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FDA approves talazoparib plus enzalutamide for HRR gene-altered mCSPC

On October 26th 2026, the U.S. Food and Drug Administration (FDA) approved talazoparib plus enzalutamide for homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).1 Prostate cancer is the leading cause of death from cancer in men, and around a quarter of patients with prostate cancer have mutations in DNA damage response genes involved in homologous recombination repair (HRR), which sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition.2,3 Standard treatment for mCSPC is androgen deprivation therapy (ADT) with an additional therapy, commonly androgen receptor pathway inhibitors (ARPIs) including enzalutamide or abiraterone.4 In the TALAPRO-2 (NCT03395197) trial, talazoparib, a PARP inhibitor, and enzalutamide significantly improved radiographic progression-free survival (rPFS) in HRR-deficient metastatic castration-resistant prostate cancer. The Phase III TALAPRO-3 (NCT04821622) trial investigated this combination at an earlier disease stage, when patients are still responsive to androgen receptor pathway modulation.2,3

The approval is based on the TALAPRO-3 trial, which randomized 599 patients with HRR gene-altered mCSPC 1:1 to receive talazoparib plus enzalutamide or placebo plus enzalutamide. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) and secondary endpoint was overall survival (OS). At median follow-up of 37.6 months in the talazoparib group and 37.7 months in the control group, PFS was 77% and 56% respectively (HR 0.48, 95% CI: 0.36-0.65, P<0.001). Median rPFS had not been reached in the talazoparib group and was 45.8 months in the control group. OS at 3 years was 78% in the talazoparib group and 72% in the control group (HR 0.77, 95% CI: 0.56-1.04). Serious adverse events (AEs) were more common in the talazoparib group, reported in 42% of patients compared with 32% in the control group. The most common of these in the talazoparib group was anemia, fatigue and decreased neutrophil count, and two treatment-related deaths were reported.2

Andrew Armstrong, MD, MS, Duke University Medical Center, Durham, NC, comments on the impact of the results across subgroups:

“And this trial was positive for its primary endpoint of delaying progression-free survival. To me, it was surprising that it was a positive study, both in all comers, particularly in BRCA patients, but also was very positive in patients with ATM and CDK12 mutations. So for me, that was practice-changing and illustrates that in the hormone-sensitive setting, there can be multiple homologous repair alterations that confer PARP sensitivity.”

This approval builds on the previous approval of talazoparib and enzalutamide in castration-resistant prostate cancer, bringing the combination forward to an earlier line of treatment in castration-sensitive disease for patients with HRR-alterations.

References:

  1. U.S. Food and Drug Administration. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with HRR gene mutations. Available here. (Last Accessed 27/10/2026).
  2. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026 Jul 30;395(5):427-439.
  3. Fizazi K, Azad AA, Matsubara N, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med. 2024 Jan;30(1):257-264.
  4. Fizazi K, Attard G, Azad AA, et al. Advanced and metastatic prostate cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2026 May;37(5):590-607.