Talazoparib (PARP inhibitor) + enzalutamide (AR antagonist) shows “early rPFS, late OS” signal in HRR–non-deficient/unknown mCRPC (post hoc)

Talazoparib is an oral PARP inhibitor combined with enzalutamide, an androgen-receptor signaling inhibitor, in first-line metastatic castration-resistant prostate cancer (mCRPC); this post hoc analysis of TALAPRO-2 (Phase 3; NCT03395197) reconstructed individual patient data from published Kaplan–Meier curves for the HRR non-deficient/unknown subgroup (636 patients reconstructed; original patient-level data unavailable). Proportional hazards was not rejected for OS (p=0.63) or rPFS (p=0.37), but interval-specific estimates suggested the lowest rPFS hazard ratio (HR) occurred at 0–6 months (HR 0.56; 95% CI 0.37–0.86; p=0.008) and the lowest OS HR at 36–48 months (HR 0.59; 95% CI 0.36–0.97; nominal p=0.039), with no significant treatment-by-log(time+1) interaction for OS (p=0.44) or rPFS (p=0.12). In FDA subgroup summaries for TALAPRO-2, OS in non-HRRm “single-negative/unknown” was essentially null (HR 0.99; 95% CI 0.67–1.47) and in non-HRRm “double-negative” trended but did not clearly separate (HR 0.77; 95% CI 0.56–1.04), underscoring that this “late OS” interval finding is exploratory and vulnerable to post hoc multiplicity; as a benchmark, enzalutamide alone in pre-chemotherapy mCRPC historically delivered large rPFS benefit versus placebo (PREVAIL: median rPFS not reached vs 3.9 months), so incremental early rPFS gains on top of ARPI therapy need clear patient-level durability and safety tradeoff to matter clinically.