHK2/p53 pathway, CHK2, although less common, are also observed across cancer types including colon, kidney, breast and prostate cancer.325 However, the most frequently mutated gene across cancer types is TP53, which may also suffer LOH through allelic deletion of chromosome 17p in cancer.326 Overall, as aberrations in the ATM/CHK2/p53 axis frequently occur in cancer, targeting these specific defects could contribute to effective cancer treatments. Moreover, although ATM deficiency causes loss of DSB DNA repair and consequently genomic instability, it also increases the dependence of cancer cells on other repair mechanisms, such as repair of replication stress, particularly in dividing cells. Based on this, the inhibition of other kinases (e.g., ATR) involved in these alternative pathways has been considered a potential mechanism for SL in cancers lacking ATM,241 justifying the clinical exploration of ATMi in combination with ATRi. Besides, ATM kinase inhibition sensitizes cancer cells to the cytotoxic effects of IR and DSBs-inducing agents, such as etoposide and doxorubicin.327 Specifically, ATMi act as potent radiosensitizers that by blocking ATM-mediated DNA damage signaling and checkpoint activation, prevent the repair of radiation-induced DSBs and enhance cancer cell lethality.328,329 Crucially, ATM inhibition also promotes the accumulation of micronuclei and cytosolic DNA, which, similar to ATRi, activate the cGAS-STING pathway and increase lymphocyte infiltration into the TME, providing evidence that ATM might be a promising target to enhance ICI therapy.330 Preclinical models also demonstrated that the inhibition of ATM potentiated the effects of olaparib in different cancer cell lines328,331 and breast cancer xenografts.327,329 In fact, an SL interaction between PARP and ATM was found in trastuzumab-resistant cells.332
A few ATMi are currently undergoing clinical trials (Supplementary Fig. S3). Firstly, AZD0156, which is an orally bioactive ATMi (IC50 = 0.58 nM),333 was evaluated in a Phase I clinical trial alone or in combination with other antitumoral treatments in patients with advanced cancer (NCT02588105). This compound was later discontinued by AstraZeneca to prioritize the development of their other ATMi, AZD1390. AZD1390 is another ATMi that demonstrated to cross the intact blood–brain barrier in a positron emission tomography study with healthy volunteers (NCT03215381) and in a Phase 0/IB study in glioma patients (NCT05182905), supporting its indication for glioblastoma or other brain malignancies.334 Indeed, this CNS-penetrant profile is a critical differentiator for the current generation of ATMi, as it allows for the potentiation of RT in the treatment of primary brain tumors and brain metastases, where previous inhibitors failed due to poor permeability. For this reason, this drug is currently being evaluated in a Phase I trial associated with RT in patients with brain cancer (NCT03423628). Preliminary results indicated good tolerability for AZD1390 and encouraging efficacy as radiosensitizer.335 Preclinical data showed that AZD1390 blocks ATM-dependent DDR pathway activity and combined with RT induces G2 cell cycle phase accumulation, micronuclei, and apoptosis. It was also able to radiosensitize lung cancer and TP53-mutant glioma cell lines. In PDXs of glioma and lung cancer brain metastasis, it significantly induced tumor regression and increased animal survival compared to IR alone.328 Its role as radiosensitizer is also being studied in several Phase I trials in solid tumors (NCT04550104, NCT05116254 and NCT05678010). In addition, another Phase II/III is evaluating AZD1390 in combination with the SOC (RT + temozolomide) in newly diagnosed MGMT methylated and unmethylated glioblastoma (NCT03970447).
Another CNS-penetrant ATMi, WSD0628, also entered a Phase I trial (NCT05917145) with RT for recurrent brain tumors. This compound had previously shown a promising role in combination with RT in glioblastoma multiforme and melanoma metastatic to the brain in preclinical models.336
Lartesertib (M4076) is an ATP-competitive ATMi (IC50 < 1 nM) that was able to sensitize tumor cell lines to radiation in vitro and in vivo.337 In a FIH study (NCT04882917) of lartesertib in patients with advanced solid tumors the MTD of this compound was determined, and target exposure and engagement were achieved without significant hematological toxicity.338 Besides, based on the described SL mechanism between ATM and ATR, a Phase II trial in epithelial ovarian cancer (NCT06433219) and a Phase I in solid tumors (NCT05396833) combining lartesertib with the ATRi tuvusertib are ongoing. These two clinical trials are also studying lartesertib associated with the PARPi niraparib (NCT06433219) or with the anti-PD-L1 avelumab (NCT05396833).
Multiple other small-molecule ATMi are still in preclinical phases, and some others are not further being developed. For instance, the ATMi M3541 (IC50 = 0.25 nM) was also studied in a Phase I study in combination with palliative RT in solid tumors (NCT03225105), but it was prematurely terminated based on the sponsor’s decision.339 Additionally, several compounds that are under clinical development demonstrated inhibition capacity over different DDR kinases. For instance, XRD-0394 is a novel dual ATM/DNA-PK inhibitor developed by XRad Therapeutics that in a FIH study trial, potently radiosensitized the tumors and suggested synergy with PARPi and TOP1i (NCT05002140340). Another Phase 0/I study is being held to assess the safety and tolerability of XRD-0394 in combination with RT in patients with high-grade gliomas (NCT06829173).
In summary, while preclinical models suggest broad synergy with various DNA-damaging agents, clinical translation is currently focused on high-precision strategies. Efforts are concentrated on localized radiosensitization for CNS malignancies and, to a lesser extent, on SL-based combinations with ATR or PARP inhibitors and ICIs (e.g., avelumab). This shift prioritizes mechanistically grounded synergy over the overlapping systemic toxicities often encountered with traditional CTx.
DNA-PK inhibitors (DNA-PKi)
DNA-PK responds to DSB and plays a pivotal role in the c-NHEJ repair pathway. The DNA-PK holoenzyme comprises DNA-PKcs, a catalytic subunit with kinase activity, and Ku70/80 heterodimer, which is activated upon binding to broken DNA ends. Recent studies have demonstrated that overexpression of DNA-PK is associated with resistance to CTx and/or RT by promoting DSB repair through c-NHEJ,341–343 and with poor prognosis.344 Actually, DNA-PKi have been shown to impair DNA repair and re-sensitize cancer cells to chemo- and/or radiotherapeutic agents.345,346 Several DNA-PKi are currently undergoing clinical trials (Supplementary Fig. S4).
CC-115 is an oral CNS-penetrant dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-PK with IC50 of 21 nM and 13 nM, respectively.347 This compound was studied in a FIH trial (NCT01353625) for advanced solid and hematologic malignancies, where it showed toxicities consistent with mTOR inhibitors and promising efficacy, especially in an endometrial carcinoma patient who remained in complete remission for more than 4 years.348 Another Phase IB trial (NCT02833883) of CC-115 in combination with enzalutamide in mCRPC showed good tolerability and a significant trend towards improved prostate-specific antigen response in patients with PI3K/AKT/mTOR pathway alterations.349 In a Phase II trial (NCT02977780) comparing temozolomide with CC-115 for glioblastoma, CC-115 did not demonstrate a significant benefit in PFS or OS, and it was associated with high toxicity characteristic of mTOR inhibition.350
Peposertib (M3814, MSC2490484A or nedisertib) is another orally bioavailable DNA-PKi that was able to sensitize a variety of cancer cell lines to DSB-inducing agents and IR.351 A FIH study in advanced solid tumors or chronic myeloid leukemia (CML) (NCT02316197) showed good tolerability but modest efficacy of peposertib monotherapy.352 In other Phase I trials, peposertib plus palliative RT was also well-tolerated (NCT02516813353), and antitumor activity was found limited when combined with avelumab with or without palliative RT in patients with advanced solid tumors (NCT03724890354). Additionally, in a Phase IB/II study (NCT03770689) associating this drug with capecitabine and RT for locally advanced rectal cancer, peposertib did not improve CR rates at tolerable dose levels.355 Another clinical study (NCT04702698) did not detect the influence of food on peposertib’s pharmacokinetics but suggested that when combining this drug with CTx or RT, the delay in maximum concentration should be considered to optimize the sensitization effect.356 Finally, initial data of the Phase I trial (NCT04555577) of peposertib and RT in adults with newly diagnosed MGMT-unmethylated glioblastoma showed favorable safety and preliminary signs of efficacy potentiating the effect of RT.357 Currently, a large number of other Phase I (e.g., NCT05868174, NCT04750954 and NCT04092270) and Phase I/II (e.g., NCT04172532, NCT04068194 and NCT04071236) clinical trials with this compound as monotherapy or in combination with CTx, RT and/or the ICI avelumab for different solid tumors are ongoing. An early evaluation of the Phase I/II trial in advanced prostate cancer not responsive to hormonal therapy (NCT04071236) showed good tolerability and a significant decrease in PSA velocity with the triplet combination of RT, peposertib and avelumab compared to the doublet (RT plus peposertib),358 suggesting that DNA-PKi might enhance the “immunogenic” effect of RT. A European proof-of-concept therapeutic stratification Phase I/II trial of molecular anomalies in relapsed or refractory tumors is also studying peposertib associated with avelumab and metronomic temozolomide (NCT02813135). This compound is also being explored in a Phase I study with the ATRi tuvusertib for advanced solid tumors (NCT05687136).
AZD7648 is a DNA-PKi with IC50 value of 0.6 nM and >100-fold selectivity against mainly closely related kinases such as ATM, ATR and other PIKKs.359 This compound enhanced RT, CTx and olaparib activity in xenografts.216,360 A Phase I/IIA trial (NCT03907969) of AZD7648 alone or with doxorubicin in advanced cancer patients reported greater toxicity than expected with limited antitumor efficacy, what lead to early study termination. Proteomic analysis from this trial suggested that while target engagement was achieved at higher doses, it triggered compensatory activation of other DDR pathways, such as FA/BRCA and HRR, which may explain the limited efficacy.361
M9831 (VX-984) is a DNA-PKi that inhibits the repair of radiation-induced DNA DSB in glioblastoma cells and enhances the radiosensitivity of brain tumor xenografts.362 This compound was studied in a Phase I trial in combination with CTx in advanced solid tumors (NCT02644278), but its development was discontinued during dose escalation due to business-related issues.363
BY101298 is an oral DNA-PKi from Chengdu Baiyu Pharmaceutical Co. that is currently undergoing a Phase I trial as a single agent or in combination with RT in patients with advanced solid tumors (NCT06462716). Preliminary results from a FIH trial (Chinese Clinical Trial Register information number: CTR20230997) reported that BY101298 exhibited a favorable safety profile and manageable toxicity for advanced solid tumors.364
Samotolisib (LY3023414, GTPL8918) is an oral ATP-competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK that exhibits potent in vivo efficacy via intermittent target inhibition.365 This compound demonstrated a manageable safety profile and single-agent activity in a FIH trial in patients with advanced cancers (NCT01655225366). Its pharmacokinetic profile was characterized by rapid absorption and elimination in another Phase I trial (NCT02536586367). A Phase IB/II (NCT02407054) study then investigated enzalutamide ± samotolisib for mCRPC with progression on prior abiraterone treatment, and found significantly improved PFS, and a clinically meaningful benefit in patients with PTEN intact and no androgen receptor splice variant 7.368 In a Phase II study (NCT02549989) in patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, samotolisib showed modest activity as monotherapy.369 Moreover, in a Phase I trial (NCT02124148) associated with the CHK1i prexasertib, preliminary efficacy was detected in advanced cancer patients, although the combination led to some toxicity.370 Based on this, another Phase II trial studied the efficacy of samotolisib plus prexasertib in patients with metastatic TNBC (NCT04032080), but results have not been published. Another Phase I trial is analyzing samotolisib and fulvestrant associated with the CDK4/6i abemaciclib for metastatic breast cancer (NCT02057133). However, in a Phase II trial (NCT02981342) testing this combination for pancreatic adenocarcinoma, abemaciclib-based therapy did not improve survival compared with SOC CTx.371 In contrast, in a Phase I study (NCT02079636) for advanced NSCLC, stable disease as best response and acceptable safety were reported using combinations of abemaciclib and either samotolisib or pembrolizumab.372 Samotolisib associated with abemaciclib ± letrozole is also being explored in a Phase II trial in endometrial or low-grade serous ovarian cancer patients (NCT03675893). Samotolisib has also been explored in a Phase II study (NCT02443337) in NSCLC patients associated with the FDA-approved EGFR antibody necitumumab, and although the combination was safe and tolerable, the study was terminated due to lack of efficacy.373 Finally, a Phase II trial in pediatric patients with relapsed or refractory advanced solid tumors, NHL or TSC1/2- or PI3K/mTOR-mutated histiocytic disorders was completed, but results have not yet been reported (NCT03213678). Another Phase II pediatric study for treating patients with relapsed or refractory advanced solid tumors, NHLs or histiocytic disorders is ongoing (NCT03155620).
Despite the encouraging clinical progress of some DNA-PKi, the development of these compounds faces some challenges. Firstly, the difficulty in achieving good selectivity for DNA-PK over other closely related PI3K-family members due to high structural homology, often resulting in off-target mTOR-related toxicities (as seen with CC-115).374,375 While recent Cryo-EM advancements have resolved the activated DNA-PK holoenzyme at near-atomic resolution, the protein’s vast size and inherent conformational plasticity continue to hinder the discovery of inhibitors of this kinase using computer modeling.374,376 Given the modest efficacy of DNA-PKi as monotherapy, it seems that the field is pivoting toward the identification of combination therapies that may improve the antitumoral effect of DNA-PKi.377 As c-NHEJ is the primary mechanism for the repair of radiation-induced damage, lots of efforts are focused on the role of DNA-PKi as radiosensitizers.378,379 However, emerging clinical strategies are exploring synergy with TOP1i (e.g., the dual ATM/DNA-PK inhibitor XRD-0394) and ATRi (e.g., peposertib plus tuvusertib in NCT05687136).
CHK1/2 inhibitors (CHK1/2i)
CHK1 and CHK2 are two serine/threonine-protein kinases that represent the key downstream effectors of the checkpoint-associated ATR-CHK1 and ATM-CHK2 pathways, respectively. While CHK1 is essential for HRR of DSBs and its expression is restricted to S and G2 phases of the cell cycle, CHK2 is stably expressed all throughout the cell cycle, but inactive in the absence of DNA damage. Although structurally unrelated, these two kinases exhibit overlapping functions.380
Several CHK1/2i are being clinically evaluated (Supplementary Fig. S5). Firstly, prexasertib (LY2606368 or ACR-368) displays IC50 values of <1 nM for CHK1 and of 8 nM for CHK2.381 In Phase II clinical trials, monotherapy with this drug showed modest activity in patients with BRCA1/2 wild-type metastatic/recurrent TNBC (NCT02203513382) and no activity in patients with extensive-stage SCLC (NCT02735980383). In contrast, prexasertib demonstrated durable single-agent activity regardless of clinical characteristics, BRCA1/2 status, or prior therapies (including PARPi) in another Phase II trial (NCT03414047) for PtR or refractory recurrent ovarian cancer.384 Besides, another Phase II (NCT02873975) explored the role of replication stress or HRR deficiencies (alterations in BRCA1/2, PALB2, RAD51C/D, ATR, ATM, CHK2 or FA genes) in the response to prexasertib, but results have not been reported. Another Phase II study analyzed the efficacy of prexasertib plus the dual PI3K/mTOR and DNA-PK inhibitor, samotolisib (LY3023414), in patients with metastatic TNBC (NCT04032080), based on preclinical and clinical (Phase I, NCT02124148) data showing antitumor activity with this combination.370 Two other Phase II of prexasertib combinations are ongoing: associated with irinotecan and temozolomide for desmoplastic small round cell tumor and rhabdomyosarcoma (NCT04095221) and with low-dose gemcitabine for HNSCC (NCT06597565). Preliminary results from the first trial with irinotecan showed promising activity with manageable adverse events.385 Prexasertib is also being studied as monotherapy or with ultra-low dose gemcitabine in ovarian carcinoma, endometrial adenocarcinoma, and urothelial carcinoma (NCT05548296), using the phosphoproteomics ACR-368-tailored OncoSignature assay from Acrivon Therapeutics as a predictive biomarker of response.386
SRA737 (CCT245737) is another orally active CHK1i387 that was found to be SL with members of the B-family of DNA polymerases (POLA1, POLE, and POLE2) in human lung and colorectal cancer (CRC) cells.388 When associating SRA737 with PARPi this resulted in tumor regression in both PARPi-resistant and CCNE1-amplificated ovarian cancer PDX models.211 This compound was studied in a Phase I/II clinical trial (NCT02797964) as monotherapy in patients with NHL or solid tumors, where it showed good tolerability, but no activity. Expansion cohorts in this study included patients with tumors harboring specific genetic alterations expected to confer sensitivity to CHK1 inhibition (e.g., in TP53, PTEN, CDKN2A/B and ATM). No differences in response in these subpopulations were observed.389 Based on the lack of efficacy as monotherapy, another Phase I/II trial (NCT02797977) then explored SRA737 in combination with low-dose gemcitabine and cisplatin or gemcitabine alone in advanced cancer subjects. The combination of SRA737 and low-dose gemcitabine was well tolerated with lower myelotoxicity than in other similar trials, and partial tumor responses were identified in anogenital and other solid tumors, especially in patients with genomic alterations in the FA/BRCA pathway or in CDK12/ARID1A, and intermediate to high tumor mutational burden and possible increased replication stress.390
BBI-355 is a small molecule CHK1i (IC50 = 16 nM), developed as an extrachromosomal DNA (ecDNA)-directed therapy. Preclinical data showed synergistic antitumoral activity between oral BBI-355 and agents targeting amplified EGFR or FGFR2 oncogenes in multiple ecDNA-positive gastric cancer CDXs and PDXs.391 In consequence, this drug is being evaluated in a FIH clinical trial (NCT05827614) as a single agent or in combination with select targeted therapies (the ribonucleotide reductase inhibitor BBI-825, the EGFR inhibitor erlotinib and the FGFR1-4 inhibitor futibatinib) in patients with solid tumors with oncogene amplifications (e.g., EGFR, FGFR2). While the SL hypothesis between CHK1 inhibition and oncogene-amplified ecDNA was preclinically strong, the Phase I data revealed a narrow therapeutic index and significant hematological toxicity that prevented reaching the doses needed for robust antitumor activity. Based on this, monotherapy and combination arms of BBI-355 in this clinical trial have been recently discontinued.
The oral and selective ATP-competitive CHK1i ESP-001 (LY2880070) is being explored in two Phase I/II trials: in participants with advanced or metastatic solid tumors as monotherapy and in combination with gemcitabine (NCT02632448) and in a Phase II for Ewing sarcoma or Ewing-like sarcoma in combination with low-dose gemcitabine (NCT05275426). Preliminary results from the first trial (NCT02632448) reported generally good tolerability and promising efficacy in combination with low-dose gemcitabine in patients with advanced or metastatic ovarian cancer.392 Strikingly, although no evidence of clinical activity was observed for pancreatic adenocarcinoma, in vitro efficacy was observed for the combination in patient-derived organoids.393
PEP07 (CASC-578) is an oral CNS-penetrant CHK1i that is being studied in two Phase I trials as a single agent for advanced or metastatic solid tumors (NCT05983523) and AML and mantle cell lymphoma (NCT05659732). PEP07 was active as monotherapy in lung cancer xenografts and displayed synergistic antitumoral activity in combination with the WEE1i AZD-1775 in multiple solid tumor cell lines and in NSCLC tumor xenografts.394
SMP-3124LP is a liposome-encapsulated CHK1i developed by Sumitomo Pharma America that showed tumor regression in PDX models of ovarian cancer,395 leading to the initiation of a Phase I/II trial (NCT06526819) in patients with advanced solid tumors.
In recent years, several other clinical-stage CHK1i have been discontinued. GDC-0575 (ARRY-575, RG7741) is a potent CHK1i discovered by Array BioPharma and developed by Genentech (subsidiary of Roche) that demonstrated synergistic effect with CTx in cancer cells, PDX models and patient tumors.396,397 In a Phase I study in combination with gemcitabine in patients with refractory solid tumors, antitumoral activity was observed but limited to a small number of patients (NCT01564251398). Rabusertib (LY2603618) is another CHK1i that in a Phase I trial (NCT01139775) in combination with pemetrexed and cisplatin, showed partial response in 2 NSCLC patients and stable disease in 8.399 In the posterior Phase II part, an increased number of thromboembolic events were detected with this combination.400 In contrast, no significant clinical activity was found of LY2603618 combined with pemetrexed in another Phase II study (NCT00988858) in patients with advanced NSCLC401 and in a Phase I/II trial (NCT00839332) in combination with gemcitabine for pancreatic cancer.402 In consequence, the development of this compound was discontinued. The same happened with AstraZeneca’s CHK1i AZD7762 owing to the unpredictable cardiac toxicity detected in a Phase I study (NCT00413686403). As for another CHK1i, MK-8776 (SCH900776), despite evidence that augmented DNA damage in circulating leukemic blasts in a Phase II trial (NCT01870596) with cytarabine in relapsed AML patients,404 it seems to have been discontinued by Merck. This compound was also included in a Phase I trial for participants with solid tumors or lymphoma with and without gemcitabine (NCT00779584).
PHI-101 is a CHK2i with additional activity against FLT3 tyrosine kinase that showed preclinical antitumoral activity in ovarian and breast cancer cell lines. Moreover, in vivo studies suggested a synergistic effect between PHI-101 and PARPi for breast and ovarian cancer treatment.405 This drug is being studied in a Phase IA dose-escalation study for PtR ovarian, fallopian tube, and primary peritoneal cancer (NCT04678102). As mutations in FLT3 are the most common genetic alteration in AML,406 and PHI-101 also inhibits FLT3, it is being explored in a Phase I trial in AML (NCT04842370). Preliminary data showed good tolerability and significant efficacy, particularly in FLT3-mutant AML.407
The clinical landscape of CHK1/2i is increasingly defined by biomarker-driven stratification and the exploitation of replication stress. While broad application has been hindered by toxicities, exemplified by the recent discontinuation of the ecDNA-directed agent BBI-355 due to a narrow therapeutic window, the success of prexasertib in serous endometrial cancer validates the use of phosphoproteomic signatures to identify SL vulnerabilities. Furthermore, the field is pivoting toward ‘induced SL’ by pairing CHK1i with replication stressors (e.g., ultra-low dose gemcitabine associated with prexasertib in NCT05548296), as well as toward the inclusion of expansion cohorts with specific genetic abnormalities expected to confer sensitivity to CHK1 inhibition (e.g., CCNE1 amplification, BRCA1/2 or ATM deficiency or GOF/amplification of CHK1 or ATR, amongst others) due to high replication stress.
WEE1, PKMYT1, CDKs and PLK1 inhibitors
WEE1 is a nuclear-localized protein kinase that inhibits both CDK1 and CDK2 in response to DNA damage, thereby activating the G2/M checkpoint of the cell cycle to allow time for DNA repair.408 Cancer cells with dysregulated G1/S cell cycle checkpoints rely on functional G2/M checkpoints to prevent excessive DNA damage.409 Since p53-deficient cells lack a functional G1 checkpoint, they become uniquely and broadly dependent on the WEE1-regulated G2/M arrest to maintain genomic stability. Therefore, blocking G2/M checkpoints with WEE1i results in loss of genomic integrity due to increased replication stress.410 Several preclinical studies have confirmed that this dependency creates a ‘classic’ SL interaction, where WEE1i causes mitotic lethality specifically in p53-deficient cells and sensitizes them to RT and DNA-damaging agents.30,32 Moreover, using the knowledge of the SL interaction between ATRX and WEE1, researchers reported that the proliferation of glioma and hepatocellular cells with ATRX mutations was selectively inhibited with the WEE1i adavosertib.411 Furthermore, cyclin E1, encoded by the CCNE1 gene, interacts in normal cells with CDK2 to drive the transition from G1 to S phase, where DNA replication occurs. Upon DNA damage, WEE1 phosphorylates and inactivates the cyclin E1/CDK2 complex to halt cell cycle progression and allow time for repair. In many malignancies (e.g., gynecological cancers) CCNE1 amplifications cause CDK2 hyperactivation, accelerating G1/S cell cycle progression and inducing massive replication stress.412 Mutations in other regulators of G1/S transition, such as TP53 and CDKN2A, exacerbate the effects of CCNE1 amplification. In this high replication stress state, cancer cells become “addicted” to the S and G2/M checkpoints to prevent premature and lethal entry into mitosis before DNA replication is completed.413,414 Consequently, these tumors are highly susceptible to WEE1 inhibition, which forces a “mitotic catastrophe” driven by premature CDK1/cyclin B complex activation in the presence of CDK2-mediated replication stress. This mechanism provides a robust framework for SL, where WEE1i synergize with different DNA-damaging agents to overwhelm the cell’s repair capacity. Several of these agents have progressed to clinical trials (Supplementary Fig. S6).
Adavosertib (AZD1775 or MK-1775) is a potent WEE1i that was able to induce apoptosis and arrest at G2/M in trastuzumab-resistant breast cancer cells.415 CCNE1 overexpression was able to sensitize TNBC cells and PDX to adavosertib.416 Adavosertib also led to tumor inhibition and enhanced gemcitabine efficacy in sarcoma cells.417 Several Phase I clinical trials for cancer treatment were performed with this compound as monotherapy or in combination with CTx/RT (e.g., NCT00648648 and NCT02037230) and found that adavosertib was in general safe and tolerable.418,419 Several Phase II studies are ongoing or have already been completed. Clinical benefit was observed in a Phase II trial of adavosertib plus paclitaxel and carboplatin in women with PtS TP53-mutant ovarian cancer (NCT01357161420). Subsequently, in Phase II clinical trials, adavosertib also enhanced carboplatin (NCT01164995421) and gemcitabine (NCT02101775, also known as NCT02151292422) efficacy in TP53-mutated tumors. Moreover, adavosertib demonstrated clinical potential in RAS/TP53-mutant metastatic CRC in another Phase II trial (EUDRACT 2012-005111-12423). In a biomarker-driven SCLC umbrella study, no objective response was found with adavosertib monotherapy, but stable disease was observed in 25% of the patients without selected biomarker and in 43% of the participants with MYC family amplification or CDKN2A and TP53 co-alteration (NCT02593019424). In another study (NCT02513563) with the same cancer type, the primary endpoint (mPFS of 4.8 months) was met with the combination of adavosertib with carboplatin and paclitaxel, but response rates and mPFS of Pt-doublet combination were similar to historical data from other trials.425 No ORRs were observed in another Phase II trial in SCLC combining adavosertib plus carboplatin (NCT02937818426). These results underscore the necessity of improved combinatorial approaches or stringent biomarker selection in SCLC. Based on data indicating that TNBC models harboring CCNE1 amplification exhibited higher sensitivity to adavosertib,416 a Phase II study was designed to assess adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors (NCT03253679). Adavosertib monotherapy showed promising clinical activity in CCNE1-amplified solid tumors, especially in ovarian cancer,427 as well as in uterine serous carcinoma (NCT03668340428). Antitumor activity was also observed in patients with the same cancer type previously treated with Pt (NCT04590248429), and when combined with CTx in patients with PtR ovarian cancer (NCT02272790430). Contrarily, adavosertib combined with cisplatin in metastatic TNBC missed the pre-specified cutoff of >30%. The finding of immune-infiltrated tumors in patients experiencing clinical benefit suggested further study of the combination between WEE1i and PD-1/PD-L1 inhibitors (NCT03012477431). Meaningful response was not detected when combining adavosertib with carboplatin for advanced solid tumors (NCT01827384432). However, when combined with gemcitabine and RT for pancreatic cancer in a Phase I/II trial (NCT02037230), OS was substantially higher than prior results of gemcitabine with RT.419 Finally, results from the first Phase II study of adavosertib in pediatrics with irinotecan demonstrated that the association was of sufficient activity to support further study in neuroblastoma, and possibly other pediatric tumor types with recurrent ATRX mutation (NCT02095132433). The increased level of hematologic toxicity reported for adavosertib as a single agent or in combination has become a challenge in several clinical trials and should be further studied to optimize the treatment with this drug.430
Azenosertib (ZN-c3) is another selective, and orally bioavailable WEE1i that has progressed to clinical trials. A Phase I study of this compound for solid tumors (NCT04158336) showed early signal of clinical activity and appeared to be safe and tolerable as a single agent.434 Particularly, azenosertib demonstrated clinical activity in subjects with recurrent or advanced uterine serous carcinoma,435 which is currently being validated in a Phase II study in these patients (NCT04814108). Also ongoing is the Phase II DENALI trial (NCT05128825) of azenosertib in PtR ovarian cancer, which consists of a first part enrolling patients without considering biomarker status, and a second one testing patients for cyclin E1 overexpression. Preliminary results reported clinically meaningful response rates and duration of response with azenosertib monotherapy in women with cyclin E1-positive tumors.436 Another Phase II biomarker trial of azenosertib for uterine serous carcinoma is ongoing (NCT06369155). Azenosertib was tested in combination with niraparib in a Phase I trial (MAMMOTH trial) in subjects with PtR ovarian cancer who had failed PARPi MT (NCT05198804), but as efficacious drug exposures were not reached, this combination is not further being studied.437 Azenosertib plus CTx or bevacizumab is being explored in a Phase IB trial in patients with PtR or refractory ovarian cancer (NCT04516447). Preliminary data indicated that the association was well-tolerated and exhibited encouraging clinical activity, with durable responses. Remarkably, patients with cyclin E1 overexpressing tumors demonstrated significantly higher improvement in ORR and PFS.438 This compound is also being explored in another Phase I in participants with metastatic BRAF V600E mutant CRC in association with the BRAF inhibitor (BRAFi) encorafenib and cetuximab (NCT05743036). While the results in BRAFi-naïve patients were encouraging, the sponsor decided not to proceed with the dose expansion phase due to resource prioritization and an evolving treatment landscape.437 Regarding pancreatic cancer, a Phase I trial (NCT04005690) aiming to identify biomarkers of response, and a Phase II (NCT06015659) testing the association of azenosertib and gemcitabine are also enrolling. Two Phase I/II studies are testing azenosertib plus carboplatin and pembrolizumab for metastatic TNBC (NCT06351332), and plus gemcitabine in both adult and pediatric subjects with relapsed or refractory osteosarcoma (NCT04833582). Preliminary results showed greater event-free survival than historical control cohorts of salvage therapy in these patients.439 Finally, a Phase I trial is analyzing azenosertib associated with trastuzumab for stomach cancer or other solid tumors (NCT06364410). Based on the positive results, azenosertib was granted FDA Fast Track status in January 2025 for patients with PtR epithelial ovarian, fallopian tube or primary peritoneal cancer with cyclin E1 overexpression.440
Debio-0123 is an orally available CNS-penetrant ATP-competitive WEE1i that has progressed to clinical trials. A Phase I trial of Debio-0123 with carboplatin in advanced solid tumors (NCT03968653) showed a manageable safety profile and observable preliminary antitumor activity.441 This compound also elicited strong synergy with the PKMYT1i lunresertib in preclinical models of CCNE1-overexpression and in a tumor xenograft using intermittent Debio-0123/lunresertib dosing at subtherapeutic monotherapy doses.442 Based on these data, a Phase I study (NCT04855656) of lunresertib alone or in combination with Debio-0123 in patients with CCNE1-amplified or FBXW7-/PPP2R1A-mutant advanced solid tumors is ongoing. Preliminary results showed that the combination is safe and effective in these patients.443 This strategy, targeting both WEE1 and PKMYT1, aims to maximize CDK1 hyperactivation while preventing compensatory survival mechanisms. In another Phase I (NCT05815160), Debio-0123 in combination with carboplatin and etoposide has led to promising antitumor activity with good tolerability in participants with recurrent SCLC previously treated with standard Pt.444 Preliminary data from another Phase I (NCT05109975) have reported that continuous dosing of Debio-0123 as monotherapy exhibits a manageable safety profile and linear pharmacokinetics for advanced solid tumors.445 Moreover, in preclinical models of glioblastoma, Debio-0123 demonstrated significant efficacy as monotherapy and improved response to CTx or RT.446 This evidence supported the design of a Phase I/II study in combination with temozolomide for recurrent glioblastoma, and with temozolomide and RT for newly diagnosed glioblastoma (NCT05765812). Additionally, based on synergistic antitumoral activity of Debio-0123 associated with sacituzumab govitecan in preclinical models of breast cancer,447 a Phase I/II evaluating this combination in TNBC or HR+/ HER2- advanced breast cancer has recently started (NCT06612203).
The other WEE1i that are currently undergoing clinical trials are potrasertib, SY-4835 and APR-1051. Potrasertib (IMP7068) is a potent and selective WEE1i being tested in a Phase I study for advanced solid tumors (NCT04768868). Preliminary results showed that IMP7068 was well-tolerated and exhibited a meaningful pharmacodynamic effect and preliminary antitumor activity.448 SY-4835 (NCT05291182) and APR-1051 (NCT06260514) are other WEE1i being studied in FIH studies in patients with advanced solid tumors.
PKMYT1, also named Myt1, is a cell cycle-regulating kinase similar to WEE1 that acts by negatively regulating CDK1 through its phosphorylation and cytoplasmic sequestration.449 CCNE1 amplification is SL with PKMYT1 inhibition. In fact, the overexpression of CCNE1 disrupts CDK1 homeostasis.450 WEE1 and PKMYT1 were also found to be SL,451–453 as simultaneous WEE1 and PKMYT1 inhibition synergistically promoted CDK1/2 activation, aggravating DNA replication stress and fork replication collapse, providing a potential approach for cancer treatment. Upregulation of PKMYT1 promoted acquired resistance of cancer cells to the WEE1i adavosertib, an effect that was reversed by PKMYT1 knockdown.454 Repare Therapeutics has developed a first-in-class PKMYT1i, lunresertib (RP-6306), that is currently undergoing Phase I and II clinical trials (e.g., NCT05601440, NCT05605509 and NCT06107868) for different solid tumors alone or in combination with CTx, the ATRi camonsertib or the WEE1i Debio-0123 in patients with specific mutation profiles (e.g., TP53/KRAS/FBXW7/PPP2R1A mutations or CCNE1 amplifications). This is based on preclinical data reporting synergy of lunresertib and the ATRi camonsertib to induce cytotoxicity and durable antitumor activity in CCNE1-amplified ovarian and endometrial cancer cell lines, CDXs and PDXs, especially in those carrying genomic biomarkers predictive of lunresertib sensitivity (CCNE1 amplification and FBXW7 and PPP2R1A LOF).455 Results from the Phase I MINOTAUR study (NCT05147350) showed that the combination of lunresertib and FOLFIRI was well tolerated and demonstrated promising efficacy in heavily pretreated patients with CCNE1-amplificated and FBXW7-mutant advanced gastrointestinal cancers.456 A strong response was also reported from the MYTHIC Phase I clinical trial (NCT04855656) evaluating the combination of lunresertib and camonsertib in patients with endometrial cancer and PtR ovarian cancer harboring lunresertib-sensitizing biomarkers (CCNE1 amplifications and mutations in FBXW7 or PPP2R1A).457
To address the limitations of monotherapeutic checkpoint targeting, ACR-2316 has emerged as a potential first-in-class, dual WEE1/PKMYT1 inhibitor. Unlike combinatorial approaches that use two separate drugs, ACR-2316 is a single small molecule rationally designed to prevent the compensatory PKMYT1 signaling that typically results in WEE1i resistance.458 Preclinical data using Acrivon’s Predictive Precision Proteomics (AP3) platform demonstrated that ACR-2316 induces superior DNA damage and mitotic catastrophe compared to selective WEE1i.459 This drug is currently being evaluated in a Phase I study (NCT06667141) for advanced solid tumors.
Inhibitors of the different CDKs have also entered clinical trials. The most clinically advanced are the CDK4/6 inhibitors (CDK4/6i), palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®), which have received global approvals for metastatic breast cancer and are also included in Phase III clinical trials (eg., NCT04966481, NCT04862663 and NCT02152631). Newer generations of inhibitors are directed to other CDK family members, such as CDK2 (e.g., AVZO-021, INCB123667, PF-07104091 and INX-315), CDK7 (e.g., samuraciclib, Q-901 and SY-5609) and CDK9 (e.g., PRT2527). Some pan-CDK inhibitors (e.g., seliciclib and milciclib) are also being developed, although the trend is toward more selective therapeutics. Sensitivity to these agents has been related to reduced expression of the genes CDKN2A,460 which codifies for the CDK4/6 inhibitors p16INK4a and p14ARF, CCNE1461 and TP53,462 and to increased expression of MYC,463 CCND1 and the retinoblastoma tumor suppressor gene (RB1).461 As for CDK4/6i, palbociclib demonstrated antitumor activity in patients with CDKN2A alterations in Phase II trials in chordoma (NCT03110744) and head and neck cancer (NCT02693535).464,465 Additional alterations in PIK3CA, PTEN, MTAP, or MET genes related to response were identified.465 Resistance to palbociclib was detected in tumors with high CCNE1 mRNA expression in a Phase III trial (NCT01942135) testing palbociclib plus fulvestrant.466 While the other CDK4/6i abemaciclib, showed better outcomes in patients with anaplastic thyroid cancer (NCT04552769467) and mesothelioma (NCT03654833468) with CDKN2A loss, some other clinical trials failed to identify sufficient activity with this drug in CDKN2A-deficient tumors.469,470 Palbociclib and abemaciclib monotherapy did not demonstrate clinical activity in two trials in patients with pretreated RB1-positive anaplastic oligodendroglioma (NCT02530320471) or metastatic TNBC (NCT03130439472), respectively. Amongst the different hypotheses for this lack of response, the authors of the last study suggested this could be due to the rewiring of the cell cycle machinery in these tumors rendering them non-dependent on CDK4/6.472 In addition, abemaciclib-based therapy (e.g., associated with the PI3K/mTOR/DNA-PK inhibitor samotolisib) did not show clinical benefit in a Phase II trial (NCT02981342) in pancreatic ductal adenocarcinoma patients.371 A Phase IB clinical trial (NCT02057133) is currently analyzing the combination of abemaciclib, samotolisib and fulvestrant in metastatic breast cancer patients. Meanwhile, the CDK2 inhibitor INCB123667 showed encouraging antitumor activity in a Phase I study (NCT05238922) in patients with advanced PtR and refractory ovarian cancer and cyclin E1 overexpression,473 which is currently being explored in Phase II (NCT07023627) and III (NCT07214779) trials. Based on the inconsistent clinical outcomes with CDK inhibitors, further studies on the mechanisms of response and resistance to these drugs should be performed.
PLK1 is another serine/threonine kinase that displays a key role as a regulator of mitosis by participating in the cell cycle G2/M checkpoint. After being activated by AURKA, PLK1 inhibits WEE1 and PKMYT1 via their phosphorylation, resulting in the consequent activation of CDKs.474,475 PLK1 has been found to be overexpressed in cancer, often associated with poor outcomes.476 The clinical progression of PLK1 inhibitors has been constrained by the appearance of resistance and by lack of PLK1 selectivity, which causes low efficacy and dose-limiting toxicities.477 PLK1 contains two main domains, the kinase domain and the polo-box domain.478 According to this, the different PLK1 inhibitors can be classified as ATP competitors (e.g., volasertib and onvansertib), which compete with ATP for binding the kinase domain, and non-ATP competitors (e.g., allopole), which target the polo-box domain. The discovery of SL interactions between PLK1 and KRAS,479 BRCA1,480 CCND1,481 TP53,482 MYC483 and FA/BRCA pathway genes,484 amongst others, has opened a new path to the clinical application of PLK1 inhibitors for tumors with specific alterations in these genes. In fact, onvansertib was granted the Fast Track Designation by the FDA for its development as second-line treatment in patients with KRAS-mutated metastatic CRC associated with FOLFIRI and bevacizumab.485 Significant activity was reported in the Phase IB/II trial (NCT03829410) analyzing this combination, particularly in patients without prior exposure to bevacizumab.486 This led to the exploration of the combination in the first-line setting (NCT06106308). Another Phase II trial is assessing whether onvansertib is useful in patients with relapsed SCLC carrying TP53 mutations or MYC overexpression (NCT05450965).
In summary, the clinical landscape of cell cycle inhibitors is undergoing a paradigm shift from broad applications toward biomarker-driven precision strategies and multi-node checkpoint disruption. While first-generation WEE1i inhibitors like adavosertib provided proof-of-concept, their clinical utility was constrained by a narrow therapeutic window and hematologic toxicities. The emergence of more selective agents, such as the WEE1i azenosertib and the first-in-class PKMYT1i lunresertib, and of the next-generation dual WEE1/PKMYT1 inhibitor ACR-2316, represents a new frontier in the exploitation of SL in this context. The clinical success of these next-generation therapeutics increasingly relies on the identification of robust predictive biomarkers (most notably CCNE1 amplification and FBXW7/PPP2R1A mutations) and the implementation of combinatorial strategies that prevent bypass signaling. However, maximizing the utility of these biomarkers will require overcoming clonal heterogeneity, potentially through the integration of liquid biopsies (ctDNA) to monitor real-time SL dependencies and guide adaptive treatment strategies. The FDA’s recent regulatory milestones for these compounds underscore a growing confidence in targeting G2/M and S-phase dependencies. Future efforts must focus on optimizing intermittent dosing schedules and identifying mechanisms of acquired resistance to fully integrate these cell cycle modulators into the standard of care for refractory solid tumors.
POLQ inhibitors (POLQi)
Another target being explored within the end-joining pathway, in particular the alt-NHEJ, is Polθ, also called POLQ. The helicase domain of POLQ is responsible for annealing small sequences of microhomology flanking the DSB that are then repaired by the polymerase domain.487 POLQ is upregulated in numerous cancers and its overexpression is associated with poor prognosis.488,489 Several preclinical studies showed that POLQ deficiency is SL with various DDR pathway genes, including BRCA1/2, ATM, ATR, XRCC6 (encoding the Ku70 protein), RAD52 and FANCD2.215,217,490–493 Furthermore, as HRD cancer cells seem to overexpress POLQ and be hypersensitive to POLQ knockdown,217 an inhibitor of POLQ could constitute a promising drug to be associated with PARPi to avoid the acquisition of reversion mutations and restoration of HRR-activity in these tumors.
The availability of crystal structures for both the helicase and the polymerase domain of POLQ has helped in the development of potent inhibitors of this protein,494,495 since both domains contain druggable sites.494 Four main biotech companies have developed POLQi that are currently in clinical trials: Artios Pharma (Cambridge, UK), IDEAYA Biosciences (San Francisco, USA), Repare Therapeutics (Montreal, Canada) and Synrx Therapeutics (Hangzhou, China). The structure of these compounds has not yet been disclosed. It has been reported that POLQ might contribute to the acquisition of PARPi resistance,219 which may occur via loss of 53BP1, an SL gene with POLQ.491,496 This leads to the conclusion that using POLQi in combination with PARPi, or as second-line therapy, might prolong drug response and delay the acquisition of resistance.
Artios Pharma is clinically evaluating two POLQi, ART4215 and ART6043, as monotherapy and in combination with other drugs. ART4215 is a highly selective, oral small molecule inhibitor targeting the POLQ polymerase domain, which is included in a Phase I/IIA trial as monotherapy and in combination with the PARPi talazoparib in advanced or metastatic solid tumors (NCT04991480). ART6043 is another selective, orally bioavailable, small-molecule inhibitor of POLQ that is being explored in a Phase I/IIA study for advanced/ metastatic solid tumors as monotherapy or in combination with PARPi olaparib or niraparib (NCT05898399). Based on encouraging clinical activity and good tolerability reported in this trial,497 the FDA has recently granted Fast Track Designation to ART6043 in combination with olaparib for gBRCA1/2m HER2- locally advanced or metastatic breast cancer not priorly exposed to a PARPi.
GSK4524101 (GSK-101 or IDE705) is being developed by IDEAYA Biosciences as a POLQi in combination with niraparib in a GSK-sponsored Phase I/II clinical trial for solid tumors (NCT06077877).
The SYN818 from Synrx Therapeutics entered clinical trials with a Phase I study (NCT06666270) administered orally for advanced solid tumors and showed a preliminary favorable safety profile.498
Repare Therapeutics is developing the POLQ ATPase inhibitor RP-3467. This compound is being studied in a FIH trial alone and in combination with olaparib for advanced solid tumors (NCT06560632).
Similar to RP-3467, the antibiotic novobiocin was identified in a high-throughput screen as a specific POLQ ATPase inhibitor that selectively kills HRD tumor cells in vitro and in vivo (Supplementary Fig. S7).220 A Phase I trial (NCT05687110) sponsored by the National Cancer Institute is studying novobiocin in patients with solid tumors carrying HRR or DDR alterations that are PARPi-naïve or exhibit resistance to these drugs.
Collectively, the rapid clinical progression and regulatory support for POLQi underscore their potential to transform the treatment landscape for HRD malignancies, particularly as a strategy to circumvent or overcome the limitations of current PARPi therapies.
USP1 inhibitors (USP1i)
USP1, which is associated with UAF1, is a deubiquitinating enzyme involved in regulating both the FA/BRCA pathway and TLS by deubiquitinating the FANCI/FANCD2 complex and PCNA, respectively.499,500 USP1-deficient mice harbor genomic instability and are highly sensitive to DNA damage, resembling the FA phenotype. Meanwhile, USP1−/− cells exhibit impaired FANCD2 foci assembly and a defect in HRR and induced growth arrest at G2/M.501,502 The inhibition of USP1 by different USP1i also sensitized cancer cells to chemotherapeutic agents, including Pts, doxorubicin, PARPi and TOPI/II inhibitors.502–504
USP1i are another class of inhibitors that have recently entered clinical trials with the orally bioavailable compound KSQ-4279 from KSQ Therapeutics (Supplementary Fig. S8). Mechanistic studies indicated that the accumulation of ubiquitinated PCNA was the likely cause of SL in BRCA1/2/HRD cell lines. Synergistic activity was frequently observed with PARPi across a large panel of cancer cell lines, and especially in those with BRCA1/2 alterations.505 More concretely, RO7623066 (KSQ-4279 or RG6614) is a potent and selective USP1i that was identified using the CRISPRomics platform from KSQ Therapeutics. In 2023, the compound entered a worldwide license and collaboration agreement with Roche. Preclinical data demonstrated the capacity of this compound to induce durable tumor regression of PARPi–resistant tumors when dosed in combination with PARPi.504 Based on this data, RO7623066 is being tested in a Phase I clinical trial alone and in combination with PARPi in patients with advanced solid tumors (NCT05240898).
XL309 (previously ISM3091) is another orally bioavailable USP1i identified through Insilico Medicine’s artificial intelligence platform that has been recently licensed to Exelixis for its global development and commercialization. In vitro data revealed synergistic activity between XL309 and olaparib in HRD cell lines. Dose-dependent single-agent inhibitory activity was also observed in multiple CDX and PDX models. The antitumoral response was more robust and durable when combining XL309 and olaparib in a BRCA1/2 wild-type ovarian PDX model with acquired resistance to this drug.506 Based on these findings, a Phase I study (NCT05932862) of XL309 alone and in combination with olaparib in patients with advanced solid tumors is recruiting.
Overall, USP1i represents a promising strategy to bypass PARPi resistance by disrupting PCNA-mediated TLS and the FA/BRCA pathway. The clinical entry of RO7623066 and XL309 marks a shift toward targeting these pathways in HRD tumors. As these Phase I clinical trials progress, the key challenge will be identifying the optimal therapeutic window and robust biomarkers to maximize the efficacy of these combinations in the refractory setting.
RAD51 inhibitors (RAD51i)
RAD51 recombinase is a major component of HRR, fundamental for maintaining genomic stability. HRR provides error-free repair of DSBs during S and G2 phases of the cell cycle. Initially, CtIP associates with the MRN complex (MRE11, RAD50 and NBS1) and stimulates bidirectional DNA end resection.507 DNA resection of the DSB 5′-ends, generates 3′-ended ssDNA overhangs that are first coated by RPA, which is then replaced by RAD51, forming a nucleoprotein filament, a process mediated by BARD1, BRCA1/2, PALB2 (FANCN) and RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3).508 Then the filament of RAD51-ssDNA initiates the search for complementary sequences, strand invasion and DNA polymerization, processes by which the sequence surrounding the break site is resynthesized, via the formation of a D-loop that serves as a primer and template for DNA synthesis.509 DNA DSB induction and recognition lead to nuclear accumulation of RAD51, which is detectable as nuclear foci. These foci serve as a surrogate marker of HRR functionality that can be used as a biomarker to select cancer patients for drug response, such as with PARPi.192 RAD51 has been detected as overexpressed in several malignancies,510,511 which has been associated with enhanced DNA repair and increased resistance to anti-cancer treatments.512,513 Based on these findings, RAD51 inhibition is considered a promising strategy for the treatment of these tumors.
Emzadirib (CYT-0851) is a potent, selective and oral first-in-class inhibitor of RAD51-mediated DNA repair that in a Phase I/II clinical trial (NCT03997968) showed good tolerability and promising and broad clinical activity in advanced hematologic malignancies and solid tumors.514 However, Cyteir Therapeutics announced in 2023 the discontinuation of the development of emzadirib, due to a lack of overall clinical efficacy according to the company’s criteria.
Several other RAD51i are still in preclinical stages. B02 is a RAD51i discovered by researchers from the National Cancer Institute that has demonstrated promising results in preclinical studies, particularly in combination with other chemotherapeutic agents or CHK1i.515,516 The structure of this compound has served as a starting point to design other RAD51i with enhanced potency, selectivity, and pharmacokinetic properties.516,517 SAT-122 from Satya Pharma was able to disrupt RAD51-BRCA2 interaction and attenuated RAD51 foci formation and tumor progression in different cancer cell lines.518 The RAD51i SCR-6992 developed by Simcere Pharmaceutical also showed encouraging antitumoral activities, including synergy with chemotherapeutic drugs, in cancer cell lines and animal models.519
To sum up, while the clinical progress of RAD51i has been hampered by the discontinuation of its most advanced candidate, the biological rationale for targeting RAD51 remains robust. The current focus is shifting toward developing next-generation inhibitors with higher binding affinity, identifying predictive biomarkers of response and exploring combinatorial regimens designed to sensitize HRR-proficient tumors to PARPi.
WRN inhibitors (WRNi)
Werner syndrome ATP-dependent helicase (WRN) is a member of the RecQ DNA helicase family, encoded by the WRN gene, that participates in DNA replication and repair, transcription, and telomere maintenance. More specifically, WRN mediates the choice between different DSB pathways by promoting c-NHEJ while suppressing alt-NHEJ; additionally, it facilitates HRR through its roles in DSB resection and CHK1-mediated RAD51 loading.520 Mutations in this gene cause the autosomal recessive disorder Werner syndrome, characterized by the appearance of premature aging (progeria) and aging-related disorders, including increased cancer incidence, due to impaired DNA damage repair and telomeric shortening.521 Preclinical data identified a SL relationship between WRN and microsatellite unstable (MSI) cancers. In MSI-high (MSI-H) cells, the genome is characterized by the accumulation of unstable TA nucleotide repeats, which tend to form non-canonical DNA secondary structures (such as cruciforms or large loops) that cause replication fork collapse. WRN is uniquely required to unwind these structures and maintain fork progression; therefore, WRN inactivation causes DSBs and activated DSB responses, leading to apoptosis and G1 or G2/M cell cycle arrest preferentially in MSI cells. Based on this finding, WRN was considered a promising drug target for MSI cancers, such as a subtype of colorectal, endometrial, gastric and ovarian cancers.522,523 Several WRNi have recently entered clinical trials (Supplementary Fig. S9).
GSK4418959 (IDE275/GSK959) is an oral WRNi discovered by IDEAYA in collaboration with GlaxoSmithKline that is undergoing a Phase I/II study (NCT06710847) alone or in combination with a PD-1 inhibitor in MMR-deficient or MSI-H solid tumors.
HRO761 from Novartis is a potent, allosteric WRNi that was identified through an innovative hit-finding and lead-optimization strategy. Preclinical data showed the ability of this compound to lead to WRN degradation and inhibit tumor cell growth selectively in MSI cells in a p53-independent manner. Additionally, it caused dose-dependent DNA damage induction and tumor growth inhibition in MSI CDX and PDX.524 This oral WRNi is being studied in a Phase I clinical trial alone or combined with pembrolizumab or irinotecan in patients with solid cancer with MSI or MMR-deficiency (NCT05838768).
RO7589831 (VVD-133214) is another oral allosteric WRNi that was discovered by Vividion Therapeutics and later licensed to Roche. This compound binds WRN and causes DNA DSBs, nuclear swelling and cell death selectively in MSI-H cells, compared to microsatellite-stable cells. In MSI-H CRC cells and PDXs, it also resulted in robust reduction of tumor growth.525 A Phase I study (NCT06004245) of this compound alone and associated with pembrolizumab for MMR-deficient or MSI solid tumors is recruiting. Preliminary results have shown that RO7589831 is generally safe and well tolerated and exhibits promising clinical responses in these patients.526
In summary, the WRN-MSI axis represents a highly selective SL vulnerability that has translated from discovery to clinical evaluation. By targeting the unique dependency of MSI-H cells on WRN to resolve replication-stalling non-canonical DNA structures, WRNi offer a potent, precision-oncology approach for MMR-deficient tumors, particularly for patients who have exhausted SOC immunotherapy.
APE1 inhibitors (APE1i)
The reduction-oxidation (redox) factor 1 - apurinic/apyrimidinic endonuclease (Ref-1/APE1) is the main apurinic/apyrimidinic endonuclease in eukaryotic cells, participating in the removal of non-bulky DNA lesions in the BER pathway and in redox signaling. This endonuclease cleaves abasic sites and generates ssDNA nicks 5′ to the abasic site, which are then processed by short- or long-patch BER. Ref-1/APE1 also functions as a redox signaling protein that modulates the activity of critical transcription factors, such as NF-κB, AP-1, HIF-1α and STAT3.527,528 Ref-1/APE1 expression is upregulated in many tumors, which has been associated not only with increased cancer cell proliferation, migration and survival, but also with chemoresistance.529,530 Several small-molecule inhibitors of the endonuclease activity of APE1 involved in DDR have been described (e.g., CRT0044876, AR03) but none of them have entered clinical trials.
APX3330 (Supplementary Fig. S10) is an orally bioavailable inhibitor of Ref-1/APE1’s redox function that showed signs of clinical activity in a Phase I trial (NCT03375086) with an unselected population of patients with advanced solid tumors.531 However, this compound acts as a selective antagonist of the Ref-1 redox signaling domain by disrupting transcriptional co-activation while sparing APE1 endonuclease activity. Consequently, its therapeutic potential in the DDR landscape lies more in its ability to suppress adaptive stress signaling rather than direct BER inhibition.532 In contrast, TRC102 (also known as methoxyamine) covalently binds to the reactive aldehyde of abasic sites, effectively blocking APE1 endonuclease from recognizing and processing BER intermediates. Clinical trials with this drug aim to exploit an induced SL state caused by several DNA-damaging agents (e.g., temozolomide, pemetrexed) that overwhelm the cell’s DNA repair capacity. A Phase I/II study (NCT02535312) showed a tolerable safety profile and antitumor activity of TRC102 in combination with cisplatin and pemetrexed for advanced solid tumors, and of TRC102 with pemetrexed for malignant mesothelioma progressed to prior pemetrexed therapy.533 Promising durable disease control was also reported when combining it with temozolomide in another Phase I/II trial (NCT01851369) in patients with granulosa cell ovarian cancer.534
Altogether, the APE1-BER axis represents a complex therapeutic target where the distinction between disrupting oncogenic redox signaling (APX3330) and blocking DDR (TRC102) allows for precise, context-dependent strategies to overcome chemoresistance in solid tumors.
Targeting SL interactions beyond DDR genes
Although more than 70% of clinical candidate drugs targeting SL focus on DDR, other emerging drugs that have progressed to the clinical setting target other pathways outside DDR,535 such as metabolic enzymes (e.g., PRMT5, MAT2A), chromatin regulators (e.g., SMARCA4, SMARCA2, ALC1) or RNA helicases (e.g., DHX9).
Regarding metabolic SL, MTAP, MAT2A, and PRMT5 participate in the methionine/S-adenosyl-L-methionine (SAM) cycle, whose regulation is critical for maintaining cellular homeostasis. Loss of the MTAP gene, which often occurs in cancer (e.g., gliomas, NSCLC) due to its proximity to the frequently deleted CDKN2A/B locus,536,537 was found to be SL with the inhibition of MAT2A and PRMT5.538 This SL was enhanced when combining MAT2A and PRMT5 inhibitors (MAT2Ai and PRMT5i), leading to a more potent antitumoral effect.539 In fact, upon MTAP depletion, an accumulation of the MTAP substrate MTA, which is a PRMT5 potent and selective inhibitor, occurs. This results in reduced PRMT5 activity and increased sensitivity to PRMT5i. Moreover, MAT2A produces the PRMT5 substrate SAM, and therefore, the inhibition of MAT2A also causes a reduction in PRMT5 methylation activity and, in turn, a reduction of tumor growth in MTAP-depleted cells.540 GSK3326595 (EPZ015938) is a FIH PRMT5i optimized from GSK3235025 (EPZ015666). The analog GSK3235025 showed antiproliferative activity in TNBC cells and PDX, as well as synergy with the EGFR inhibitor erlotinib.541 It also showed activity in AML preclinical models, especially in those with MLL rearrangements.542 In a Phase I/II trial (NCT03614728) GSK3326595 monotherapy displayed limited clinical activity in heavily pretreated patients with myeloid neoplasms despite robust target engagement, leading to study termination.543 It also showed modest antitumor activity with hematopoietic dose-limiting toxicities as a single agent in a Phase IB trial (NCT02783300) in patients with solid tumors and NHL.544 Another Phase II trial (NCT04676516) in HR+ breast cancer is complete, but results have not been reported. The lack of clinical activity and the dose-limiting toxicities of first-generation PRMT5i led to the development of the next-generation MTA-cooperative agents, which selectively bind the PRMT5-MTA complex elevated in MTAP-deleted cells, thereby sparing healthy tissues. BMS-986504 (MRTX1719) is one of these MTA-cooperative PRMT5i that is currently undergoing Phase II/III trials with pembrolizumab and CTx for first-line metastatic NSCLC with homozygous MTAP deletion (NCT07063745) and with paclitaxel/gemcitabine for untreated metastatic pancreatic ductal adenocarcinoma with homozygous MTAP deletion (NCT07076121), as well as other Phase I or II clinical trials (e.g., NCT06672523 and NCT06855771). In a Phase IB study (NCT05245500) in patients with MTAP-deleted advanced solid tumors, this compound showed durable antitumor activity,545 including in those with heavily pretreated NSCLC with EGFR and ALK alterations.546 Preliminary data of a Phase I/II trial (NCT05094336) with the PRMT5i AMG193 demonstrated a favorable safety profile and promising antitumor activity across a variety of MTAP-deleted solid tumors.547 Several other next-generation MTA-cooperative PRMT5i are undergoing Phase I/II clinical trials in solid tumors with MTAP loss: BAY3713372 alone and in combination with other anticancer agents (NCT06914128); AZD3470 monotherapy (NCT06130553); and the compounds from Tango Therapeutics TNG908 as single agent (NCT05275478), TNG462 alone or with pembrolizumab (NCT05732831) and combined with RAS inhibitors (NCT06922591), and TNG456 alone or with abemaciclib (NCT06810544). AZD3470 is also being tested as a single agent and in combination with other anticancer agents in participants with hematologic malignancies (NCT06137144).
Concerning MAT2Ai, S095033 (AG-270) is a first-in-class oral small molecule MAT2Ai that demonstrated antiproliferative activity in MTAP-deleted cancer cells and CDX and PDX models, and these effects were synergistic with taxanes both in vitro and in vivo.548 This resulted in an FIH trial (NCT03435250) as monotherapy in patients with advanced malignancies, which showed that this compound displays a manageable safety profile, although dose escalation was limited by off-target hepatobiliary toxicities and preliminary evidence of clinical activity.549 This off-target effect may be avoided by the development of a second-generation MAT2Ai, S095035, that is currently being analyzed in a Phase I/II trial (NCT06188702) as a single agent and in combination with the PRMT5i TNG462 in participants with advanced or metastatic solid tumors with deletion of MTAP. Two other MAT2Ai have progressed to Phase I clinical trials for advanced solid tumors with MTAP loss: IDE397 as a single agent and combined with taxanes (docetaxel or paclitaxel) or sacituzumab govitecan (NCT04794699) and ISM3412 as monotherapy (NCT06414460).
Epigenetic dysregulation, including alterations in chromatin remodelers, is considered a major driver of tumorigenesis. Mutations in genes encoding components of the SWI/SNF complex occur in approximately 20% of all human cancers, confirming their role as critical tumor suppressors.550 This complex regulates chromatin remodeling for active transcription through the activity of two mutually exclusive ATPase catalytic subunits, SMARCA4 (BRG1) and SMARCA2 (BRM), which work together with other subunits, such as SMARCC1 and 2, SMARCB1 and ARIDs (e.g., ARID1A and B, ARID2).551,552 Several co-dependencies have been identified in SWI/SNF-mutant cancers that can be targeted therapeutically, most notably the SMARCA4-SMARCA2 axis, where the loss of one paralog creates a dependency on the other. Other identified SWI/SNF-related SL pairs include: SMARCA4-ARID2, SMARCA4-ACTB, SMARCC1-SMARCC2 and ARID1A-ARID1B.553–555 To exploit this specific vulnerability, Prelude Therapeutics developed two SMARCA2 degraders, PRT3789 and PRT7732, that are currently undergoing clinical trials for SMARCA4-mutant advanced or metastatic solid tumors. PRT3789, currently in a Phase II study in combination with pembrolizumab (NCT06682806), was well tolerated and showed encouraging signs of anti-tumor activity in a previous Phase I trial (NCT05639751556). Similarly, the SMARCA2 inhibitor LY4050784 (FHD-909) is being evaluated in Phase I studies in SMARCA4-mutated solid tumors alone or associated with several antitumoral agents (NCT06561685 and NCT06561685), based on preclinical data showing synergistic activity with pembrolizumab or KRAS inhibitors.557 In contrast to these selective approaches, the orally bioavailable dual SMARCA4/SMARCA2 inhibitor FHD-286 with antitumor activity in mouse xenografts,558 is being tested in another Phase I trial for advanced myeloid malignancies (NCT04891757). Recent data reported significant safety challenges, with approximately 10-15% of patients exhibiting the life-threatening differentiation syndrome despite some evidence of blast reductions.559
Inhibition of the methyltransferase EZH2, the catalytic subunit of the other chromatin-remodeling factor with repressive functions PRC2, is SL with the inactivation of ARID1A, PBRM1, SMARCA4, SMARCB1.560 Based on this, the FDA-approved EZH2 inhibitor tazemetostat (EPZ-6438) has progressed to several Phase I–II trials involving pediatric patients with SMARCA4-/SMARCB1-deficient advanced solid tumors, NHL, sarcomas and rhabdoid tumors, amongst others (e.g., NCT03155620, NCT02601937, NCT03213665, NCT05407441). In the Phase I study (NCT02601937) in SMARCB1-negative synovial sarcomas, tazemetostat showed promising antitumor activity.561 In another trial (NCT03213665) in children with SMARCB1 or SMARCA4 loss, tazemetostat did not produce significant objective responses, but prolonged stable disease was observed in 33% of patients across different histologic diagnoses.562 This drug is also being tested in Phase II studies in adult patients with SMARCA4, SMARCB1 or ARID1A mutant advanced solid tumors (e.g., NCT05023655, NCT02601950, NCT03348631, NCT05151588). A Phase II study of tazemetostat in adults with soft tissue sarcomas (NCT02601950), resulted in long-term clinical activity in 2/13 patients with SMARCB1-negative sarcomas and 1/16 with a SMARCB1-negative solid tumor with generally mild to moderate adverse effects.563 The other EZH2 inhibitor tulmimetostat showed efficacy in ARID1A mutant solid tumor models and improved cisplatin response in CTx-resistant models.564 This compound is being studied in a Phase I/II clinical trial (NCT04104776), where it has shown preliminary signs of antitumor activity in ARID1A-mutated ovarian and endometrial cancers.565
ALC1 (CHD1L) is a nucleosome-remodeling enzyme that is recruited at DNA-damaged sites by PAR chains synthesized by PARP1/2 in order to facilitate chromatin relaxation.566 ALC1 depletion induces the accumulation of toxic BER intermediates resulting in ssDNA gaps and replication fork collapse. Moreover, ALC1 loss is SL with HRD and, therefore, the inhibition of ALC1 could be employed to target HRD cancers. To this must be added that ALC1 loss confers enhanced sensitization to PARPi by increasing PARP trapping on chromatin.567 A brain-penetrant ALC1 inhibitor, EIS-12656, is being studied in a Phase I/II trial alone and in combination with olaparib or trastuzumab in patients with HRD solid tumors (NCT06525298).
DHX9 is a multifunctional ATP-dependent DExH-box RNA helicase with important roles in many processes, such as the regulation of DNA replication, transcription, translation and maintenance of genome stability.568 The overexpression of DHX9 has been found in cancer and was correlated with poor prognosis.569 In addition, the downregulation of DHX9 is SL in tumors with MSI-H or defective MMR570 and with BRCA1/2 LOF,571 making DHX9 inhibitors (DHX9i) promising targets to treat these cancers. The oral DHX9i ATX-559 was being studied in a FIH trial for advanced or metastatic solid tumors, including BRCA1/2-/MMR-deficient and MSI-H tumors (NCT06625515), but has been recently terminated due to an adverse event profile.
Beyond the DDR, SL is being exploited through metabolic dependencies, such as targeting the MAT2A-PRMT5 axis in MTAP-deleted tumors, and epigenetic vulnerabilities, notably SMARCA2 in SMARCA4-mutant cancers. Emerging strategies also include inhibiting the methyltransferase EZH2 in SMARCB1-deficient cancers, the nucleosome remodeler ALC1 to enhance HRD sensitivity, and the RNA helicase DHX9 in MSI-H or BRCA1/2-deficient contexts. While early-generation agents often faced dose-limiting toxicities, the field is now shifting toward biomarker-dependent and isoform-selective molecules, such as the MTA-cooperative PRMT5i and the SMARCA2-specific degraders, in order to maximize the therapeutic index and minimize off-target effects.
Conclusion and perspective
Targeting specific genetic vulnerabilities in tumors using the SL concept has redefined modern oncology and represents a cornerstone of precision cancer medicine. A prominent example is the success of PARPi, which exploit the existing SL interaction between PARP and a deficient HRR pathway, particularly due to BRCA1/2 mutations. Since their approval, PARPi have transformed the prognosis for patients with previously limited therapeutic options and have generated billions in revenues for pharmaceutical companies. Global sales for olaparib alone are expected to exceed $4 billion (accounting for 68% of the PARPi market share) by 2027, boosted by new licenses for early-line MT and novel combinations.572 In terms of clinical outcomes, the approval of olaparib for the treatment of BRCA1/2m ovarian cancer has significantly enhanced both survival rates and quality of life of these patients. The expansion of indications, the commercialization of subsequent PARPi and their strategic inclusion as MT have redefined the treatment paradigm for HRD ovarian, breast, prostate, and pancreatic cancers. While landmark clinical trials (e.g., SOLO1, PAOLA1, PRIMA, VELIA, BROCADE3) demonstrated significant improvements in PFS, translating this benefit into final OS remains a variable challenge across different cancer types and patient cohorts. Moreover, recent evidence suggests that defects in other specific genes involved in HRR and/or associated DNA repair pathways, especially PALB2, and to a lesser extent ATM or CHK2, may also confer sensitivity to PARPi. Indeed, favorable clinical responses to PARPi in cancers with alterations in these genes have been found (e.g., NCT01682772, NCT01891344, etc.), but additional trials with bigger cohorts are needed to fully define the predictive value of PARPi response. Despite the huge impact of PARPi on cancer treatment, safety concerns, often linked to non-selective trapping of PARP1 and PARP2, and the emergence of resistance remain critical hurdles. While trapping is essential for anti-tumor activity, its lack of isoform selectivity is linked to hematopoietic and gastrointestinal toxicities. Based on these findings, next-generation PARPi are shifting toward high-potency, PARP1-selective inhibitors (e.g., saruparib and AZD9574), which aim to maximize the therapeutic index by sparing PARP2 and avoiding the off-target effects associated with pan-PARP inhibition. Furthermore, despite the good initial response to PARPi, patients frequently develop resistance through different mechanisms, resulting in cancer relapse. Amongst the potential strategies to overcome this, combinations of therapies have been proposed, with the goal of amplifying the antitumoral efficacy of PARPi and targeting the acquired resistance mechanisms. Apart from their combination with CTx, RT or ICIs, PARPi may be associated with inhibitors of key effector kinases of the RSR (e.g., ATR, CHK1 and WEE1), as PARPi-resistant tumors seem to accumulate high levels of replication stress.210,573 Additionally, they could be combined with POLQi, as HRD cancer cells tend to overexpress this gene and seem to be hyper-dependent on its knockdown. Indeed, cancer cells with acquired resistance to PARPi through inactivation of the 53BP1-shieldin pathway also show hypersensitivity to these drugs. This stems from the fact that POLQ provides a critical “gap-filling” activity that effectively compensates for the HRR deficit, allowing the tumor to maintain replication continuity. Consequently, combining PARPi with ATR or POLQ inhibitors holds the potential to “unmask” this latent vulnerability by simultaneously disrupting the RSR, exhausting cell cycle checkpoints, and forcing the re-accumulation of lethal ssDNA gaps. As novel PARPi with higher selectivity and lower toxicity enter the market, along with ongoing research into combination therapies involving PARPi and other drugs, such as ICIs or other targeted therapies, the impact on patients’ prognosis may become even more significant.
Beyond the BRCA1/2 and PARP axis, other interesting DDR-related SL interactions are under clinical investigation, such as the targeting of the DDR-kinases ATR, ATM, CHK1/2, DNA-PK and WEE1, the POLQ polymerase, the USP1 deubiquitinating enzyme, the RAD51 recombinase and APE1. These molecules are key members of the cellular response to DNA damage, and their inhibition in cancers with specific SL interactions leads to tumor cell death. These drugs are also able to sensitize cancer cells to CTx, RT, immunotherapy and other targeted therapy. Notably, the ATRi ceralasertib has progressed to Phase III clinical trials in NSCLC associated with durvalumab plus docetaxel (NCT05450692) or only with durvalumab (NCT06732401), while alnodesertib has recently received FDA Fast Track Designation for ATM-negative mCRC. Preclinical evidence also suggests that simultaneous inhibition of the three PIKKs, ATM, ATR and DNA-PK, may cause severe synergistic SL compared to single or dual kinase inhibition,574,575 though the systemic tolerability of such broad DDR disruption requires further elucidation. The identification of novel SL interactions through advanced screening methods, such as CRISPR-Cas9, remains also essential to enhance the therapeutic potential of these drugs. DDRi have also demonstrated significant potential to chemo- and radiosensitize resistant tumors by impairing the repair of therapy-induced DNA lesions. By blocking key DDR proteins, these agents can enhance the cytotoxic effects of CTx or RT, leading to increased tumor cell death and improved clinical efficacy. Synergistic effects between DDRi and PARPi were also reported, but clear knowledge of optimal treatment schedules and factors producing distinct responses to these combinations is still missing. The identification of predictive biomarkers of response to DDRi (or the development of companion diagnostics) is also necessary to enable the stratification of patients in responders or non-responders, or to select those who may benefit the most from combination therapies. Additionally, resistance to other DDRi apart from PARPi, through different mechanisms including reversion mutations, epigenetic modification, stabilization of the replication fork and increased drug efflux, has also been reported and needs further research. The emergence of such resistance is often driven by clonal heterogeneity, needing more dynamic monitoring strategies such as liquid biopsy to monitor real-time SL dependencies. The successful application of novel DDR-based SL therapies also requires considering factors such as the zygosity of the target genetic alteration, its prevalence and role in a particular cancer, the potential on-target and off-target side effects (acute and long-term) resulting from the inhibition, the effect size and the penetrance of the SL interaction. An in-depth analysis of the synergistic effects and overlapping and/or cumulative toxicities from combination treatments should also be performed, as some clinical trials were terminated due to dose-limiting toxicities. SL is expected to evolve beyond genetic interactions into a contextual paradigm that will address additional tumor-specific conditions, such as metabolic SL, shaping the future of more precise and adaptive cancer therapies. Finally, while the vast majority of oncologic clinical trials focusing on SL target DDR, an increasing number of drugs in the clinical or preclinical setting inhibit non-DDR pathways for their use in a SL approach. These include inhibitors of metabolic enzymes (e.g., MAT2A, PRMT5), chromatin regulators (e.g., SMARCA4, SMARCA2, ALC1) or RNA helicases (e.g., DHX9), which suffer from the same limitations in their development as DDRi, including the requisite for robust patient-selection biomarkers and the identification of optimal combinatorial regimens with other oncologic drugs to prevent the emergence of resistance.
In conclusion, the growing interest in drugs targeting SL represents a revolutionary advancement in personalized cancer therapy, with drugs already approved that have reached important milestones and multiple others in the pipeline. These ongoing clinical trials explore SL interactions at different levels, which may broaden the arsenal of available effective cancer drugs, potentially offering tailored and potent treatments for cancer based on genetic profiling. Apart from the genetic interactions, the SL approach is expected to evolve into a more contextual paradigm that considers additional tumor-specific conditions, such as metabolic SL. This strategy holds potential to make a great impact on cancer treatment by offering highly specific therapies that selectively target cancer cells minimizing their effects over normal tissues, consequently providing more effective and less toxic treatments. However, continued research is essential to fully understand the intricate complexity of SL in the DDR context, maximize the therapeutic potential of SL-based therapies and discover additional druggable SL interactions.
Supplementary information
Supplementary Materials for: Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation
Acknowledgements
We would like to thank all financial institutions for supporting this study: the Spanish Ministry of Science, Innovation and Universities (PID2024-155624OB-I00 project financed by MICIU/AEI/10.13039/501100011033/FEDER/UE and Prueba de Concepto PDC2025-165867-I00 project financed by MICIU/AEI/10.13039/501100011033), the Autonomous Community of Catalonia (PI-G7180 HSP), the Instituto de Salud Carlos III (ISCIII) (ICI22/00076), the ICREA-Acadèmia program (Fundació Institut Català de Recerca i Estudis Avançats), the Agència de Gestió d’Ajuts Universitaris i de Recerca (2021-SGR-00835, 2023-2025), the Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) and the Fanconi Cancer Foundation. Figures were created with BioRender.com.
Author contributions
Cristina Camps-Fajol participated in the acquisition, analysis, visualization and writing of the data of the review article. Jordi Minguillón and Jordi Surrallés made substantial contributions to the conceptualization, design and revision of the work. All authors met authorship criteria, drafting the work or revising it critically for important intellectual content. All authors have read and approved the article.
Competing interests
Jordi Surrallés has signed agreements (advisory boards, service provision, research collaboration or material transfer) in the last 3 years with Boehringer Ingelheim, Glaxo Smith Kline, Moderna Therapeutics, Roche, Rocket Pharmaceuticals and Pfizer. Jordi Surrallés and Jordi Minguillón have a patent repurposing of afatinib issued to IR Sant Pau, UAB and CIBER. Cristina Camps-Fajol declares that she has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
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Supplementary information
The online version contains supplementary material available at https://doi.org/10.1038/s41392-026-02954-4.
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Supplementary Materials for: Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation