Therapeutic advances and application of PARP inhibitors in breast cancer

Highlights

• •Clinical Efficacy: Olaparib and talazoparib are more effective than chemotherapy in treating BRCA-mutated breast cancer, improving survival rates in both early and metastatic stages as per OlympiA, OlympiAD, and EMBRACA trials.
• •Mechanistic Novelty: PARP inhibitors induce synthetic lethality by trapping PARP-DNA complexes and disrupting LLPS, hindering DNA repair in HRD tumors.
• •Resistance & Solutions: HRR reactivation, reduced PARP trapping, and P-glycoprotein efflux cause resistance. Combinations with ATR, WEE1, or CDK1 inhibitors may help overcome this.
• •Guideline Support: Olaparib is globally recommended for high-risk early-stage and metastatic BRCA1/2-mutated HER2-negative breast cancer, while talazoparib's use is restricted in China.
• •Future Trends: Next-gen PARP1-selective inhibitors like AZD5305 aim to reduce hematologic toxicity, and combining PARPi with ADCs or immunotherapy shows potential beyond BRCA mutations.

Abstract

Targeting of DNA repair pathway is the main therapeutic approach for BRCA1 and BRCA2 associated tumors, including breast cancer. BRCA1/2 genes play a pivotal role in HRR pathway. Mutations in BRCA1/2 leads to DDR deficiency, which cause the increasing of genome instability, thus rendering cancer cells vulnerable to inhibition of DNA repair related proteins, such as PARP1. Pre-clinical studies has demonstrated that cancer cells with BRCA1/2 deficient are sensitive to PARPi, which are an emerging class of small molecule drug. Several clinical trials demonstrated the promising efficacy of PARP inhibitors for BRCA1/2 mutated breast cancer patient through selectively induce synthetic lethality cancer cells. Currently, four PARP inhibitors had been approved by FDA for clinical use. PARPi demonstrated to improve progression-free survival, while resistance to PARPi is inevitable. In this review article, we highlighted the advances in the PARPi clinical trials, resistance mechanism and coping strategies in breast cancer patients. We also summarized the international guideline and recommendations on PARP inhibitor usage in breast cancer.

Abbreviations: Poly (ADP-ribose) polymerase inhibitors, PARPi; triple-negative breast cancer, TNBC; homologous recombination repair, HRR; DNA damage repair, DDR; DNA double-strand breaks, DSBs; estrogen receptor-negative, ER-; estrogen receptor-positive, ER+; hormone receptor-positive, HR+; metastatic breast cancer, mBC; CDK4/6 inhibitor, CDK4/6i; HER2-amplified, HER2+; single-strand break, SSB; Food and Drug Administration, FDA; invasive disease-free survival, IDFS; distant disease-free survival, DDFS; overall survival, OS; pathologic complete response, pCR; event-free survival, EFS; median progression-free survival, mPFS; hazard ratio, HR; disease control rate, DCR; median response duration, DOR; objective response rate, ORR; germline BRCA-mutated, gBRCAm; homologous recombination deficiency, HRD; base excision repair, BER; single-strand breaks, SSBs; non-homologous end joining, NHEJ; liquid-liquid phase separation, LLPS; multidrug resistance, MDR; Ataxia telangiectasia and Rad3-related, ATR; P-glycoprotein, P-gp; ATP-binding cassette, ABC; myelodysplastic syndrome, MDS; acute myeloid leukemia, AML; complete blood count, CBC; next-generation sequencing, NGS; antibody-drug conjugates, ADCs; genomic instability scores, GIS; therapy-related myeloid neoplasms, t-MN.

Introduction

Breast cancer is the second prevalent malignancy among women in 2022, accounting for 2.3 million new cases (11.6 % of all cancers) globally. With 666,000 deaths (6.9 % of cancer-related fatalities), it ranked as the fourth leading cause of cancer mortality worldwide. Notably, breast cancer represented the most frequently diagnosed cancer and the leading cause of cancer death in women, dominating incidence patterns in 157 countries and mortality in 112 nations. These disparities highlight the urgent need for tailored prevention and therapeutic strategies across diverse populations [1].

Triple negative breast cancer (TNBC), a highly aggressive subtype, disproportionately affects younger women. Approximately 11.2 % of TNBC patients harbor pathogenic germline mutations in BRCA1 or BRCA2, genes critical to homologous recombination repair (HRR) [2]. In China, large-scale genomic analyses report an overall BRCA mutation frequency of 5.3 % in unselected breast cancer cohorts, with BRCA1 and BRCA2 mutations observed in 1.8 % and 3.5 % of patients, respectively; co-occurrence of both mutations is rare (0.04 %) [3]. Striking geographical disparities exist in DNA damage repair (DDR)-related gene alterations: while a U.S. study documented DDR mutations in 17.4 % of patients [4]. Chinese cohorts exhibit markedly higher rates (38.1 %), suggesting distinct genetic or environmental influences on tumorigenesis [5].

DNA double-strand breaks (DSBs), the most genotoxic form of DNA damage, engage robust cellular repair mechanisms. Among these, homologous recombination repair (HRR) stands out for its high fidelity, employing a network of proteins—including BRCA1 and BRCA2—to accurately restore genomic integrity. Mutations in BRCA1/2 compromise HRR, inducing homologous recombination deficiency (HRD), a state marked by defective DDR, genomic instability, and increased susceptibility to therapies targeting compensatory DDR pathways [6].

Tumor cells harboring germline BRCA1/2 mutations exhibit heightened sensitivity to PARPi. These small-molecule agents exploit synthetic lethality by trapping PARP enzymes at sites of single-strand DNA breaks, leading to replication fork collapse and apoptosis in HRD tumors [7,8]. This review comprehensively examines (i) molecular hallmarks of DDR-deficient breast cancer, (ii) clinical advances in PARP inhibitor therapy (including survival outcomes and adverse event profiles), (iii) mechanisms underpinning resistance, and (iv) evidence-based guideline recommendations for navigating therapeutic implementation.

Characteristics of DDR deficient breast cancer patients

Characteristics of BRCA-mutant breast cancer

Germline BRCA1/2 mutations confer distinctive clinicopathological features in breast carcinomas, distinguishing them from sporadic cases [9]. Patients with BRCA1-mutant tumors present at a younger median age (39.9 years) compared to BRCA2 carriers (42.8 years) [10]. These malignancies exhibit aggressive histopathological profiles: 77 % of BRCA1-associated and 50 % of BRCA2-associated tumors are classified as grade III. While HER2 overexpression is uncommon in both subtypes, hormonal receptor status diverges markedly. Approximately 60–90 % of BRCA1-mutant tumors are estrogen receptor negative (ER-) and align with basal-like molecular subtypes, whereas >75 % of BRCA2-mutant cancers are estrogen receptor positive (ER+), predominantly luminal [11].

At the molecular level, BRCA1-deficient tumors frequently harbor somatic alterations, including TP53 mutations, PTEN loss, c-MYC amplification, and EGFR overexpression [9]. Clinically, BRCA1/2-mutant cancers demonstrate heightened sensitivity to platinum-based chemotherapy in both neoadjuvant and metastatic settings. However, real-world evidence from the CARES study reveals that patients with HER2-negative, Hormone receptor positive(HR+) metastatic breast cancer (mBC) harboring BRCA mutations experience significantly shorter time to first subsequent therapy following CDK4/6 inhibitor (CDK4/6i) treatment compared to wild-type or unselected cohorts [12], suggesting potential resistance mechanisms in this subset.

These findings underscore the prognostic and therapeutic implications of BRCA mutational status, advocating for molecular-driven stratification to optimize regimens such as platinum therapies while highlighting the need for alternative strategies in CDK4/6i-treated HR+ BRCA-mutant mBC.

Characteristics of non-BRCA-mutant DDR deficient breast cancer

Beyond BRCA1/2 mutations, DDR-deficient breast carcinomas are predominantly associated with pathogenic variants in PALB2 and CHEK2. While these tumors frequently demonstrate sensitivity to endocrine therapies, HRR deficiency is less prevalent in HR+ and HER2-amplified (HER2+) tumors [9,13,14]. Notably, TNBC exhibit high rates of HRR defects. A subset of sporadic TNBCs displays BRCAness – a phenotypic and molecular mimicry of BRCA1-mutant tumors characterized by functional HRR impairment despite lacking germline mutations - often through diminished BRCA1 expression via epigenetic silencing or somatic alterations. This observation raises critical questions about whether such sporadic BRCA1 loss confers therapeutic vulnerabilities comparable to canonical BRCA1 mutations [9,15].

Clinical advances in PARP inhibitors for breast cancer therapy

PARP inhibitors exploit synthetic lethality by targeting PARP, a critical enzyme in single-strand break (SSB) repair via the base excision repair pathway. PARP inhibition traps PARP-DNA complexes, stalling replication forks and converting unrepaired SSBs into DSBs during DNA replication. In tumors with HRR deficiencies—such as those harboring BRCA1/2 mutations—the inability to resolve DSBs through error-free HRR drives genomic instability and apoptosis [16,17].

Olaparib, the first-in-class PARP inhibitor, has gained Food and Drug Administration (FDA) approval for BRCA1/2-mutant breast cancers, demonstrating clinically significant efficacy as monotherapy and in combinatorial regimens [18]. This milestone underscores the translational success of synthetic lethality strategies, establishing PARP inhibition as a paradigm-shifting therapeutic approach for DDR-deficient malignancies.

PARP inhibitors in BRCA-mutant early breast cancer

Olaparib

The phase III OlympiA trial [8] —a randomized, double-blind study—evaluated adjuvant olaparib in patients with germline BRCA1/2-mutated, HER2-negative, high-risk early breast cancer. At initial analysis, olaparib significantly improved three-year invasive disease-free survival (IDFS: 85.9 % vs. 77.1 %; HR 0.58, 99.5 % CI 0.41–0.82; P < 0.001) and distant disease-free survival (DDFS: 87.5 % vs. 80.4 %; HR 0.57, 99.5 % CI 0.39–0.83; P < 0.001) compared to placebo. Extended follow-up revealed a sustained overall survival (OS) benefit, with a 32 % reduction in mortality risk at four years (OS: 89.8 % vs. 86.4 %; HR 0.68, 99 % CI 0.47–0.97; P = 0.009). Updated findings presented at the 2024 San Antonio Breast Cancer Symposium (median follow-up: 6.1 years) further demonstrated a 28 % mortality risk reduction (hazard ratio [HR] 0.72, 95 % CI 0.56–0.93), with 87.5 % of olaparib-treated patients surviving versus 83.2 % in the placebo arm.

Olaparib remains the first PARP inhibitor to demonstrate a definitive OS advantage in a global phase III trial for high-risk, HER2-negative, early-stage BRCA-mutant breast cancer. It is approved in the US, EU, Japan, and multiple regions for adjuvant treatment following neoadjuvant or adjuvant chemotherapy in this population.

Veliparib

The phase III BrighTNess trial (NCT02032277) [19] evaluated neoadjuvant carboplatin/paclitaxel with or without veliparib in TNBC. Despite preliminary activity, veliparib failed to significantly improve pathologic complete response (pCR) rates compared to carboplatin/paclitaxel alone (53 % vs. 58 %, P = 0.36). Long-term follow-up further revealed no statistically significant benefit in event-free survival (EFS) or OS with the veliparib combination, underscoring its limited therapeutic value in this setting [20].

Based on the above study evidence, olaparib adjuvant therapy is recommended for early-stage, high-risk, HER2- breast cancer patients with germline BRCA1/2 mutations (class I recommendation). Other PARP inhibitors for the treatment of early - stage breast cancer are not currently accessible. Current clinical trials for PARP inhibitors in early - stage breast cancer are summarized in Table 1.

Table 1.

Ongoing clinical trials of PARPi for early breast cancer.

PARPi	Trial No	Study stage	Target population	Stage	Intervention protocol	Study status	Estimated completion time
Olaparib	NCT03150576	Ⅲ	TNBC and/or gBRCAm	Neoadjuvant	Olaprib+CTx vs CTx	Recruiting	2024
	NCT05498155	Ⅱ	HER2- BC with gBRCAm	Neoadjuvant	Olaprib+Durvalumab	Recruiting	2024
	NCT03740893	Ⅱ	NACT resistant residual TNBC	Adjuvant	Olaprib+Durvalumab	Recruiting	2025
Niraparib	NCT04915755	Ⅲ	HER2- BC with gBRCAm or TNBC without BRCAm	Adjuvant	Niraparib vs Placebo	Active	2025
Fluzoparib	NCT05891093	Ⅲ	HR+/HER2- SNF3-subtype	Adjuvant	Fluzoparib+Endocrine Therapy vs Endocrine Therapy	Recruiting	2028

Note: gBRCAm, germline BRCA mutation;.

PARP inhibitors for BRCA-mutant advanced breast cancer

Olaparib

The phase III OlympiAD trial [18,21]—an international, randomized, open-label study—compared olaparib monotherapy with physician’s choice chemotherapy (TPC: capecitabine, eribulin, or vinorelbine in 21-day cycles) in patients with germline BRCA1/2-mutated, HER2-negative metastatic breast cancer. Olaparib reduced the risk of progression or death by 42 % versus TPC (median progression-free survival [mPFS]: 7.0 vs. 4.2 months; HR 0.58, 95 % CI 0.43–0.80; P < 0.001).

Subgroup analyses revealed consistent benefit across TNBC and HR+ cohorts, with the largest mPFS improvement observed in TNBC (HR 0.43, 95 % CI 0.29–0.63). In patients receiving first-line metastatic treatment, olaparib was associated with a median OS of 22.6 months versus 14.7 months with TPC (HR 0.51, 95 % CI 0.29–0.90).

OlympiAD represents the first head-to-head comparison of a PARP inhibitor versus standard chemotherapy in BRCA-mutant advanced breast cancer, establishing olaparib as a clinically meaningful option for HER2-negative metastatic disease with germline BRCA1/2 alterations.

The phase II MEDIOLA trial (NCT02734004) [22] evaluated olaparib combined with the PD-L1 inhibitor durvalumab in germline BRCA1/2-mutated, HER2-negative advanced breast cancer patients previously treated with ≤2 lines of chemotherapy and naïve to PARP/immune checkpoint inhibitors. Patients received olaparib monotherapy for 4 weeks, followed by olaparib plus durvalumab until progression. At 12 weeks, the combination achieved a disease control rate (DCR) of 80 % (90 % CI: 64.3–90.9), with median response duration (DOR) of 9.2 months and mPFS of 8.2 months.

While these results highlight potential synergies between PARP inhibition and immunotherapy, the study’s non-comparative design precludes definitive conclusions. Randomized trials are warranted to (i) identify predictive biomarkers and (ii) evaluate whether combination therapy outperforms olaparib monotherapy in long-term outcomes.

Talazoparib

The phase III EMBRACA trial [23] evaluated talazoparib versus physician’s choice chemotherapy (TPC: capecitabine, eribulin, or vinorelbine) in patients with germline BRCA1/2-mutated advanced breast cancer—including TNBC and HER2-/HR+ subtypes—who had received ≤3 prior lines of therapy. Talazoparib significantly reduced the risk of disease progression or death by 46 % (mPFS: 8.6 vs. 5.6 months; HR 0.54, 95 % CI 0.41–0.71; P < 0.001). Despite this, no statistically significant OS difference was observed (OS: 22.3 vs. 16.3 months; HR 0.76, 95 % CI 0.55–1.06; P = 0.11).

Consistent with the OlympiAD trial, EMBRACA confirmed PARP inhibitor superiority in PFS over chemotherapy for BRCA-mutant advanced breast cancer, securing talazoparib a Category 1 recommendation in NCCN guidelines [24]. However, regulatory approval barriers currently restrict talazoparib access in China.

Niraparib

The phase III BRAVO trial [25] evaluated niraparib monotherapy versus chemotherapy TPC in patients with gBRCA1/2-mutated HER2-negative advanced breast cancer who had received ≤2 prior chemotherapy lines. Niraparib failed to significantly PFS or OS compared to TPC. In contrast, the phase II TOPACIO/KEYNOTE-162 trial demonstrated clinical activity for niraparib combined with pembrolizumab in advanced triple-negative breast cancer (TNBC), including pretreated (1st–3rd line) patients. The combination achieved an objective response rate (ORR) of 18 % in the overall population, with higher remission rates in biomarker-selected subgroups: 47 % (BRCA-mutant) versus 11 % (BRCA wild-type) and 40 % (HRR-deficient) versus 9 % (HRR-proficient).

These findings suggest potential synergy between PARP inhibition and anti-PD-1 therapy in TNBC, particularly within BRCA/HRR-mutant subsets. However, BRAVO underscores the need for biomarker-driven patient selection and further validation in randomized trials.

Other PARP inhibitors

Beyond olaparib and talazoparib, veliparib has also been explored in BRCA-mutant advanced breast cancer. The phase III BROCADE3 trial [26] assessed veliparib combined with carboplatin/paclitaxel in BRCA-mutant, HER2-negative advanced breast cancer patients with ≤2 prior chemotherapy lines. Veliparib reduced the risk of progression or death by 29 % versus placebo (mPFS: 14.5 vs. 12.6 months; HR 0.71, 95 % CI 0.57–0.88; P = 0.0016), with enhanced PFS benefits observed in first-line therapy subgroups. However, confirmation of long-term survival benefits requires further investigation [26].

Based on the above collective study evidence on multiple PARP inhibitors, single - drug olaparib is recommended for germline BRCA - mutated (gBRCAm), HER2 - negative advanced breast cancer (class I recommendation). For other PARP inhibitors, either insufficient evidence on drug efficacy or associated problems with drug accessibility limit their usage in China. Table 2 summarizes several ongoing clinical trials of PARPi combinations for advanced or metastatic breast cancer.

Table 2.

Ongoing clinical trials of PARPi combination for advanced breast cancer.

PARPi	Trial No	Study stage	Target population	Intervention protocol	Study status	Initiator	Estimated completion time
Olaparib	NCT05033756	Ⅱ	HER2- BC with HRD	Olaparib+Pembrolizumab	Recruiting	MSD	2024
	NCT04053322	Ⅱ	ER+/HER2- BC with HRRm	Durvalumab+Olaparib+Fulvestrant	Active	UNICANCER	2027
	NCT02849496	Ⅱ	HER2- BC with BRCAm	Olaparib+Atezolizumab	Active	NCI	2024
Talazoparib	NCT03964532	I/Ⅱ	advanced breast cancer	Talazoparib+Avelumab	Active	Georgetown University	2024
	NCT04039230	I/Ⅱ	advanced breast cancer	Talazoparib+Sacituzumab Govitecan	Recruiting	Massachusetts General Hospital	2024
Niraparib	NCT06201234	Ⅱ	HR+/HER2- BC	Niraparib+Elacestrant	Recruiting	German Breast Group	2028
	NCT04508803	Ⅱ	HER2-breast cancer with HRRm	Niraparib+HX008	Recruiting	Fudan University	2024
Veliparib	NCT02158507	Ⅱ	TNBC	Veliparib+ Lapatinib	Active	University of Alabama at Birmingham	2024
Fluzoparib	NCT04296370	Ⅲ	HER2 -breast cancer with gBRCAm	Fluzoparib+apatinib vs. fluzoparib vs. physician’s choice	Recruiting	Jiangsu Hengrui	2025
	NCT04355858	Ⅱ	TNBC with gBRCAm	Fluzoparib+CDK4/6 inhibitor	Recruiting	Fudan University	2025

Note: gBRCAm, germline BRCA mutation; CDK4/6 inhibitor, cyclin-dependent kinase 4/6 inhibitor.

PARP inhibitors in patients with DDR mutation (non-gBRCA mutation)

TBCRC 048 study

The phase II TBCRC 048 trial [27] evaluated olaparib in advanced breast cancer patients with non-germline BRCA DDR mutations. Olaparib achieved an ORR of 82 % and mPFS of 13.3 months. Among patients with somatic BRCA1/2 mutations, ORR was 50 %, suggesting activity in this subset. Although promising, subsequent randomized validation is required to confirm efficacy in non-gBRCA DDR-deficient populations.

CHANGEABLE trial

The single-arm phase II CHANGEABLE study assessed niraparib combined with the PD-1 inhibitor HX008 in metastatic HER2-negative breast cancer patients with germline DDR mutations (BRCA1/2, PALB2, or CHEK2). Preliminary data demonstrated 71 % ORR (22/31 patients), including 3 complete responses, and mPFS of 7.3 months. Survival outcomes (OS) remain immature [28].

Mechanism of PARPi in the treatment of HRD tumors

PARPi exert synthetic lethality in homologous recombination deficiency (HRD) tumors through dual mechanistic actions. In normal cells, PARP1/2-mediated base excision repair (BER) resolves single-strand breaks (SSBs), while BRCA1/2-dependent HRR provides backup protection for replication-associated DSBs [29]. HRD tumors (e.g., BRCA1/2-mutated) lose this repair redundancy: PARPi not only catalytically inhibit PARP auto-PARylation to block SSB repair, but also "trap" PARP-DNA complexes that physically impede replication fork progression. This dual assault generates catastrophic DSBs that overwhelm error-prone non-homologous end joining (NHEJ) repair, driving lethal genomic instability through chromothripsis and micronucleus formation(See Fig. 1) [[30], [31], [32], [33], [34], [35]].

Fig. 1.

Synthetic lethality mediated by PARP inhibition in HRD tumor cells.

Recent studies reveal that PARP1 undergoes liquid-liquid phase separation (LLPS) upon DNA damage, forming dynamic condensates that recruit repair factors (e.g., XRCC1, DNA-PK) to the sites of damage [36,37]. This LLPS-driven compartmentalization enhances repair efficiency by concentrating repair proteins in a localized microenvironment, facilitating efficient DNA repair. However, PARPi not only inhibit the catalytic activity of PARP but also disrupt the phase separation process by altering PARylation patterns. This disruption prevents the proper assembly of repair complexes at damage sites, thus exacerbating replication stress in HRD tumors and contributing to the accumulation of lethal DNA lesions [38].

The therapeutic window arises from differential repair capacity: normal cells retain intact phase separation mechanisms, allowing efficient DNA repair, whereas HRD tumors exhibit "LLPS fragility" under PARPi treatment. This fragility leads to impaired repair and the accumulation of unresolved DSBs, driving genomic instability. Clinically, this mechanism extends beyond BRCA mutations to tumors with epigenetic HR silencing (e.g., BRCA1 promoter methylation) or upstream DDR defects (e.g., ATM loss). Rational combinations with platinum chemotherapeutics further amplify DSB burden, demonstrating synergistic efficacy in HRD contexts while sparing normal tissues through spatial-temporal modulation of DNA damage delivery.

Mechanism and coping strategies of PARP inhibitor resistance

Possible mechanisms of drug resistance

The clinical utility of PARPi is constrained by multiple resistance mechanisms: (1) Reactivation of HRR capacity through BRCA1/2 reversion mutations, epigenetic reprogramming, or compensatory DNA repair pathway activation; (2) Stabilization of replication forks via upregulation of protective factors (e.g., EZH2, PTIP) that mitigate replication stress and promote tumor survival; (3) Compromised PARP-1 trapping efficiency caused by reduced chromatin-binding affinity (e.g., PARP1 R591C mutations), thereby diminishing cytotoxic PARP-DNA complex formation; and (4) Enhanced drug efflux mediated by multidrug resistance transporters (e.g., P-glycoprotein), which significantly reduces intracellular PARPi retention. These adaptive responses collectively undermine therapeutic efficacy through distinct molecular pathways (See Fig. 2) [39,40].

Fig. 2.

Overview of PARP inhibitor resistance mechanism (Adapted from:Kim DS, et al. Exp Mol Med. 2021 Jan.).

HRR recovery

HRR pathway restoration is a cardinal driver of resistance to PARPi. In tumors with germline BRCA1/2 mutations, secondary intragenic mutations or frameshift reversions in BRCA1/2 can restore functional open reading frames, enabling proficient HRR. Similar genetic reversion events occur in other HRR-related genes, such as RAD51C, RAD51D, and PALB2, reinstating DNA repair capacity and conferring PARPi resistance [39,41,42]. Epigenetic alterations, including BRCA1 promoter demethylation, further rescue HRR activity, offering an alternative route to bypass synthetic lethality [43].

A distinct but complementary mechanism involves loss of 53BP1 or its associated resection antagonists (e.g., RIF1, REV7, shieldin). In BRCA1-deficient cells, 53BP1 suppresses homologous recombination by blocking DNA end resection. Depletion of 53BP1 restores resection activity, allowing HRR-mediated repair to proceed in the absence of BRCA1, thereby rescuing cell viability under PARPi pressure [44].

The Ataxia telangiectasia and Rad3-related (ATR) signaling also plays a pivotal role in HRR recovery. By stabilizing replication forks and enforcing cell cycle checkpoints during DNA damage, ATR facilitates error-free repair of PARPi-induced lesions [45]. Preclinical studies highlight that ATR inhibitors (e.g., cerelasertib) synergize with PARPis to overcome HRR-dependent resistance in BRCA-mutant triple-negative breast cancer [46], offering a promising therapeutic strategy.

Attenuation of PARPi capture function

PARPi efficacy critically depends on their ability to trap PARP-1 onto damaged DNA, forming cytotoxic PARP-DNA complexes. The weakening of this trapping function represents a key resistance mechanism. For instance, the PARP1 R591C mutation reduces PARP-1 chromatin binding, impairing complex formation and conferring therapeutic resistance [40]. Similarly, decreased PARP-1 expression diminishes PARPi-induced DNA damage persistence, as observed in veliparib-resistant tumors where PARP1 protein levels are markedly downregulated [47]. These findings collectively highlight that both structural alterations in PARP-1 and its quantitative depletion undermine PARPi efficacy by attenuating DNA trapping, necessitating strategies to restore or bypass impaired PARP-1 engagement.

P-glycoprotein-mediated drug efflux

P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) transporter, drives PARP inhibitor resistance by actively effluxing drugs from tumor cells, reducing intracellular concentrations below therapeutic thresholds [48]. Notably, talazoparib—a potent PARP trapper—exhibits susceptibility to P-gp-mediated efflux, correlating with reduced efficacy in ABCB1-overexpressing models [49]. Conversely, olaparib and niraparib demonstrate lower P-gp substrate affinity, suggesting drug-specific vulnerability to this mechanism [50]. To counteract efflux-driven resistance, the co-administration of P-gp inhibitors, such as elacridar and tariquidar, has been shown to increase intracellular PARPi levels and re-sensitize resistant tumors in preclinical studies [51]. However, clinical translation requires careful evaluation of toxicity from broad-spectrum ABCB1 inhibition.

Other mechanisms of drug resistance include: changes in cell cycle control and miRNA expression, epigenetic modification, abnormalities in related signal pathways, reverse mutations, repair of ADP-ribosylation and pharmacological changes [40,52].

Coping strategies for PARP inhibitor resistance

To counteract PARPi resistance, combinatorial therapeutic approaches targeting distinct molecular vulnerabilities are under investigation. Given that HRR restoration is a primary resistance mechanism, agents such as 6-thioguanine (inducing synthetic lethality in BRCA2-defective PARPi-resistant tumors) combined with cisplatin have shown efficacy in resensitizing HR-proficient tumors to PARPi. Additionally, strategies combining PARPi with targeted therapies or immunomodulators address diverse resistance pathways [40,50,52]. Key preclinical combination approaches include:(i)HSP90 Inhibitors: Disrupt HR-mediated repair by destabilizing nuclear BRCA1/2 and RAD51, thereby suppressing DSB resolution [51].(ii)MET Inhibitors: Amplify PARPi-induced DNA damage by increasing unresolved DSBs through dysregulated repair signaling [53].(iii)WEE1 Inhibitors: Exacerbate replication stress via nucleotide depletion and potentiate PARP trapping, driving mitotic catastrophe in HR-deficient cells [54].(iv)CDK1 Inhibitors: Impair HR by blocking CDK1-mediated phosphorylation of BRCA1, critical for its DNA repair function [55].

These strategies highlight the potential of rational drug combinations to bypass resistance mechanisms. Clinical validation is ongoing to determine optimal dosing, biomarker selection, and therapeutic windows for these regimens.

Applicable population and treatment recommendations of PARP inhibitors in breast cancer

Guidelines and recommendations at home and abroad (See Table 3)

Table 3.

Guidelines for PARP inhibitors in breast cancer.

	Guideline	Disease stage	Recommendations of PARP inhibitors
1	NCCN guidelines for breast cancer diagnosis and treatment (2025 v2 Edition) [56]	early stage	Adjuvant olaparib therapy is recommended for patients with HER2 negative breast cancer who are eligible for OlympiA study
		advanced	gBRCA1/2-mutant advanced breast cancer patients, prefer olaparib, talazoparib
2	ASCO guidelines for hereditary breast cancer (2023 Edition)[57,58]	early stage	Patients with HER2 negative breast cancer who are eligible for OlympiA study, recommend olaparib adjuvant therapy for 1 years
		advanced	BRCA1/2-mutant metastatic HER2 negative breast cancer patients, recommend olaparib or talazoparib instead of chemotherapy for 1–3 line therapy
3	St Gallen consensus (2023 Edition)[59]	early stage	93 % experts recommend olaparib adjuvant therapy for HER2 negative breast cancer patients who met the OlympiA study
4	Guidelines and specifications for breast cancer diagnosis and treatment by China Cancer Association (2025 Edition)[60]	early stage	Patients with HER2 negative breast cancer who are eligible for OlympiA study, recommend olaparib adjuvant therapy for 1 years
		advanced	BRCA1/2-mutant advanced breast cancer patients, prefer PARP inhibitors (olaparib, talazoparib) or platinum therapy
5	CSCO guidelines for breast cancer diagnosis and treatment (2024 Edition) [61]	early stage	Patients with triple negative breast cancer who are eligible for OlympiA study, recommend olaparib adjuvant therapy for 1 years
		advanced	Recommend olaparib for BRCA1/2-mutant advanced TNBC patients who failed anthracycline treatment

Note: patients eligible for OlympiA study: gBRCA1/2-mutant, received local treatment and neoadjuvant/adjuvant chemotherapy, with high-risk clinical pathological factors, HER2 negative early breast cancer patients. High-risk clinicopathological factors: TNBC patients who did not achieve pCR after neoadjuvant therapy and had large tumor (≥pT2) or lymph node metastasis (≥pN1) after adjuvant therapy; or hormone receptor positive HER2 negative patients who did not achieve pCR after neoadjuvant therapy and CPS+EG score (comprehensive clinical stage, pathological stage, estrogen receptor status, tumor grade score) ≥3, and ≥pN2 after adjuvant therapy.

Approved indications

Olaparib: In 2018, the FDA approved olaparib for patients with germline BRCA1/2 pathogenic/likely pathogenic variants and HER2-negative metastatic breast cancer progressing after prior neoadjuvant, adjuvant, or metastatic chemotherapy. For HR+ disease, eligibility requires prior endocrine therapy or documentation of endocrine therapy ineligibility [62].

Talazoparib: Concurrently, talazoparib received FDA approval for germline BRCA1/2-mutated advanced or metastatic HER2-negative breast cancer, irrespective of hormone receptor status [63].

Early-Stage Expansion: Based on the phase III OlympiA trial, the FDA expanded olaparib’s indication in March 2022 to include adjuvant therapy for high-risk, HER2-negative early breast cancer with germline BRCA1/2 mutations, following completion of neoadjuvant or adjuvant chemotherapy [64,65].

Usage and dosage

Olaparib tablet specifications: 150 mg and 100 mg, the recommended dose is 300 mg, twice a day, and the total daily dose is 600 mg. It can be taken orally, with meals or on an empty stomach. For adjuvant treatment, Olaparib should be taken for 1 year. For metastatic stage, treatment until disease progression or intolerable toxicity [64].

Talazoparib specifications: 0.25 mg, 0.5 mg, 0.75 mg and 1 mg. The recommended dose is 1 mg, once a day. It can be taken orally, with meals or on an empty stomach. Treatment should continue until disease progression or intolerable toxicity [62].

Adverse reactions

Hematological toxicities

PARP inhibitor therapy is associated with predominantly hematological toxicities, including anemia, thrombocytopenia, and neutropenia. Although most events are low-grade (CTCAE grade 1–2) [21], these cytopenias correlate mechanistically with PARP-DNA trapping and typically manifest within the first 3 months of treatment, resolving spontaneously in most cases. To mitigate delayed hematotoxicity risks—notably myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)—strict monitoring protocols are recommended: weekly complete blood count (CBC) during the first month, monthly CBC for 11 subsequent months, and periodic assessments thereafter [66].

Patients developing refractory cytopenias should be promptly referred to hematology for multidisciplinary evaluation. MDS, characterized by gradual-onset cytopenias (e.g., refractory anemia in low-risk cases), and AML, presenting acutely with infection, bleeding, or fatigue, require integrated diagnostic workflows:(i)Morphological assessment: Bone marrow/peripheral blood smear analysis.(ii)Immunophenotyping: Flow cytometry to detect aberrant blast populations.(iii)Molecular profiling: Cytogenetic karyotyping and next-generation sequencing (NGS) for mutations in TP53, ASXL1, or fusion genes.

Notably, >90 % of PARPi-related MDS/AML cases occur in patients with prior genotoxic exposures (platinum-based chemotherapy, radiotherapy) and emerge within 2 years of PARPi initiation [66]. Unexplained or persistent cytopenias warrant immediate PARPi discontinuation, bone marrow biopsy, and hematology-led management to differentiate treatment-emergent MDS/AML from reversible myelosuppression.

Non-Hematological toxicities

Non-hematological adverse events, including gastrointestinal disturbances (nausea, vomiting), neurological symptoms (headache, insomnia), and cardiovascular effects (hypertension, palpitations), have been reported with PARP inhibitor use. These toxicities typically emerge within 4–8 weeks of treatment initiation and rarely necessitate therapy discontinuation [67]. Notably, insomnia and headache require differential diagnosis to exclude central nervous system metastases or endocrine dysfunction. Cognitive-behavioral interventions and sleep hygiene education, guided by specialists, are recommended for refractory cases. Cardiovascular toxicities, particularly hypertension and tachycardia, are most prevalent with niraparib and necessitate routine blood pressure and heart rate monitoring. ACE inhibitors remain the preferred antihypertensive therapy due to their safety profile in oncology populations [67].

Next-Generation PARP inhibitors

Current FDA-approved PARP inhibitors (olaparib, talazoparib, niraparib) non-selectively inhibit PARP1 and PARP2. The role of PARP2 in hematopoiesis exacerbates bone marrow suppression, contributing to dose-limiting cytopenias [68]. To address this limitation, AZD5305, a novel PARP1-selective inhibitor, was developed to minimize hematological toxicity while enhancing target engagement. In the first-in-human PETRA trial, AZD5305 demonstrated superior tolerability and sustained PARP1 occupancy compared to conventional PARP inhibitors [69]. Preclinical studies further reveal synergistic activity between AZD5305 and antibody-drug conjugates (ADCs)—notably the HER2-directed trastuzumab deruxtecan [70] and TROP2-targeting datopotamab deruxtecan [71]—highlighting its potential in combinatorial regimens. Early-phase clinical trials are actively evaluating these combinations.

Conclusions and future perspectives

The clinical integration of PARPi represents a paradigm shift in managing BRCA1/2-mutated, HER2-negative advanced breast cancer, as evidenced by landmark trials such as OlympiAD (olaparib) and EMBRACA (talazoparib). These agents have established synthetic lethality in HRD beyond germline BRCA mutations, with growing evidence supporting their activity in tumors harboring somatic BRCA alterations or defects in other HRR-associated genes (e.g., PALB2, RAD51C/D) [18,23]. However, their broader application in sporadic HRD cancers requires refined biomarker validation, particularly through harmonized assays for genomic instability scores (GIS) or functional HRD testing, to avoid the pitfalls of tumor-agnostic approvals [8].

Resistance driven by HRR restoration (e.g., BRCA1/2 reversion mutations, 53BP1 loss) or PARP-1 trapping attenuation remains a critical barrier [40,44]. Strategic combinations—such as PARPi with ATR inhibitors (e.g., cerelasertib) to target replication stress or PD-1/L1 inhibitors to augment immunogenicity—show preclinical promise in overcoming intrinsic and acquired resistance [45,70]. The recent success of adjuvant olaparib in the OlympiA trial underscores the potential of extending PARPi use to early-stage, high-risk HRD populations, though long-term surveillance for therapy-related myeloid neoplasms (t-MN) remains imperative [8,66].

Future efforts must prioritize three axes:

(i)Precision Targeting: Develop next-generation selective PARP1 inhibitors (e.g., AZD5305) to mitigate hematological toxicity while enhancing combinatorial efficacy with ADCs like trastuzumab deruxtecan [69,70].

(ii)Dynamic Biomarker Integration: Leverage ctDNA monitoring to detect emergent resistance mechanisms (e.g., BRCA reversions) and guide adaptive therapy.

(iii)Global Accessibility: Address disparities in PARPi availability, particularly in regions like China where regulatory approvals lag despite NCCN guideline endorsements [64].

By anchoring clinical development to mechanistic insights and real-world heterogeneity, PARPi may evolve from BRCA-centric therapies to backbone agents in the HRD oncotherapeutic arsenal.

CRediT authorship contribution statement

Teng Zhou: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Jian Zhang: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no conflicts of interest to disclose. All authors have contributed to the research and manuscript preparation without any financial or personal relationships that could inappropriately influence or bias the content of this work.