FDA Approves Talazoparib/Enzalutamide in HRR-Mutated Prostate Cancer

The FDA approved talazoparib (Talzenna) in combination with enzalutamide (Xtandi) on October 26, 2026, for adults with metastatic androgen pathway modulation–naive or –sensitive (mAPMN/S) prostate cancer harboring homologous recombination repair (HRR) gene mutations detected by an FDA-authorized test.¹ The decision expands the combination’s use to an earlier disease setting and was supported by findings from the phase 3 TALAPRO-3 trial (NCT04821622).

Talazoparib is a PARP inhibitor, while enzalutamide targets the androgen receptor pathway. The combination is intended for patients whose tumors carry genetic alterations that can affect DNA damage repair.

TALAPRO-3 Demonstrates Improved Progression-Free Survival

TALAPRO-3 was a randomized, double-blind, placebo-controlled trial that enrolled 599 patients with HRR-mutated mAPMN/S prostate cancer. Patients were randomly assigned 1:1 to receive talazoparib plus enzalutamide or placebo plus enzalutamide. All patients also received continuous androgen deprivation therapy.

The primary end point was investigator-assessed radiographic progression-free survival (rPFS), evaluated using RECIST version 1.1 for soft tissue disease and Prostate Cancer Working Group 3 criteria for bone disease.

Median rPFS was not reached (95% CI, not reached [NR]-NR) in the talazoparib combination arm compared with 45.8 months (95% CI, 37.7-NR) in the placebo combination arm. Treatment with talazoparib plus enzalutamide reduced the risk of radiographic progression or death by 52% compared with placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).¹

Previous TALAPRO-3 findings, which demonstrated the rPFS benefit supporting the expanded indication.² The FDA granted priority review to the supplemental application in July 2026.³ Overall survival (OS) data were immature at the time of the rPFS analysis.

HRR Mutations and Companion Diagnostic Testing

For enrollment in TALAPRO-3, eligible patients must have mutations in at least 1 of 12 HRR genes: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C. Investigators determined mutation status using next-generation sequencing of tumor tissue or circulating tumor DNA.

The FDA identified FoundationOneCDx and FoundationOne Liquid CDx as companion diagnostic devices to identify patients with HRR gene alterations who may be eligible for the combination. These tests can help guide treatment selection by identifying relevant tumor mutations.

Recommended Dosage and Safety Considerations

The recommended dose of talazoparib is 0.5 mg orally once daily with enzalutamide until disease progression or unacceptable toxicity. Patients should also receive a gonadotropin-releasing hormone analog concurrently or have undergone bilateral orchiectomy to maintain androgen deprivation.

The prescribing information includes warnings for myelodysplastic syndrome and acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. In the phase 3 trial, serious adverse events occurred in 42% of patients receiving talazoparib plus enzalutamide compared with 32% receiving placebo plus enzalutamide. Grade 3 or higher anemia was reported in 51% of patients in the talazoparib arm.²

The FDA reviewed the application under Project Orbis, an initiative supporting concurrent oncology drug reviews among international regulatory partners. The agency collaborated with the Australian Therapeutic Goods Administration and Health Canada, where reviews were ongoing at the time of the FDA decision.¹

REFERENCES

1. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with HRR gene mutations. News release. US FDA. October 26, 2026. Accessed October 26, 2026. https://tinyurl.com/srwh9vtr.

2. Agarwal N, Matsubara A, Azad A, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026;395:427-439. doi:10.1056/NEJMoa2604126.

3. FDA grants priority review for Pfizer’s Talzenna Plus Xtandi or the treatment of metastatic prostate cancer. News release. Pfizer. July 23, 2026. Accessed October 26, 2026. https://tinyurl.com/ms7ufmfc