Talazoparib (PARP inhibitor) + enzalutamide (AR inhibitor) halves rPFS risk in HRR-altered mCSPC

Talazoparib is an oral PARP inhibitor that exploits homologous recombination repair (HRR) deficiency, and enzalutamide is an androgen-receptor signaling inhibitor; in the double-blind Phase 3 TALAPRO-3 trial (NCT04821622), men with HRR-altered mCSPC on ADT were randomized 1:1 to talazoparib + enzalutamide vs placebo + enzalutamide (n=599; cutoff Feb 18, 2026; median follow-up ~37.6–37.7 mo). Investigator-assessed rPFS improved with talazoparib + enzalutamide (HR 0.481; 95% CI 0.357–0.647; p<0.0001; median not reached vs 45.8 mo), with a larger effect in BRCA-mutated disease (HR 0.368; n=207; 34.6%) than non-BRCA HRR alterations (HR 0.567; n=392; 65.4%); interim OS numerically favored the combo but was not statistically significant (74 vs 91 deaths; HR 0.767; 95% CI 0.564–1.044). Compared with enzalutamide + ADT as a mCSPC benchmark (ARCHES rPFS HR ~0.39 vs ADT alone), TALAPRO-3 is a different question—whether adding PARP inhibition on top of enzalutamide improves outcomes in an HRR-selected population—at the cost of substantial hematologic toxicity: anemia 71.2% (all-grade), neutropenia 22.1% (all-grade), and talazoparib discontinuation due to TEAEs in 18.7%; “no new safety signals” were reported.