The FDA approved talazoparib (Talzenna) with enzalutamide (Xtandi) for adults with metastatic androgen pathway modulation-naïve or -sensitive prostate cancer carrying homologous recombination repair (HRR) gene mutations. The decision was based on results from the randomized, double-blind, placebo-controlled TALAPRO-3 trial (599 patients), with all participants receiving continuous androgen deprivation therapy. In TALAPRO-3, the combination achieved a statistically significant improvement in investigator-assessed radiographic progression-free survival (rPFS). Median rPFS was not reached with talazoparib plus enzalutamide versus 45.8 months with placebo plus enzalutamide (HR 0.48; P<.0001), using RECIST 1.1 and PCWG3 criteria. Overall survival data were immature at the time of analysis, but the approval extends a treatment option for a subgroup characterized by more aggressive disease and limited choices. The HRR-mutated population included mutations such as BRCA1/2, ATM, ATR, PALB2, CHEK2, and others, determined prospectively via tumor tissue or circulating tumor DNA sequencing. The FDA’s action adds to the expanding framework of biomarker-driven approvals in metastatic prostate cancer and further validates PARP inhibition in HRR-mutant disease in combination regimens.