Efficacy and safety of PARP inhibitors in the treatment of prostatic cancer: a systematic review and network meta-analysis

Introduction

With an age-standardized incidence rate of 29.4 per 100,000 and a mortality rate of 7.3 per 100,000, prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related death in men (1). Annually, over 400,000 fatalities are attributed to metastatic PCa, and according to current projections, this figure may more than double by the year 2040 (2).

Over the last decade, significant changes have occurred in the treatment landscape of metastatic PCa due to the emergence and approval of several drugs that have been shown to improve overall survival (OS) and other efficacy profiles. In addition to androgen deprivation therapy (ADT) (3-6), radioligand therapies (7,8) have also been approved for the treatment of metastatic PCa. The treatment for advanced PCa predominantly involves second-generation androgen-receptor pathway inhibitors (ARPis). Despite their effectiveness, these therapies do not offer a cure, and it is common for patients to eventually progress to metastatic castration-resistant PCa (mCRPC), a stage of PCa that is resistant to current androgen receptor-targeted treatments (9).

The poly (adenosine diphosphate-ribose) polymerase (PARP) enzyme family plays an essential role in the maintenance of genomic stability, primarily executing DNA damage repair through homologous recombination repair (HRR) and base excision repair pathways (10). PARP inhibitors (PARPis) induce tumorous cell death via two principal mechanisms. First, by competitively binding to the active site of PARP against its natural substrate nicotinamide adenine dinucleotide (NAD)⁺, the inhibitors thwart the repair of single-strand breaks (SSBs). This obstruction transforms unrepaired SSBs into double-strand breaks (DSBs) as DNA replication proceeds, leading to the accumulation of lethal DSBs and subsequent cell death (11,12). Second, PARPis “trap” PARP1 and PARP2 at the sites of DNA damage. This trapping prevents PARP1 and PARP2 from dissociating from DNA, not only incapacitating DNA repair but also interfering with essential cellular processes, such as DNA replication and transcription (13).

The Food and Drug Administration (FDA) has approved four PARPis for the treatment of mCRPC patients with BRCA mutations: olaparib, rucaparib, niraparib, and talazoparib, with talazoparib approved for patients with HRR mutations (14-18). In a notable advancement in the therapeutic landscape, the pivotal PROfound phase III study showed olaparib significantly enhanced radiographic progression-free survival (rPFS) and the objective response rate of mCRPC patients harboring HRR gene aberrations, compared with conventional treatments (19). Likewise, rucaparib demonstrated efficacy in the TRITON-2 phase II study, highlighting its considerable clinical benefits in treating mCRPC patients with BRCA mutations and prompting accelerated FDA endorsement (15).

In relation to the efficacy of PARPis combined with ARPis in the treatment of mCRPC, questions concerning the benefits of this combination therapy have arisen, irrespective of BRCA mutation status, in light of the final OS results data from the PROpel, MAGNITUDE, and TALAPRO-2 trials (20-23). The combined treatment appears to be most beneficial for patients with BRCA mutations, beneficial to a lesser extent for those harboring HRR alterations, and showed no benefit for the HRR-negative mCRPC patients (24).

Ongoing research into PARPis is advancing continuously. Current clinical trials are evaluating the efficacy and safety of novel PARPis, either as monotherapies or in combination with other agents, opening avenues for promising new treatments for metastatic PCa (25,26). Previous research has shown that PARPis improve the rPFS and OS of patients with mCRPC (27). The safety of various PARPis was compared in a previous network meta-analysis (NMA), which assessed the safety of these inhibitors in patients with breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and pancreatic adenocarcinoma (28). However, the efficacy and safety of various PARPis in mCRPC patients remain unclear, presenting a significant challenge for clinicians when making treatment decisions. To address this, we conducted two indirect comparisons to evaluate the efficacy and safety of olaparib, niraparib, rucaparib, and talazoparib. This comprehensive and updated evaluation aims to provide clinicians with a clearer understanding of the efficacy and safety profiles of these PARPis in patients with mCRPC. We present this article in accordance with the PRISMA NMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-82/rc)

Methods

Search strategy

The study was registered on PROSPERO (registration number: CRD42024516386).

A comprehensive literature search was performed of the PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) databases to identify the relevant studies. This search was limited to articles written in English and published from the inception of each database until November 8, 2023. The search terms used included “PARP inhibitor”, “olaparib”, “fluzoparib”, “rucaparib”, “niraparib”, “pamiparib”, “talazoparib”, “veliparib”, “mCRPC”, and “metastatic castration-resistant prostate cancer”. Four reviewers (Y.H., H.H., L.L., and Y.Z.) screened the titles and abstracts independently to assess the eligibility of each article for inclusion in this study. RCTs evaluating both PARPi monotherapy and PARPis in combination with APRis were considered for inclusion.

Inclusion and exclusion criteria

During the initial literature search, four reviewers (Y.H., H.H., L.L., and Y.Z.) independently evaluated the studies based on the PICOS criteria, and only those that met the eligibility criteria were included in the meta-analysis. The studies included in the meta-analysis adhere to the following specified criteria:

• Participants (P): patients with mCRPC;
• Intervention (I): treatments with a PARPi;
• Comparison (C): placebo treatments without a PARPi;
• Outcomes (O): rPFS, OS, all grades of adverse events (AEs), and AEs ≥ grade 3;
• Study type (S): randomized controlled trials (RCTs).

The retrieved articles were screened by the researchers according to the pre-established inclusion and exclusion criteria. Studies were included in the analysis if they met the following criteria: (I) related to PARPi therapy and novel hormonal therapy in patients with mCRPC; (II) reported on a randomized, phase 2/3 clinical trial; and (III) conducted a head-to-head comparison of the efficacy and safety of two therapies. Articles were excluded from the analysis if they: (I) were duplicates; (II) were not related to mCRPC; (III) were not original article; (IV) were not published in English; and/or (V) did not contained extractable data.

If any disagreements arose as to the inclusion of an article, a third reviewer was asked to determine whether the article met the inclusion criteria.

Data extraction and quality assessment

The relevant data were extracted by two authors (Y.H. and H.H.) and independently cross-checked. The following data were extracted from the studies: name of first author, publication year, study name, National Clinical Trial (NCT) number, RCT phase, treatment of each arm, sample size of each arm, median age of patients (years), baseline of median serum prostate-specific antigen (µg/L), the proportion of patients with a Gleason score ≥8, median treatment duration, OS, rPFS, and AEs.

Two reviewers (Y.H. and H.H.) independently assessed the risk of bias and quality of the studies using the version 2 of the Cochrane risk-of-bias tool (29). The quality assessment considered five domains, such as bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result. In the event of any discrepancies among the findings of the four researchers, a discussion was held to reach a consensus.

Statistical analysis

A Bayesian NMA was conducted using the GeMTC package in R 4.3.2 to compare the selected endpoints. For the outcomes of rPFS and OS, the hazard ratios (HRs) reported in the trials were used as the study data. Random-effects models were used for indirect treatment comparisons involving different combination therapies (30,31). In the assessment of AEs, the incidence rates of the AEs were used to estimate the safety of all the interventions. The surface under the cumulative ranking (SUCRA) value was used to rank the efficacy and safety of each intervention (32). As there was only a single dataset available for each intervention, there was no source for an inconsistency analysis.

A perspective subgroup analysis was conducted to evaluate rPFS and OS among the mCRPC patients with or without BRCA1/2 and HRR mutations.

The quality of the included articles was assessed using Cochrane’s RevMan Review Manager software version 5.4.1and the version 2 of Cochrane risk-of-bias tool for randomized trials (RoB 2) Heterogeneity was evaluated using the I² statistic, and an I² exceeding 50% was considered significant.

Results

Search results

Using the specified keywords, a total of 1,916 articles were initially retrieved: 345 in PubMed, 575 in Web of Science, 794 in Embase, 184 in the Cochrane Library, and 18 in CNKI. Duplicates were removed (n=857), and irrelevant studies were excluded (n=567), after which a full-text review of the remaining articles was conducted. Subsequently, 485 articles were excluded as they were not original article. Ultimately, seven high-quality articles were selected for inclusion in the systematic review (19-23,33,34). Among these articles, two reported different recent outcomes from the MAGNITUDE trial (Figure 1). As a result, six phase 2/3 clinical trials met the criteria and were included in the NMAs.

Figure 1 PRISMA flow chart of the studies identified and included in this study. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Studies characteristics and quality assessment

NMAs were conducted of six large, randomized phase 2/3 clinical trials, comprising a total of 3,205 patients. Details of the included trials are set out in Table 1. Each trial comprised two study arms; the patients were randomly assigned to receive PARPis or second-generation ARPis in the experimental and control arms. The median age of the patients across the trials ranged from 67 to 72 years, and there was minimal variation in the proportion of different Gleason scores between the arms of each trial. Most of the trials adopted rPFS as the primary endpoint, and OS as the secondary endpoint, and reported the rates of AEs. The results of the quality assessment of the trials are summarized in Figure 2. Two NMAs were conducted due to the different design of the six included clinical trials (Figure 3). The network A analysis indirectly compared the efficacy and the safety among olaparib, niraparib, and talazoparib, while the network B analysis assessed the same outcomes between olaparib and rucaparib.

Figure 2 Quality evaluation of the included studies. (A) Quality assessment of the included studies. (B) Overall quality evaluation of the included studies. Green “+” indicates the low risk of bias; yellow “?” indicates the unclear risk of bias.

Figure 3 Network plots of comparisons for NMAs of (A) olaparib, niraparib, and talazoparib, and (B) olaparib and rucaparib. ARPi, androgen-receptor pathway inhibitor; NMA, network meta-analysis.

rPFS

Almost all the studies reported that PARPis extended rPFS compared with ARPis in patients with mCRPC. The indirect comparison with a random-effects model of olaparib, niraparib, and talazoparib showed that olaparib significantly improved rPFS with a HR of 0.67 [95% confidence interval (CI): 0.46–0.96] (Figure 4A). In the rank probability analysis, talazoparib exhibited a higher probability of being the preferred treatment (58.6%), followed by olaparib (35.5%), and niraparib (5.8%) (Table 2). Talazoparib also had the highest SUCRA value (0.82), followed by olaparib (0.74), and niraparib (0.38) (Table 3).

Figure 4 NMAs of (A) rPFS in network A, (B) rPFS in network B, and (C) OS in network A. CI, confidence interval; ARPi, androgen-receptor pathway inhibitor; NMA, network meta-analysis; rPFS, radiographic progression-free survival; OS, overall survival.

In the NMA of olaparib and rucaparib, both interventions were found to improve the rPFS of mCRPC patients. However, the indirect comparison revealed no significant difference between the two therapies (Figure 4B). In the rank probability analysis, rucaparib had a slightly higher probability of being the preferred treatment (54.3%) compared to olaparib (44.9%). Rucaparib also achieved a marginally higher SUCRA value (0.75) than olaparib (0.70).

OS

No significant differences were found in the indirect comparison of olaparib, niraparib, and talazoparib (Figure 4C). A comparison of network B could not be conducted due to insufficient data. In the ranking probability analysis, olaparib showed a 52.9% probability of being the preferred treatment, followed by talazoparib (33.7%), and niraparib (12.3%) (Table 2). Additionally, the SUCRA values for olaparib, niraparib, and talazoparib were 0.78, 0.32, and 0.62, respectively (Table 3). Notably, due to the immaturity and scarcity of the survival data in a majority of the studies, the results regarding OS should be considered preliminary.

AEs

In relation to the AEs, the number of events and the sample size of each arm of the included studies were used to determine the odds ratio (OR). Due to the significant heterogeneity (Figure 5), a NMA with a random-effects model was used to analyze the safety outcome in the grade ≥3 AE subgroup in network A as well. All the PARPis, including olaparib, niraparib, and talazoparib, showed increased rates of grade ≥3 AEs with ORs of 2.0 (95% CI: 0.89–5.3), 3.0 (95% CI: 1.3–7.4), and 3.7 (95% CI: 1.1–12.0), respectively (Figure 6A). However, the difference in rates of grade ≥3 AEs between olaparib and placebo plus ARPis was not statistically significant.

Figure 5 Heterogeneity analysis of grade ≥3 AEs in network A. CI, confidence interval; ARPi, androgen-receptor pathway inhibitor; NA, not available; HRR, homologous recombination repair; AE, adverse event.

Figure 6 NMA of (A) grade ≥3 AEs in network A, (B) grade ≥3 AEs in network B, (C) all grades of AEs in network A, and (D) all grades of AEs in network B. CI, confidence interval; ARPi, androgen-receptor pathway inhibitor; NMA, network meta-analysis; AE, adverse event.

In the rank probability analysis, olaparib had the greatest probability of being the first recommended treatment (3.5%) (Table 2). Additionally, olaparib had the highest SUCRA value (0.57) followed by niraparib (0.29), and talazoparib (0.16) (Table 3).

In the indirect comparison of olaparib and rucaparib, no significant differences were observed in the grade ≥3 AE subgroup between olaparib and rucaparib (Figure 6B). A similar outcome was found in all grades of AEs among olaparib, niraparib, and talazoparib (Figure 6C). However, rucaparib significantly increased the occurrence rate of all grades of AEs with an OR of 2.1×10¹⁰ (Figure 6D).

The ranking probability analysis showed that olaparib had a higher probability of being the preferred treatment in all groups of the indirect comparison among olaparib, niraparib, and talazoparib (Table 2). The same outcome was observed in terms of the SUCRA values (Table 3).

Subgroup analysis of the HRR and BRCA1/2 subgroups

The efficacy of PARPis in mCRPC patients with or without HRR or BRCA1/2 mutations is summarized in Table S1. In the analysis of the HRR subgroup, the efficacy of PARPis was assessed. Despite the anticipation of potential benefits, no statistically significant differences were observed in terms of rPFS among olaparib, niraparib, and talazoparib. Additionally, no significant differences were observed in terms of OS in mCRPC patients in the HRR-positive group (Figure S1). Similar to the HRR subgroup analysis, no significant difference was observed in terms of rPFS or OS among the above-mentioned PARPi-related interventions in BRCA1/2 subgroup (Figure S2). Overall, despite high expectations about the potential efficacy of PARPis in patients with HRR or BRCA mutations, the analysis revealed no significant benefits in terms of rPFS and OS.

Discussion

Over the last decade, studies have shown that PARPis can prolong the rPFS and OS of patients with cancer. Additionally, several meta-analyses have been conducted to compare the efficacy and safety between combined PARPi therapies or monotherapy and control therapies. For example, Cai et al. conducted a NMA to compare the safety of different PARPis and other therapies in breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and pancreatic adenocarcinoma patients, and found that serious AEs and the discontinuation of treatments did not significantly differ among olaparib, niraparib, rucaparib, and talazoparib (28). Many meta-analyses have also compared the efficacy and safety of PAPRis in PCa. For example, Messina et al. demonstrated that the combination of PARPis with ARPis significantly prolongs the rPFS of mCRPC patients with BRCA1/2 and HRR gene mutations (27). However, the study did not recommend a specific PARPi, claiming that the agent used was not relevant to a beneficial outcome.

In the present study, we conducted two NMAs to compare the survival and safety profiles of different PARPis, aiming to provide evidence-based guidance for clinicians treating patients with mCRPC. The indirect comparison of rPFS outcomes revealed that olaparib demonstrated a significant improvement over niraparib and talazoparib, with a HR of 0.67 (95% CI: 0.46–0.97). While talazoparib exhibited a HR of 0.64 and achieved the highest rank in both probability and SUCRA analyses—suggesting its potential as a preferred treatment option for mCRPC—olaparib emerged as the recommended treatment due to its statistically significant results. This conclusion is further supported by the SUCRA analysis comparing olaparib and rucaparib, which demonstrated similar values.

The OS and AEs profiles also support the same conclusion. Olaparib demonstrated no statistically significant increase in the occurrence rate of grade ≥3 AEs compared with placebo plus ARPis. In contrast, the other PARPis were associated with a significant increase in the rate of grade ≥3 AEs. The results of the rank probability analysis further support this conclusion. In terms of the grade ≥3 AEs, the SUCRA rankings from best to worst were olaparib, niraparib, and talazoparib. With an OR of 1.5×10¹², a significant result, was observed in the analysis of olaparib and rucaparib across all grades of AEs. On reviewing the initial data, a 100% rate of all grades of AEs was observed in the rucaparib arm, which was believed to be the cause of the statistically significant result. Such a rate implies that every patient in the rucaparib group experienced some level of AE, which skewed the OR toward a very high value. Further, in the studies of rucaparib and talazoparib, the most frequently reported grade ≥3 AEs associated with PARPis were anemia and neutropenia, which aligns with the findings of Bowling et al. (35) Notably, patients treated with niraparib displayed a high risk of hypertension. While olaparib demonstrated a favorable safety profile in this study, it’s important to note that some drug-related delayed AEs, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have been reported in other types of cancer (36).

A potential therapeutic trend was observed across the different subgroups. The benefit of using PARPis appeared to be higher in the patients harboring the BRCA or HRR mutations than in those in the BRCA⁻ or HRR⁻ subgroup, which supports the results previously published by Messina et al. (27) However, the subgroup analysis results showed no statistically significant differences in the survival profiles of the mCRPC patients in the BRCA⁺, BRCA⁻, HRR⁺, and HRR⁻ subgroups, despite large CIs. These findings emphasize the need for further research to identify effective treatment strategies for patients with mCRPC who harbor specific genetic mutations.

Clinical research has shown the efficacy of combinations of PARPis and other drugs. In the phase 1b/2 KEYNOTE-365 study, researchers assessed the efficacy and safety of pembrolizumab plus olaparib in the treatment of mCRPC, and observed notable anti-tumor activity in the mCRPC patients (37). Additionally, the phase 2 CheckMate 9KD trial results showed that rucaparib plus nivolumab was active in patients with HRR mutations post-chemotherapy or chemotherapy-naive mCRPC, particularly those with BRCA1/2 mutations (38). This suggests that clinicians have expanded PARPi-related treatment options for mCRPC patients beyond monotherapy and combinations with ARPis.

The present study has several limitations. First, our literature search was limited to five databases and studies published up until 2023, which may have affected the comprehensiveness of our analysis. Second, the small number of included studies could potentially lead to misleading conclusions and contributed to the wide CIs observed in the HRR and BRCA subgroup analysis. Third, the analysis included heterogeneous patient populations with varying prior treatment histories and other important characteristics, potentially introducing bias. Finally, as our study employed an indirect comparison methodology, it is inherently limited and does not provide the same level of evidence as a direct comparison.

Conclusions

PARPis demonstrated extended rPFS compared to ARPis in patients with mCRPC. Among olaparib, niraparib, and talazoparib, olaparib significantly improved rPFS with a HR of 0.67. Talazoparib exhibited the highest SUCRA value. Regarding safety, olaparib and rucaparib did not significantly increase the incidence of grade ≥3 AEs. When making personalized treatment decisions, clinicians should consider individual patient characteristics, treatment efficacy, and potential AEs.

Acknowledgments

This abstract was presented in the 41^st World Congress of Endourology and Urotechnology WCET 2024 in Seoul, South Korea. We would like to express our thanks to ZY Liu from King’s College London for proofreading the manuscript. We thank Dr. Manuela Andrea Hoffmann (University Medical Center of the Johannes Gutenberg-University) for the critical comments and valuable advice on this study.

Funding: This work was supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515010984), the Science and Technology Innovation Project for College Students of Guangzhou Medical University (No. 2021A003), the Special Fund for the Cultivation of Guangdong College Student’s Scientific and Technological Innovation (No. pdjh2023b0431), and the China National Innovation Training Program for College Students (No. 202210570003).

Footnote

Reporting Checklist: The authors have completed the PRISMA NMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-82/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-82/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-82/coif). H.G. serves as Bureau speaker for Bayer and Pfizer. L.C.M. receives grants from Terry Fox Research Institute, ACURA/CARO, and AMOSO, consulting fees from Tersera and participates on Advisory Board of DSMB London Health Sciences Centre, outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)