Randomized phase 2: talazoparib-enzalutamide met PSA goal but showed no clear benefit over enzalutamide alone

RCT · Nat Med · 2026-10-16. Number 2 in the UrologyWatch Top 5 for October 16, 2026.

In 54 men with high-volume mHNPC unselected for HRR mutations, talazoparib plus enzalutamide met its prespecified single-arm PSA response threshold (73% vs prespecified goal, P<0.001). The exploratory comparison to enzalutamide alone (64.7%) was not significant (P=0.54). Combination therapy caused more grade 3+ toxicity (68% vs 35%) including two fatal myeloid neoplasms.

Why it matters: Adding PARP inhibition to ARPI therapy in biomarker-unselected hormone-naive patients met its primary endpoint but showed no clear efficacy edge over enzalutamide alone in exploratory comparison, with added toxicity.

Limitation: Small phase 2 trial (n=54) not powered for a formal comparison; combination arm had substantially more severe toxicity including fatal myeloid neoplasms.

Source: Nat Med · PubMed 42875559 · DOI 10.1038/s41591-026-04671-5

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