Exploring the efficacy of PARP inhibitors in metastatic castration-resistant prostate cancer with homologous recombination repair alteration: a meta-analysis based on subgroups and reconstructed individual patient data

Background: Treatment for metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) alteration remains a challenge. Recently published trials have evaluated the Poly (ADP-ribose) polymerase inhibitors (PARPIs) in mCRPC. However, the efficacy in subgroup with specific HRR gene mutation and treatment protocol requires further elucidation. This meta-analysis aims to explore the efficacy of PARPIs based on subgroups and reconstructed individual patient data (IPD). Methods: Literature was searched using PubMed, Embase, Cochrane Library and ClinicalTrials.gov up to April 2025. The primary outcome was radiographic progression-free survival (rPFS), and the secondary outcomes included overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and adverse events (AEs). Hazard ratios (HRs) and risk ratios (RRs) were pooled as the indicators using inverse-variance and Mantel-Haenszel methods. IPD was reconstructed from Kaplan-Meier curve. Survival analysis was performed using Cox hazards model based on the reconstructed IPD. Heterogeneity was assessed by I2 and sensitivity analysis. Publication bias was examined via contour‑enhanced funnel plots. Results: Data of 1840 mCRPC patients with HRR alteration from five pivotal phase III clinical trials were analyzed. PARPIs significantly improved overall rPFS (HR: 0.55) and OS (HR: 0.85). PARPIs also prolonged rPFS across the subgroups defined by clinicopathologic features. In the BRCA1/2 subgroup, survival benefits were prominent for rPFS (HR 0.32) and OS (HR 0.70). For patients with non- BRCA alterations, no benefits of PARPIs were detected for rPFS and OS in ATM -altered patients, and for OS in CDK12 subgroup. Survival analysis indicated that PARPIs treatment was significantly associated with the improved rPFS (HR: 0.73, P < 0.001) and PSA-PFS (HR: 0.80, P = 0.020) in the overall population, and revealed OS benefit in BRCA1/2 subgroup (HR: 0.77, P = 0.030). Comparing with monotherapy, combination regimen of PARPIs provided greater benefits for rPFS (HR: 0.57, P < 0.001), and OS (HR: 0.57, P < 0.040). Conclusions: PARPIs significantly delay the progression of mCRPC in the overall population and improve survival in patients with BRCA1/2 mutation, but have no effect in those with ATM mutation. Comparing with PARPIs monotherapy, the combination regimen provides greater survival benefit in the overall population. Future investigation should validate these findings in real world setting.