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

[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, I = 82%) in the HRR-proficient subpopulation, and 46% (95% CI 35-59, I = 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, I = 93%) in the HRR-proficient subpopulation and 57% (95% CI 48-67, I = 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, I = 32%) and 0.60 (95% CI 0.50-0.72, I = 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.