Multicenter randomized phase 2 trial of talazoparib plus enzalutamide in high-volume metastatic hormone-naïve prostate cancer

Combined inhibition or PARP and AR pathway has demonstrated clinical activity in men with metastatic prostate cancer, although the extent of benefit in tumors lacking HRR gene alterations remains uncertain. A multicenter randomized phase 2 trial in Spain evaluated talazoparib plus enzalutamide versus enzalutamide alone in men with high-volume metastatic hormone-naïve prostate cancer (mHNPC). Fifty-four patients starting androgen deprivation therapy received two cycles of enzalutamide lead-in before 1:2 randomization to enzalutamide (n=17) or enzalutamide plus talazoparib (n=37). The primary endpoint was met, with a 73% (95% CI 56-86) PSA < 0.2 ng/ml response rate at 12 months in the combination arm, exceeding the prespecified efficacy threshold (p<0.001); the PSA < 0.2 rate in the control arm was 64.7% (95% CI 38-86; p=0.54 for exploratory comparison between arms). Grade ≥ 3 adverse events occurred in 68% of patients receiving the combination versus 35% with enzalutamide alone. Two fatal therapy-emergent myeloid neoplasms occurred in the combination arm in patients with underlying genomic suseceptibility. The authors conclude that talazoparib plus enzalutamide demonstrated clinical activity in patients with high-volume mHNPC but did not establish clear additional benefit over enzalutamide alone in this biomarker-unselected population, while being associated with increased toxicity.