Differential Efficacy of Poly (Adenosine Diphosphate ribose) Polymerase Inhibitors Based on Homologous Recombination Repair Alteration Status in Advanced Prostate Cancer: A Meta-Analysis

Purpose: To evaluate the efficacy and safety of poly (ADP-ribose) polymerase inhibitors (PARP inhibitors PARPi) in managing advanced prostate cancer (PCa) in patients with and without homologous recombination repair (HRR) genomic alterations (GAs). Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed, Google Scholar, and ScienceDirect for studies published through January 2025. Randomized controlled trials and observational studies assessing PARPi in advanced PCa with documented HRR GA status were included. Primary outcomes included radiographic progression-free survival (rPFS) and overall survival (OS); secondary outcomes were prostate specific antigen 50 response and safety. Data were pooled using a random-effects meta-analysis model, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated for time-to-event outcomes. Results: Of 363 articles identified, 6 studies met the inclusion criteria. In patients harboring HRR GAs, PARPi significantly improved rPFS (HR 0.61; 95% CI 0.55-0.68; P < .00001) and OS (HR 0.82; 95% CI 0.69-0.96; P = .01) compared with the control. Subgroup analysis revealed that this improvement in survival was predominantly driven by BRCA1/2 alterations. Patients carrying non-BRCA HRR GAs (eg, ATM, CHECK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) receiving PARPi did not have a significant improvement in their rPFS compared with the controls. Similarly, HRR-negative patients had no significant improvement in rPFS (HR 1.21; 95% CI 0.97-1.51; P = .10) or OS (HR 0.93; 95% CI 0.78-1.10; P = .40). Conclusions: PARPi confer superior efficacy over standard therapy in advanced PCa harboring BRCA1/2 GAs, underscoring the need for routine genomic profiling. In patients with other HRR alterations or HRR-negative PCa, the effect size has wide CIs, indicating the possibility of efficacy of PARPi in these patients. However, this survival does not reach statistical significance.