Background PARP inhibitor (PARPi)-based therapy is a well-established treatment modality for metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) deficiencies. However, its clinical efficacy in mCRPC without HRR alterations remains undefined. Objective This study aimed to evaluate the efficacy of PARPis in HRR-proficient mCRPC. Methods A systematic database search was conducted to identify clinical trials evaluating the efficacy of PARPi-based therapies in patients with HRR-proficient mCRPC. Searches were performed using PubMed, Embase Cochrane Library, Web of Science, and relevant international conference proceedings. Both single-arm and pairwise meta-analytical approaches were employed to assess the efficacy of PARPis in HRR-proficient mCRPC, while concurrently comparing the estimates with those from HRR-deficient populations within the same trials. Results A total of eight single-arm trials and eight randomized controlled trials were included, comprising 3314 patients, of whom 1727 were HRR-proficient. In the single-arm meta-analysis, the pooled prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate was 18% (95% CI 9–29, I2 = 82%) in the HRR-proficient subpopulation, and 46% (95% CI 35–59, I2 = 63%) in the HRR-deficient subpopulation, with a significant difference between subpopulations (p = 0.003). The pooled 12-month progression-free survival (PFS) rate was 42% (95% CI 29–57, I2 = 93%) in the HRR-proficient subpopulation and 57% (95% CI 48–67, I2 = 72%) in the HRR-deficient subpopulation. No significant difference was observed between the two subpopulations (p = 0.177). Subgroup analyses based on treatment regimens (PARPi monotherapy, PARPi plus androgen receptor axis-targeted (ARAT) agents, PARPi plus immune checkpoint inhibitors, and PARPi plus others) also revealed no significant difference in efficacy between HRR-proficient and HRR-deficient subpopulations. In the pairwise meta-analysis, the addition of PARPi was associated with a significantly longer PFS compared with treatment without PARPi in both HRR-proficient and HRR-deficient subpopulations, with hazard ratios of 0.69 (95% CI 0.60–0.80, I2 = 32%) and 0.60 (95% CI 0.50–0.72, I2 = 16%), respectively. Also, there was no statistically significant difference (p = 0.22) between the two subpopulations. PARPi plus ARAT showed a trend toward improved overall survival in HRR-proficient patients, with a more pronounced benefit observed in HRR-deficient patients. Conclusions The use of PARPis in the treatment of CRPC demonstrated a significant improvement in PFS irrespective of HRR status. Even in the HRR-proficient subpopulation, PARPi-based therapy conferred encouraging PFS benefits, underscoring its potential clinical relevance beyond HRR-deficient settings. Further biomarker analyses are warranted to refine patient selection and optimize therapeutic strategies.

Can PARP Inhibitors Benefit Patients with Homologous Recombination Repair-Proficient Castration-Resistant Prostate Cancer? A Meta-analysis

期刊论文
发表日期：

2025年12月3日

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Susu Zhou,
Devashish Desai,
Noriko Kishi,
Sam Benjamin,
Che-Kai Tsao

摘要

Background

PARP inhibitor (PARPi)-based therapy is a well-established treatment modality for metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) deficiencies. However, its clinical efficacy in mCRPC without HRR alterations remains undefined.

Objective

This study aimed to evaluate the efficacy of PARPis in HRR-proficient mCRPC.

Methods

A systematic database search was conducted to identify clinical trials evaluating the efficacy of PARPi-based therapies in patients with HRR-proficient mCRPC. Searches were performed using PubMed, Embase Cochrane Library, Web of Science, and relevant international conference proceedings. Both single-arm and pairwise meta-analytical approaches were employed to assess the efficacy of PARPis in HRR-proficient mCRPC, while concurrently comparing the estimates with those from HRR-deficient populations within the same trials.

Results

A total of eight single-arm trials and eight randomized controlled trials were included, comprising 3314 patients, of whom 1727 were HRR-proficient. In the single-arm meta-analysis, the pooled prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate was 18% (95% CI 9–29, I² = 82%) in the HRR-proficient subpopulation, and 46% (95% CI 35–59, I² = 63%) in the HRR-deficient subpopulation, with a significant difference between subpopulations (p = 0.003). The pooled 12-month progression-free survival (PFS) rate was 42% (95% CI 29–57, I² = 93%) in the HRR-proficient subpopulation and 57% (95% CI 48–67, I² = 72%) in the HRR-deficient subpopulation. No significant difference was observed between the two subpopulations (p = 0.177). Subgroup analyses based on treatment regimens (PARPi monotherapy, PARPi plus androgen receptor axis-targeted (ARAT) agents, PARPi plus immune checkpoint inhibitors, and PARPi plus others) also revealed no significant difference in efficacy between HRR-proficient and HRR-deficient subpopulations. In the pairwise meta-analysis, the addition of PARPi was associated with a significantly longer PFS compared with treatment without PARPi in both HRR-proficient and HRR-deficient subpopulations, with hazard ratios of 0.69 (95% CI 0.60–0.80, I² = 32%) and 0.60 (95% CI 0.50–0.72, I² = 16%), respectively. Also, there was no statistically significant difference (p = 0.22) between the two subpopulations. PARPi plus ARAT showed a trend toward improved overall survival in HRR-proficient patients, with a more pronounced benefit observed in HRR-deficient patients.

Conclusions

The use of PARPis in the treatment of CRPC demonstrated a significant improvement in PFS irrespective of HRR status. Even in the HRR-proficient subpopulation, PARPi-based therapy conferred encouraging PFS benefits, underscoring its potential clinical relevance beyond HRR-deficient settings. Further biomarker analyses are warranted to refine patient selection and optimize therapeutic strategies.