Talazoparib plus enzalutamide in high-volume metastatic hormone-naive prostate cancer: a randomized phase 2 trial

Combining inhibition of poly(ADP-ribose) polymerase and androgen receptor (AR) pathway has demonstrated clinical activity in men with metastatic prostate cancer, although the extent of benefit in tumors lacking homologous recombination repair (HRR) gene alterations remains uncertain. We conducted a randomized phase 2 trial evaluating talazoparib plus enzalutamide versus enzalutamide alone in men with high-volume metastatic hormone-naive 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% prostate-specific antigen (PSA) <0.2 ng ml^-1 response rate at 12 months in the combination arm (95% confidence interval (CI) = 56-86%), 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% patients receiving the combination versus 35% with enzalutamide alone, predominantly anemia (41%). Two fatal therapy-emergent myeloid neoplasms occurred in the enzalutamide plus talazoparib arm in patients with underlying genomic susceptibility. Analyses of paired tumor biopsies acquired at baseline and during enzalutamide lead-in phase demonstrated marked tumor transcriptional reprogramming after AR inhibition, including suppression of proliferation-associated and HRR-related gene expression programs, but without functional impairment of homologous recombination activity. Overall, talazoparib plus enzalutamide demonstrated clinical activity in patients with high-volume mHNPC but did not establish clear additional clinical benefit over enzalutamide alone in this biomarker-unselected population, while being associated with increased toxicity. ClinicalTrials.gov identifier: NCT04332744 .