ASCO 2026: Talazoparib combination delays progression in HRR-mutated metastatic prostate cancer

Clinical Takeaway: For patients with metastatic hormone-sensitive prostate cancer, genomic testing early in the disease course to identify HRR gene alterations may inform treatment intensification with PARP inhibition before progression to castration-resistant disease.

Poly (ADP-ribose) polymerase (PARP) inhibitors have already demonstrated benefit in metastatic castration-resistant prostate cancer, particularly in tumors with homologous recombination repair (HRR) gene alterations. The phase 3 TALAPRO-3 trial evaluated whether introducing PARP inhibition earlier in the disease course could improve outcomes in patients with HRR-altered metastatic hormone-sensitive prostate cancer.

The results suggest that combining PARP inhibition with androgen receptor pathway inhibition may provide clinically meaningful disease control when introduced before progression to castration-resistant disease in appropriately selected patients.

The double-blind trial randomized 599 patients with metastatic androgen pathway–sensitive prostate cancer and HRR gene alterations to receive talazoparib plus enzalutamide or placebo plus enzalutamide. All patients also received androgen-deprivation therapy.

At three years, imaging-based progression-free survival was 77% in the talazoparib group compared with 56% in the control group, corresponding to a 52% reduction in the risk of disease progression or death (hazard ratio, 0.48; 95% confidence interval [CI], 0.36-0.65; P<0.001).

An interim analysis of overall survival showed a numerical advantage for the combination regimen, with three-year survival rates of 78% versus 72% (hazard ratio for death, 0.77; 95% CI, 0.56-1.04), although overall survival data remain immature.

Treatment-related toxicity was higher with talazoparib. Serious adverse events occurred in 42% of patients receiving talazoparib plus enzalutamide compared with 32% of those receiving placebo plus enzalutamide. Anemia was the most common grade 3 or higher adverse event, occurring in 51% of patients receiving talazoparib. Two treatment-related deaths were reported in the talazoparib group.

The findings support earlier treatment intensification for patients with HRR-altered metastatic prostate cancer and reinforce the value of genomic testing at diagnosis. If confirmed with longer follow-up, the combination of talazoparib and enzalutamide could help establish a new treatment approach before progression to castration-resistant disease.

Source: Agarwal N, et al. New Eng J Med. 2026 May 30. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer