Yanfeng Su, Ruji Wu, Huien Pan, Haofeng Yuan
PARP inhibitors (PARPi) combined with androgen-receptor signaling inhibitors (ARSI) improve radiographic progression-free survival (rPFS) in homologous-recombination-repair (HRR)-altered metastatic prostate cancer, but effects across disease states and genomic subgroups remain uncertain. We searched MEDLINE, Embase, CENTRAL, Web of Science, and ClinicalTrials.gov through June 2026 for randomized trials of PARPi plus ARSI versus the same ARSI alone in HRR-altered metastatic prostate cancer. Trial-level log hazard ratios were pooled using REML random-effects models with Hartung-Knapp confidence intervals. Disease-state and BRCA/non-BRCA comparisons, including a paired ratio-of-hazard ratios [HRs] analysis, were exploratory. Five phase III trials included 2343 men. PARPi plus ARSI improved rPFS overall (HR 0.56, 95% confidence intervals 0.43-0.72). Pooled HRs were 0.36 (0.21-0.63) for BRCA-altered disease and 0.75 (0.51-1.09) for the heterogeneous non-BRCA group. The exploratory paired BRCA/non-BRCA ratio of HRs was 0.54 (0.32-0.90; P = .031), assuming zero covariance. Disease-state estimates were imprecise (mHSPC 0.56, 0.10-3.11; mCRPC 0.55, 0.29-1.07). The latest pooled overall-survival estimate was 0.75 (0.61-0.93; I² = 25%), but 2 trials remained interim. Grade ≥ 3 adverse events were consistently increased. PARPi plus ARSI improves rPFS in HRR-altered metastatic prostate cancer. The relative effect appears larger in BRCA-altered disease, but the interaction remains exploratory and non-BRCA alterations are biologically heterogeneous. Disease-state estimates do not support comparative inference. Overall-survival evidence suggests a signal, not definitive benefit, and must be balanced against increased toxicity.