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. Author manuscript; available in PMC: 2024 Nov 1.
Published in final edited form as: Cancer Treat Rev. 2023 Sep 9;120:102623. doi: 10.1016/j.ctrv.2023.102623

Efficacy and Safety of PARP inhibitors in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-analysis of Clinical Trials

Giovanni Maria Iannantuono 1,2, Elias Chandran 1, Charalampos S Floudas 3, Hyoyoung Choo-Wosoba 4, Gisela Butera 5, Mario Roselli 2, James L Gulley 3, Fatima Karzai 1
PMCID: PMC10591840  NIHMSID: NIHMS1931913  PMID: 37716332

Abstract

Introduction:

PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have shown the potential of combining PARPi with other anticancer agents. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer.

Methods:

MEDLINE, Cochrane CENTRAL, EMBASE, CINAHL, and Web of Science were searched on March 22nd, 2023, for phase 2 or 3 clinical trials. Efficacy (progression-free survival [PFS], overall survival [OS], PSA decline >50% [PSA50], and objective response rate [ORR]) and safety outcomes were assessed in the included studies.

Results:

Seventeen clinical trials (PARPi monotherapy [n=7], PARPi + androgen-receptor signaling inhibitors [ARSI] [n=6], and PARPi + immune checkpoint inhibitors [ICI] [n=4]) were included in the quantitative analyses. PARPi monotherapy improved radiographic PFS and OS over SoC in mCRPC patients with alterations in BRCA1 or BRCA2 genes but not in those with alterations in the ATM gene. Higher rates of PSA50 and ORR were reported in participants treated with PARPi + ARSI than in single-agent PARPi or PARPi + ICI. Although the rate of high-grade adverse events was similar across all groups, treatment discontinuation was higher in patients treated with PARPi-based combinations than PARPi monotherapy.

Conclusion:

The efficacy of PARPi is not uniform across mCRPC patients with alterations in DNA damage repair genes, and optimal patient selection remains a clinical challenge. No unexpected safety signals for this class of agents emerged from this analysis.

Keywords: PARP inhibitors, Prostate cancer, Efficacy, Safety, Systematic review, Meta-analysis

1. INTRODUCTION

1.1. Rationale

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths among men in the United States, with an estimated 288,300 new cases and 34,700 deaths in 2023 [1]. Over the last decade, the landscape of treatments has changed significantly with the approval of several agents that improve overall survival in patients with metastatic prostate cancer, including androgen-receptor signaling inhibitors (ARSI) (abiraterone acetate [2], enzalutamide [3], apalutamide [4], and darolutamide [5]), and radioligand therapies (radium-223 [6] and 177Lu-PSMA-617 [7]). As precision medicine evolves, increasing knowledge in the molecular characterization of this disease has led to the discovery of distinct subtypes of prostate cancer and the identification of genomic alterations predictive of response to specific treatment options [8,9].

In this context, the significant prevalence of alterations in the genes involved in DNA damage repair (DDR), especially in the homologous recombination repair (HRR) pathway, has provided the scientific rationale for the use of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in prostate cancer [10,11]. The mechanism of action of PARPi is based on synthetic lethality. PARP is a large family of different proteins, including PARP1 and PARP2, which are involved in DNA repair [12]. PARP1 is responsible for recruiting proteins involved in the DNA single-strand breaks (SSBs) repair. When PARP1 is deficient, the SSBs are converted to double-strand repair (DSBs) during DNA replication [10]. In normal cells, the occurrence of DSBs activates the HRR pathway, leading to the resolution of DSBs. In cancer cells harboring HRR deficiency (HRD), the administration of a PARPi will eventually lead to the accumulation of DSBs and cell death [10]. Furthermore, PARPi exert their anticancer effect by “trapping” PARP1 and PARP2 to the sites of damaged DNA, resulting in the prevention of DNA repair, replication, and transcription [13].

Thus far, two PARPi have been approved as monotherapy by the U.S. Food and Drug Administration (FDA) for metastatic castration-resistant prostate cancer (mCRPC) patients: olaparib and rucaparib [14,15]. The former was approved in 2020 for mCRPC patients with genomic alterations in specific HRR genes who progressed after ARSI therapy, based on the results of the PROfound study [16]. The latter was granted accelerated approval for mCRPC patients harboring genomic alterations in the BRCA1 or BRCA2 genes and previously treated with ARSI and taxane-based chemotherapy based on the results of the TRITON2 study [17]. In May 2023, the FDA approved for the first time a PARPi-based combination for mCRPC (olaparib with abiraterone and prednisone) as first-line treatment in BRCA-mutated mCRPC patients [18], following the results of the PROpel study [19]. Additionally, further combination therapies were subsequently approved for mCRPC patients: talazoparib with enzalutamide for HRR gene-mutated mCRPC [20] based on the results of the TALAPRO-2 study, [21] and the combination of niraparib with abiraterone plus prednisone for BRCA-mutated mCRPC [22] following the results of the MAGNITUDE trial [23].

Beyond these approvals, further clinical trials are currently investigating the activity of novel PARPi as monotherapy or in combination with other agents, paving the way for promising new strategies in patients with metastatic prostate cancer [24]. In this rapidly evolving landscape, we aimed to conduct a systematic review and meta-analysis of the clinical trials that investigated PARPi in patients with metastatic prostate cancer to provide a comprehensive and updated evaluation of their efficacy and toxicity profile in this population.

2. Methods

This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Supplementary Material A1) [25]. The study protocol was approved a priori by all the authors and registered on PROSPERO (registration number: CRD42023409029).

2.1. Search strategy and eligibility criteria

A comprehensive search was performed in the following five electronic databases: MEDLINE (via PubMed), CENTRAL (The Cochrane Central Register of Controlled Trials), Embase, CINAHL (The Cumulative Index to Nursing and Allied Health Literature), and Web of Science (Core Collection). The search was conducted from the database inception to March 22nd, 2023, to identify all relevant publications and limited to the English language. The search strategies were developed by a National Institute of Health librarian (GB) in accordance with two authors (GMI and FK). Full details of the adopted search strategies are reported in Supplementary Material A2.

The eligibility criteria included interventional clinical trials involving patients with metastatic prostate cancer treated with PARPi as monotherapy or combined treatment. Both phase 2 or 3 clinical trials (randomized or not randomized) were considered eligible. The following study types were excluded: phase 1 trials, retrospective studies, case series, case reports, reviews, commentaries, editorials, or in vitro studies. Finally, clinical trials reported as letters without sufficient data or published as conference meeting abstracts were excluded and not considered eligible.

2.2. Study selection and data collection

All records identified were imported by GB into the citation management software EndNote 20 (Clarivate Analytics), and duplicates were removed. Firstly, a pilot study was conducted by two authors (GMI and EC) in order to assess eligibility criteria and data extraction forms for the systematic review. After completing the pilot study, all the citations were exported from EndNote 20 into Covidence screening review software, Veritas Health Innovation, Melbourne, Australia (available at www.covidence.org).

Two authors (GMI and EC) independently scrutinized the available citations following a two-stage study selection process. All titles and abstracts were screened for potential eligibility in the first stage. Subsequently, the full-text manuscripts of potentially relevant citations were retrieved and further assessed. An agreement between the two authors was required for inclusion/exclusion at both stages. Inconsistencies were discussed with a third author (FK) and resolved by consensus. Cohen’s kappa coefficient was calculated to evaluate inter-rater reliability during the selection process (Supplementary Material A3) [26]. Finally, the references of included studies were also hand-searched for other potentially eligible publications.

Two authors (GMI and HCW) created the data extraction forms using Microsoft Excel software. As in the study selection process, two authors (GMI and EC) extracted the data independently, discussing the results in an iterative process. From the included articles, the following data were extracted: first author, year of publication, study design, enrolled population, main study findings, and outcomes. Disagreements in the data extraction required consultation with an additional author (FK) and were resolved to achieve consensus.

2.3. Definition of outcomes

The following outcome measures were identified to assess the efficacy of PARPi in metastatic prostate cancer: objective response rate (ORR), PSA decline greater than 50% (PSA50), progression-free survival (PFS), and overall survival (OS). All the outcomes were evaluated in both patients harboring genomic alterations in DDR genes or not. Furthermore, efficacy outcomes were also assessed in the subgroups of patients with alterations in three specific DDR genes: BRCA1, BRCA2, and ATM.

The outcome measures identified for the safety of PARPi were the occurrence of any high-grade (≥ G3) adverse events (AEs) and serious adverse events (SAEs). In addition, we assessed the interruption of therapy, dose reduction, treatment discontinuation, and death due to AEs. The safety outcomes were evaluated in all metastatic prostate cancer patients without any distinctions based on the presence of DDR-related gene alterations.

We used the CoCoPop framework by Munn et al. to synthesize ORR, PSA50, and the pre-specified safety outcomes [27]. In contrast, the time-to-event data were assessed using the PICO framework: metastatic prostate cancer patients represented the “population”, the “intervention” was PARPi, the “control” was the standard-of-care (SoC) treatment, and the “outcomes” were PFS and OS [28].

2.4. Risk of bias assessment

The included studies were assessed for the risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions using two well-established tools: the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [29] and the risk of bias in non-randomized studies of interventions (ROBINS-I) tools [30]. The assessment of the risk of bias was conducted by two authors (GMI and EC). Disagreements were resolved by a third author (FK).

2.5. Statistical analyses

The hazard ratios (HRs) for OS and PFS with their 95% confidence intervals (95%CI) were extracted from the included phase 3 clinical trials. The summary of these effect measures was calculated using random effects accounting for the potential heterogeneity of the included studies. Specifically, pooled estimates were quantified based on the random-effects model and reported using the “DerSimonian and Laird” method [31]. On the contrary, pooled estimates of ORR and PSA50 were calculated using a generalized linear mixed model (a random intercept logistic regression model). The same method was used to calculate the pooled estimate of all the pre-specified safety outcome measures. The list of high-grade AEs assessed in the quantitative analyses was generated by collecting the ten most frequent AEs in all the included clinical trials.

Pooled estimates of both efficacy and safety outcomes were calculated when ≥2 clinical trials reported the results of the same pre-specified outcome. Time-to-event data were assessed only in phase 3 clinical trials, while ORR, PSA50, and safety outcomes were evaluated in both phase 2 and 3 clinical trials. Pooled estimates were reported as percentages and their 95%CI. The inconsistency index (I2) was calculated to measure the heterogeneity between the included clinical trials [32]. According to pre-specified values, low heterogeneity was defined as an I2 <25%, moderate heterogeneity between 25 and 75%, and high heterogeneity when I2 was >75% [32]. Publication bias was not assessed due to the low number of clinical trials (<10) included for every outcome [33]. All the statistical analyses were performed with R version 4.2.2 (The R Foundation for Statistical Computing, 2022), with the use of the ‘meta’ package.

2.6. Protocol amendment

While we originally planned to analyze patients with BRCA1 and BRCA2 gene alterations separately, the majority of the eligible clinical trials did not separately report BRCA1 and BRCA2 status but rather reported a combined BRCA1/BRCA2 cohort. Thus, we deviated from the original plan and assessed efficacy in the combined BRCA1/BRCA2 cohort.

3. Results

3.1. Study selection and baseline characteristics

The results of the literature search and the study selection process are shown in the PRISMA flow diagram [25] (Figure 1).

Figure 1.

Figure 1.

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PRISMA flow diagram of the literature search results and studies’ selection process.

Note: The list of excluded records (n = 1,419) is available in Supplementary Material B.

3.2. Study characteristics

Nineteen clinical trials were deemed eligible after completing the systematic review (Table 1). All the clinical trials were published between 2015 and 2023. Seven (37%) studies investigated the activity/efficacy of PARPi administered as monotherapy (two phase 3 and five phase 2 studies). Furthermore, twelve (63%) clinical trials evaluated the combinations of PARPi with other anticancer agents. Among them, six (32%) clinical trials (three phase 3 and three phase 2 studies) investigated PARPi combined with an ARSI, and four (21%) the combination of PARPi with an immune checkpoint inhibitor (ICI). In addition, two phase 2 clinical trials (11%) evaluated the combination of PARPi with anti-angiogenetic therapy [35] or bipolar androgen therapy [36]. Although three clinical trials (MAGNITUDE [23], QUEST [34], and TALAPRO-2 [21]) were published after performing the literature search, they were included because of their relevance to the aim of this study (Table 1). The results of the phase 2 QUEST trial showed promising clinical activity and manageable toxicity with the use of niraparib in combination with abiraterone acetate plus prednisone in mCRPC patients [34]. The results of the phase 3 MAGNITUDE trial confirmed the efficacy of this combination over the ARSI monotherapy, leading to the FDA approval for BRCA-mutated mCRPC [22]. In addition, the results of the phase 3 TALAPRO-2 trial demonstrated the efficacy of talazoparib combined with enzalutamide over the monotherapy with enzalutamide, resulting in the FDA approval of this combination for HRR gene-mutated mCRPC [21].

Table 1.

Study design and main outcomes of the included clinical trials.

Clinical Trial Year Study design Population [n] Biomarker-selected population Samples Experimental Arm Control Arm Primary Endpoints Additional Endpoints
TOPARP-A [37] 2015 Ph2, OL, NR (Single-arm) mCRPC (PD after chemo) [50] No - Ola - Radiological Objective Response, PSA50, CTC ibPFS, PFS, OS, tPSA,
TOPARP-B [38] 2020 Ph2, OL, R (1:1) mCRPC (PD after ≤ 2 chemo lines) [98] Yes (113 DDR genes) Tissue Ola* Ola* Radiological Objective Response, PSA50, CTC ibPFS, PFS, OS, tPSA, dPSA
PROFOUND [16,39] 2020 Ph3, OL, R (2:1) mCRPC (PD on ARSI; previous TAX allowed) [387] Yes (15 DDR genes) Tissue Ola Abi, Enza§ ibPFS ORR, tPP, OS, PSA50, CTC
TRITON2 [17,40] 2020 Ph2, OL, NR (Single-arm) mCRPC (PD after ARSI and 1 TAX) [115] Yes (15 DDR genes) Tissue or blood (gDNA) Ruca - ORR DOR, PSA50, tPSA, ibPFS, OS
TALAPRO-1 [41] 2021 Ph2, OL, NT (Single-arm) mCRPC (PD after ARSI and ≤ 2 chemo lines) [128] Yes (11 DDR genes) Tissue Tala - ORR tORR, DOR, PSA50, tPSA, CTC, ibPFS, OS
GALAHAD [42] 2022 Ph2, OL, NR (Single-arm) mCRPC (PD after 1 ARSI and 1 chemo line) [223] Yes (8 DDR genes) Tissue or blood (ctDNA) Nira - ORR OS, ibPFS, tPSA, DOR
TRITON3 [43] 2023 Ph3, OL, R (2:1) mCRPC (PD after 1 ARSI and no previous chemo) [405] Yes (3 DDR genes) Tissue or blood (gDNA) Ruca Abi, Enza, or Doce§ ibPFS OS, ORR, DOR, tPSA, PSA50
NCT01576172 [44] 2017 Ph2, OL, R (1:1) mCRPC (PD after ≤ 2 chemo lines; no prior ARSI) [153] No - Veli + Abi Abi PSA50 ORR, PFS
NCT01972217 [45] 2018 Ph2, DB, R (1:1) mCRPC (PD after ≤ 2 chemo lines; no prior ARSI) [142] No - Ola + Abi Placebo + Abi ibPFS PFS2, OS, ORR, DOR, TFST, TSST, PSA50, CTC
PROpel [19] 2022 Ph3, DB, R (1:1) mCRPC (no prior therapy for mCRPC) [1103] No - Ola + Abi Placebo + Abi ibPFS PFS2, OS, ORR, DOR, TFST, TSST, PSA50, CTC
QUEST [34] 2023 Ph2, OL, NR (Single-arm) mCRPC (PD after ARSI) [24] Yes (8 DDR genes) Tissue or blood (gDNA) Nira + Abi - Radiological Objective Response, PSA50, CTC ibPFS
MAGNITUDE [23] 2023 Ph3, DB, R (1:1) mCRPC (no prior therapy for mCRPC) [423] Yes (9 DDR genes) Tissue or blood (gDNA) Nira + Abi Placebo + Abi ibPFS TCC, TSP, OS, tPSA, ORR, DOR, PSA50, PFS2
TALAPRO-2 [21] 2023 Ph3, DB, R (1:1) mCRPC (no prior therapy for mCRPC) [805] Yes (12 DDR genes) Tissue or blood (ctDNA) Tala + Enza Placebo + Enza ibPFS OS, ORR, DOR, tPSA, PSA50, PROM
NCT02484404 [46] 2018 Ph 1/2, OL, NR (Multi-cohort)** mCRPC [17] No - Ola + Durva - - ORR, PSA50
CheckMate 9KD [47] 2022 Ph2, OL, NR (Multi-cohort) mCRPC (prior ARSI and chemo allowed) [159] No - Ruca + Nivo - ORR, PSA50 DOR, tPSA, ibPFS, OS
KEYNOTE-365 [48] 2022 Ph1/2, OL, NR (Multi-cohort) mCRPC (prior TAX) [102] No - Ola + Pembro - PSA50 ORR, tPSA, DOR, DCR, ibPFS, OS
JAVELIN PARP Medley [49] 2022 Ph1/2, OL, NR (Multi-cohort)** mCRPC PD after ARSI and ≤ 2 chemo lines Yes (34 DDR genes) Tissue or blood (gDNA - ctDNA) Tala + Ave - Confirmed objective response DOR, PFS, PSA50
NCT02893917 [35] 2022 Ph2, OL, R (1:1) mCRPC (prior therapy for mCRPC) [90] No - Ola + Cedi Ola ibPFS ORR, OS, PSA50
NCT03516812 [36] 2023 Ph2, OL, NR (Single-arm) mCRPC (prior ARSI) [36] No - Ola + BAT - PSA50 ORR, ibPFS, CTC
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*

The dosages of Ola in the experimental and control arm were 400mg BID and 300mg BID, respectively.

**

In the quantitative analysis, we included the data related to the phase II part of this clinical trial for the mCRPC cohort.

§

Crossover to the experimental arm was allowed.

Abbreviations: Abiraterone Acetate (Abi), Androgen receptor signaling inhibitors (ARSI), Avelumab (Ave), Bipolar androgen therapy (BAT), Cediranib (Cedi), Chemotherapy (Chemo), CTC (Circulating Tumor Cell Conversion Rate), Circulating Tumor DNA (ctDNA), DNA Damage Repair (DDR), Disease Control Rate (DCR), Docetaxel (Doce), Double-blind (DB), Duration of Response (DOR), Durvalumab (Durva), Duration ofPSA Response (dPSA), Enzalutamide (Enza), Germline DNA (gDNA), Investigator assessed time to second progression (PFS2), Imaging-based Progression-Free Survival (ibPFS), Metastatic Castration-Resistant Prostate Cancer (mCRPC), Number of enrolled participants (n), Niraparib (Nira), Nivolumab (Nivo), Non randomized (NR), Olaparib (Ola), Open label (OL), Objective Response Rate (ORR), Pembrolizumab (Pembro), Progressive Disease (PD), Phase (Ph), PROM (Patient Reported Outcome Measures), PSA (Prostate Specific Antigen), PSA decline greater than 50% (PSA50), Randomized (R), RECIST (Response Evaluation Criteria in Solid Tumors), Rucaparib (Ruca), Talazoparib (Tala), Taxanes (TAX), Time to First Subsequent Anticancer Therapy (TFST), Time to Initiation of Cytotoxic Chemotherapy (TCC), Time to Objective Response Rate (tORR), Time to Pain Progression (tPP), Time to Second Subsequent Anticancer Therapy (TSST), Time to Symptomatic Progression (TSP), Time to PSA Progression (tPSA), Veliparib (Veli).

Seventeen clinical trials were finally included in the quantitative analyses. Two studies were excluded since they were the only ones to assess PARPi in combination with anti-angiogenetic or bipolar androgen therapy [35,36]. A total of 4,352 participants with mCRPC were enrolled in the clinical trials included in the quantitative analysis and were recruited from several countries all over the world (Supplementary Material C). The median age of participants was between 65 and 79 years. Most of the participants were white, with a lower number of other races/ethnicities included (Supplementary Material C). All clinical trials enrolled participants with an ECOG performance status (PS) equal to 0 or 1, and nine clinical trials also allowed the enrollment of participants with an ECOG PS equal to 2. The majority of the enrolled population had a Gleason Score higher or equal to 8, and about one-third of the participants were metastatic at the diagnosis. A total of 2,550 (59%) subjects received a PARPi. Specifically, patients were treated with olaparib in 41% of the studies, rucaparib in 18%, niraparib in 18%, talazoparib in 18%, and veliparib in 5%. Abiraterone acetate and enzalutamide were the only two ARSI administered in combination with PARPi, while the ICIs used for this combination strategy were durvalumab, nivolumab, avelumab, and pembrolizumab.

3.3. Results of quantitative analyses

3.3.1. Efficacy outcomes

A total of five phase 3 clinical trials were included in the quantitative analysis of the survival outcomes. The PROfound trial investigated the efficacy of PARPi monotherapy compared to single-agent ARSI monotherapy in two cohorts of mCRPC patients: cohort A consisted of patients with genomic alterations in BRCA1, BRCA2, or ATM genes, and cohort B of those with alterations in other 12 specific HRR genes [16,39]. In addition, the TRITON3 trial compared single-agent PARPi to the physician’s choice of docetaxel or ARSI monotherapy in a cohort of mCRPC patients harboring alterations in BRCA1, BRCA2, or ATM genes [43]. In contrast, PROpel, MAGNITUDE, and TALAPRO-2 trials assessed the combination of PARPi and ARSI in comparison to ARSI monotherapy in cohorts of mCRPC with genomic alterations in broader panels of DDR genes [19,21,23]. No phase 3 clinical trials investigating the combination of PARPi and ICI were found. The primary endpoint of all the studies included in the quantitative analysis was ibPFS, while OS was considered a secondary endpoint.

PARPi monotherapy improved the ibPFS of mCRPC patients harboring genomic alterations in BRCA1, BRCA2, or ATM genes compared to the SoC (HR 0.46; 95%CI, 0.26 – 0.81). Furthermore, single-agent PARPi was confirmed to improve the ibPFS in comparison to the SoC (HR 0.33; 95%CI, 0.15 – 0.75) in patients harboring genomic alterations in BRCA1 or BRCA2 genes. In contrast, PARPi monotherapy did not provide a benefit in terms of ibPFS (HR 0.99; 95%CI, 0.69 – 1.41) in mCRPC patients with alterations in the ATM gene. In addition, single-agent PARPi did not show a statistical improvement in OS (HR 0.82; 95%CI, 0.61 – 1.11) in mCRPC patients harboring genomic alterations in BRCA1, BRCA2, or ATM genes. From a single-gene perspective, PARPi monotherapy did not improve OS in the cohort of mCRPC patients with ATM gene alterations, confirming the lack of benefit in ibPFS (Figure 2). Regarding the combination of PARPi and ARSI, the results of the quantitative analysis showed an improvement in ibPFS with the combination of PARPi and ARSI over ARSI monotherapy both in patients harboring alterations in DDR genes (HR 0.57; 95%CI, 0.42 – 0.77) and unselected according to DDR gene status (HR 0.62; 95%CI, 0.53 – 0.72) (Supplementary Material D1). No data were available for OS and single-gene outcomes. Finally, all the eligible studies (Table 1) were included in the quantitative analyses to calculate the pooled estimates for PSA50 and ORR (Table 2).

Figure 2.

Figure 2.

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Forest plots of the quantitative analyses for survival outcomes in mCRPC patients with alterations in the BRCA1, BRCA2, or ATM genes and treated with single-agent PARPi.

Table 2.

Pooled estimates of efficacy outcomes (ORR and PSA50)*

PARPi (Monotherapy) PARPi + ARSI PARPi + ICI
Population Efficacy endpoint, %, (95%CI) Trials, n Participants, n Trials, n Participant s, n Trials, n Participants, n
All comers ORR NR - - 40.2 (24.8 – 57.8) 4 598 9.6 (6.1 – 14.9) 3 177
PSA50 NR - - 72.9 (58.9 – 83.4) 4 942 21.8 (12.4 – 35.4) 43 290
DDR+ patients ORR 26.8 (23.0 – 31.0) 5 504 69.4 (54.1 – 81.4) 4 146 15.2 (8.8 – 24.9) 3 79
PSA50 29.9 (21.4 – 40.1) 5 878 78.4 (36.4 – 95.8) 3 120 26.9 (18.9 – 36.8) 2 93
BRCA1/2+ patients ORR 45.3 (38.0 – 52.7) 5 292 NR - - NR - -
PSA50 53.9 (36.9 – 70.0) 5 533 NR - - NR - -
ATM+ patients ORR 7.6 (3.2 – 16.9) 4 66 NR - - NR - -
PSA50 4.1 (1.3 – 11.8) 3 74 NR - - NR - -
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*

Forest plots and funnel plots are included in Supplementary Material D2.

Abbreviations: Adverse events (AE), Androgen Receptor Signaling Inhibitor (ARSI), Breast Cancer Gene (BRCA), Confidence Interval (CI), Immune checkpoint Inhibitors (ICI), Number of clinical trials included in the quantitative analyses (CT), DNA Damage Repair (DDR), Number of participants included in the quantitative analysis (n), Not reported (NR), Objective Response Rate (ORR), PSA decline greater than 50% (PSA50).

3.3.1. Safety outcomes

More than half of mCRPC patients treated with PARPi experienced at least one high-grade AE. Specifically, 59.8% (95%CI, 50.8 – 68.2%) of participants treated with single-agent PARPi developed high-grade AEs, while 60.3% (95%CI, 47.5 – 71.9%) and 51% (95%CI, 44.9 – 57.0%) were reported with PARPi given in combination with ARSI or ICI, respectively (Supplementary Material E1). The pooled estimates of specific high-grade AEs are reported in Figure 4. The most frequently diagnosed AE in participants treated with PARPi (both as a single agent or in combination with other drugs) was anemia. Regarding single-agent PARPi, the other frequently diagnosed AEs were thrombocytopenia (8.5% [95%CI, 5.7 – 12.6%]), neutropenia (7.8% [95%CI, 6.2 – 9.7%]), and fatigue/asthenia (7.0% [95%CI, 5.0 – 9.6%]). In contrast, for PARPi combined with ARSI, the occurrence of thromboembolic events (7.5% [95%CI, 5.6 – 10.0%]), hypertension (5.2% [95%CI, 2.8 – 9.7%]), and thrombocytopenia (5.8% [95%CI, 3.1 – 10.8%]) were the most frequently diagnosed AEs. Although not all the AEs were available in the clinical trials investigating the combination of PARPi and ICI, the most commonly reported AEs after anemia were AST and ALT increase (12.5% [95%CI, 8.4 – 18.3%]), fatigue/asthenia (7.9% [95%CI, 5.3 – 11.7%], and neutropenia (6.5% [95%CI, 4.1 – 10.0%). In addition, the occurrence of any grade immune-related AEs was 13.4% (95%CI, 8.4 – 20.8%) (Supplementary Material E5). Finally, a low prevalence of gastrointestinal toxicities (constipation, diarrhea, nausea, and vomiting) and infections (urinary tract infections and pneumonia) were reported in all the participants (Supplementary Material E2–E4).

Figure 4.

Figure 4.

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Pooled estimates of high-grade AEs*

*Forest plots and funnel plots are included in Supplementary Material E.

Abbreviations: Adverse events (AE), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Androgen Receptor Signaling Inhibitor (ARSI), Confidence Interval (CI), Number of clinical trials included in the quantitative analyses (CT), Immune checkpoint Inhibitors (ICI), GGT (Gamma-glutamyl transferase), Number of participants included in the quantitative analysis (n), Not reported (NR).

SAEs occurred in more than one-third of patients treated with PARPi as monotherapy or combined with other drugs. Interruption or discontinuation of therapy due to AEs was more common in patients treated with the combination of PARPi with ARSI or ICI than PARPi monotherapy. In contrast, dose reductions due to AEs were more frequent in participants treated with single-agent PARPi compared to the combination of PARPi with ARSI. Finally, the percentage of deaths was higher in participants treated with PARPi and ARSI compared to PARPi combined with ICI and single-agent PARPi (Table 3).

Table 3.

Pooled estimates of safety outcomes*

PARPi (Monotherapy) PARPi + ARSI PARPi + ICI
Safety outcome, % (95%CI) Trials, n Participants, n Trials, n Participants, n Trials, n Participants, n
Serious AE 38.7 (32.0 – 45.7) 5 1039 34.7 (32.0 – 37.6) 5 1103 36.1 (20.5 – 55.3) 2 261
Interruption owing to AE 50.3 (44.0 – 56.6) 5 1056 54.3 (30.9 – 76.0) 3 493 NR - -
Dose reduction owing to AE 31.1 (25.9 – 36.7) 7 1204 25.8 (20.6 – 31.9) 4 705 NR - -
Discontinuation owing to AE 13.9 (10.9 – 17.4) 7 1204 25.5 (21.4 – 30.1) 3 681 23.0 (18.3 – 28.5) 2 261
Death from AE 2.3 (1.2 – 4.6) 6 1154 1.7 (0.3 – 8.5) 5 1103 2.2 (0.4 – 10.1) 2 261
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*

Forest plots and funnel plots are included in Supplementary Material F

Abbreviations: Adverse events (AE), Androgen Receptor Signaling Inhibitors (ARSI), Confidence Interval (CI), N: Number of clinical trials included in the quantitative analyses (CT), Immune Checkpoint Inhibitors (ICI), Number of participants included in the quantitative analysis (n), Not reported (NR).

3.4. Risk of Bias in studies

Full details of the risk of bias assessment performed with the RoB 2 and ROBINS-I tools are available in Supplementary Material G.

4. Discussion

In the last decade, the treatment landscape of mCRPC has been revolutionized by new treatment options which prolong OS, including ARSIs, radioactive isotopes, and PSMA targeting agents [9,50]. Among these new therapeutic options, a significant role has also been played by PARPi, a class of targeted therapies that have already changed the treatment paradigm of ovarian and breast cancer [51]. Since 2009, when preliminary evidence of the potential activity of PARPi in mCRPC was reported [52], several studies have investigated the activity of PARPi in this population (10). So far, the FDA has approved two PARPi (olaparib and rucaparib) as monotherapy for mCRPC harboring specific genomic alterations in HRR genes [14,15]. In addition, the FDA recently approved three PARPi-based combinations for mCRPC patients: i) olaparib with abiraterone and prednisone for mCRPC with alterations in BRCA genes [18]; ii) talazoparib with enzalutamide for HRR gene-mutated mCRPC [20]; iii) niraparib with abiraterone plus prednisone for BRCA-mutated mCRPC [22]. In parallel, emerging data have demonstrated the potential of combining PARPi with other agents, providing new potential treatment options for this population [51]. In this rapidly evolving landscape, we sought to provide a comprehensive and updated evaluation of the role of PARPi in mCRPC by systematically reviewing the literature and assessing their efficacy and safety by performing a meta-analysis.

Thus far, seven phase 2 or 3 clinical trials have been published on the activity/efficacy of monotherapy with PARPi in mCRPC (Table 1). The results of our quantitative analysis confirmed the benefit of single-agent PARPi in mCRPC patients with alterations in DDR genes. However, while a greater benefit was demonstrated in mCRPC patients with alterations in BRCA1 or BRCA2 genes, reduced activity was found in mCRPC patients with alterations in the ATM gene (Table 2). In line with these results, the quantitative analysis of survival outcomes confirmed this difference in predicting the response to single-agent PARPi. Indeed, mCRPC patients harboring genomic alterations in BRCA1, BRCA2, or ATM genes achieved a longer ibPFS when treated with single-agent PARPi compared to the SoC (Figure 2). However, a higher efficacy was found in mCRPC patients with BRCA1 or BRCA2 alterations, whereas no benefit was demonstrated in patients with ATM gene alterations (Figure 2). Furthermore, we found a not-statistically significant OS improvement in patients with alterations in BRCA1, BRCA2, ord ATM genes treated with single-agent PARPi compared to SoC (Figure 2). As for the ibPFS, both the TRITON3 and PROfound trials showed an OS benefit in mCRPC patients harboring alterations in BRCA1 or BRCA2 genes treated with single-agent PARPi [39,43], while our results showed a lack of benefit for those carrying alterations in the ATM gene (Figure 2). Overall, these results highlight that the benefit of PARPi monotherapy is not uniform across all DDR gene alterations in mCRPC. Notably, the survival rates reported in the cohorts of mCRPC patients with heterogeneous alterations in DDR genes seem to be mainly driven by the high benefit achieved by those with BRCA1/2 gene alterations. Finally, the quantitative analyses for safety outcomes confirmed the known toxicity profile of single-agent PARPi without any new or unexpected signals [54].

In recent years, several clinical trials have also sought to investigate combination strategies to enhance PARPi efficacy and expand the population of mCRPC patients who may benefit from these drugs. Thus far, five phase 2 or 3 clinical trials have evaluated the activity/efficacy of PARPi combined with ARSI (Table 1). The results of our meta-analysis showed a benefit in ibPFS for mCRPC patients harboring genomic alterations in DDR genes treated with the combination of PARPi and ARSI compared to ARSI monotherapy (Supplementary Material D). Although no efficacy data from a single-gene perspective were available, the pooled estimates for ORR and PSA50 showed a higher rate of radiological and biochemical responses in patients with DDR alterations treated with the combination of PARPi and ARSI compared to single-agent PARPi (Table 2). However, higher rates of thromboembolic events and treatment discontinuation due to AEs were found in patients treated with PARPi and ARSI compared to those who received PARPi monotherapy (Figure 4 and Table 3). Overall, these results confirm the promising perspective represented by combining PARPi and ARSI. However, the approval of olaparib combined with abiraterone in only BRCA-mutated patients and the lack of mature OS data of other phase 3 trials highlight that further data are needed to understand if the addition of ARSI can expand the population of mCRPC who can benefit from PARP inhibition and to further delineate the mechanism of activity. In this context, there is still a lack of positive signals concerning the efficacy of adding ICI to PARPi. Our quantitative analyses showed a lower rate of ORR and PSA50 in patients treated with ICI and PARPi compared to PARPi and ARSI combination therapy and single-agent PARPi. In line with this, an early press release reported that the phase 3 clinical trial evaluating the combination of olaparib and pembrolizumab was stopped for futility [56], and no phase 3 clinical trials investigating the addition of ICI to PARPi in mCRPC patients have been published yet.

In parallel, further clinical trials are ongoing to provide new perspectives on the clinical benefit of this combination strategy. Specifically, a phase 3 trial is assessing the efficacy of combining rucaparib and enzalutamide (NCT04455750) [57], while a phase 2 study is investigating the combination of talazoparib and enzalutamide in the setting of metastatic castration-sensitive prostate cancer (NCT04821622) [58]. In addition, several phase 2 trials are currently evaluating the possibility of combining PARPi with other anticancer agents. For example, two studies are currently assessing the activity of combining olaparib with ATR inhibitors (NCT03787680, NCT03682289) [59,60], bromodomain and extra-terminal motif (BET) inhibitors (NCT05252390) [61], radioactive isotopes (NCT03317392) [62], telaglenastat, a glutaminase inhibitor (NCT04824937) [63], or vitamin C (NCT05501548) [64]. Additionally, novel perspectives are emerging from phase I clinical trials investigating PARPi in combination with other agents, including histone deacetylases inhibitors (NCT04703920) [65], RNA polymerase I inhibitors (NCT05425862) [66], and PI3Kα inhibitors (NCT04586335) [67].

Overall, this systematic review and meta-analysis confirm the well-established role of single-agent PARPi in a specific biomarker-selected subgroup of patients with mCRPC. Currently, the National Comprehensive Cancer Network (NCCN) guidelines recommend rucaparib for the treatment of mCRPC patients with somatic and/or germline alterations in the BRCA1 and BRCA2 genes (category 2A) [68]. In contrast, olaparib is recommended (category 1) in mCRPC patients previously treated with ARSI and harboring a pathogenic alteration (somatic and/or germline) in a broader panel of genes, including BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L [68]. However, our results show that the efficacy of single-agent PARPi is not uniform across all genomic alterations in DDR genes, and the highest benefit is achieved by mCRPC patients harboring alterations in BRCA1 and BRCA2 genes. Although the data from the included clinical trials did not allow us to perform separate quantitative analyses for patients with single gene alterations in BRCA1 or BRCA2 genes, the available preliminary evidence suggests that PARPi are more effective in patients with BRCA2 than BRCA1 alterations [69]. In addition, our results confirmed that the presence of genomic alterations in the ATM gene is not a predictor of response to PARPi monotherapy in mCRPC, and thus, caution should be paid when administering these drugs in this subgroup of patients. Despite only two phase 3 clinical trials being included in the quantitative analyses, there was an evident lack of survival benefit and low ORR and PSA50 in patients with ATM gene alterations, confirming data from previous single-arm clinical trials available in the literature [40]. In this context, the strategy of combining PARPi with other anticancer agents (ARSI, ICI, and targeted therapy) could potentially expand the pool of mCRPC patients who can benefit from PARP inhibition.

In addition, our results emphasize the essential role of genetic assessment for optimal patient selection for PARP inhibition. Notably, mCRPC patients with DDR-related gene alterations should not be considered a homogeneous group but individual entities with different responses to PARPi. Therefore, it will be crucial to design future clinical trials that can provide more robust data on the predictive value of specific single gene alterations. As shown in our systematic review, the mCRPC population enrolled in clinical trials assessing the efficacy of single-agent PARPi was highly heterogeneous, with several DDR-related genes considered for eligibility (Table 1). While the list of genes eligible for enrollment in the TOPARP-B study included 113 DDR-related genes [38], three other clinical trials selected participants based on smaller lists of about 10 genes [16,17,42]. In addition, divergences were also observed in the type of samples used to detect genomic alterations (somatic and/or germline alterations considered for eligibility). Initial evidence from clinical trials investigating the efficacy of PARPi monotherapy suggests that plasma-derived circulating tumor DNA (ctDNA) can complement tissue analysis in identifying patients eligible for PARPi treatment, providing a significant perspective for those with unavailable or insufficient tissue for genomic testing [70]. Indeed, a post-hoc analysis of cohort A of the PROfound trial showed a concordance of approximately 80% between ctDNA and tumor tissue testing for BRCA/ATM alterations [71]. These results align with the TRITON2 trial’s findings, where a concordance rate of about 75% was detected in matched samples of tumor tissues and ctDNA [72]. In terms of efficacy, an exploratory analysis of the PROfound trial showed an improved efficacy of olaparib over the control arm in patients with BRCA/ATM alterations retrospectively detected by ctDNA testing, comparable to the patients with BRCA/ATM alterations prospectively detected by tumor tissue testing [71]. Moreover, a recent meta-analysis showed no differences between germline versus somatic mutations in predicting the efficacy of PARPi monotherapy in mCRPC patients [73]. However, no data are currently available for PARPi-based combination strategy in this direction, thus warranting future investigation. Collectively, despite the significant progress made in precision medicine and the possibility of investigating combined treatment strategies to expand the applicability of PARPi to a broader population, more efforts are required to understand the genomic alterations underscoring better responses to PARPi at a single-gene level for optimal patient selection. Finally, ongoing research is currently addressing the issue of the acquired resistance of PARPi in mCRPC. Several studies demonstrated the role of reversion mutations of HRR genes in mCRPC treated with PARPi monotherapy as a mechanism of resistance [74–76]. Besides, further studies are awaited to investigate the occurrence of a cross-resistance between platinum-based chemotherapy and PARPi in mCRPC since this phenomenon has been well-described in other tumors [77]. Currently, contrasting data about the use of platinum-based chemotherapy after PARPi are available for mCRPC patients. While retrospective evidence has shown antitumor activity with platinum-based chemotherapy after PARPi progression [78], other data suggest more cross-resistance with the use of the platinum-based chemotherapy after PARPi rather than the opposite [79]. Therefore, despite the well-established role of PARPi in the treatment of mCRPC, further reaserch is needed to better comprehend the resistance to PARPi and define the best sequence of treatments for mCRPC patients.

4.1. Limitations

The present study has several limitations that may have impaired the results of the final analyses. First, the results of the quantitative analyses derive from aggregate data and not individual patient data. Secondly, since a higher number of clinical trials have been published for single-agent PARPi than PARPi-based combinations, the reported pooled estimates of ORR, PSA50, and safety outcomes were derived from a different number of patients. In addition, some clinical trials did not report the efficacy outcomes for all the mCRPC subgroups included in this study nor specified all the high-grade AEs experienced by the participants. Finally, it is essential to highlight that the PARPi assessed in the different trials have differences in their pharmacokinetic and pharmacodynamic characteristics.

5. Conclusion

The advent of PARPi has changed the treatment landscape of mCRPC patients. This systematic review and meta-analysis confirm the efficacy of PARPi monotherapy in mCRPC patients, with no unexpected safety signals. However, the benefit of this treatment is not uniform across the DDR genes in mCRPC, highlighting the importance of utilizing tumor or germline genetics to predict clinical benefit from PARPi. In this context, PARPi-based combinations may expand the pool of mCRPC patients who can significantly benefit from PARP inhibition. Despite the recent approval of olaparib combined with abiraterone, there is still a lack of data on the benefit of PARPi-based combination in non-BRCA mutated patients. Therefore, it will be essential to design clinical trials able to provide data on the efficacy of these drugs from a single-gene perspective to identify the optimal genomic profile predictive of benefit with PARP inhibition and the best sequence of treatments for mCRPC patients.

Supplementary Material

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HIGHLIGHTS.

  • PARPi are a standard-of-care treatment option in patients with mCRPC.

  • The benefit of PARPi is not uniform in mCRPC patients.

  • The optimal patient selection for PARPi remains a clinical challenge.

Acknowledgment

We thank Seth M. Steinberg, PhD for his statistical advice and constructive comments on the article.

Funding

This work was supported by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research. The interpretation and reporting of these data are the sole responsibility of the authors.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of Interest

The authors declare no conflict of interest.

Declarations of interest: none

CRediT Roles

Conceptualization (GMI and FK); Formal analysis (GMI, HCW); Investigation (GMI and EC); Methodology (GMI and FK); Resources (GB); Visualization (GMI and CF); Writing - Original Draft (GMI, EC, HW, GB); Writing - Review & Editing (CF, MR, JG, FK); Supervision (FK).

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Associated Data

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Supplementary Materials

1
NIHMS1931913-supplement-1.pdf (255.7KB, pdf)
2
NIHMS1931913-supplement-2.pdf (1.3MB, pdf)
3
NIHMS1931913-supplement-3.pdf (160.3KB, pdf)
4
NIHMS1931913-supplement-4.pdf (334.7KB, pdf)
5
NIHMS1931913-supplement-5.pdf (699.5KB, pdf)
6
NIHMS1931913-supplement-6.pdf (211.8KB, pdf)
7
NIHMS1931913-supplement-7.pdf (28.8KB, pdf)

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