FDA Expands Talazoparib Plus Enzalutamide Indication to HRR-Mutated Metastatic Prostate Cancer

Clinical Summary: 

• Regulatory Update: The FDA has approved talazoparib plus enzalutamide for patients with metastatic androgen pathway modulation-naïve or -sensitive prostate cancer harboring HRR gene mutations, as determined by an FDA approved test.  
• Key Outcomes: This approval was supported by results from the phase 3 TALAPRO-3 trial which demonstrated that the combination significantly improved radiographic progression-free survival compared with placebo plus enzalutamide, reducing the risk of radiographic progression or death by 52%.  
• Clinical Relevance: This approval expands the use of talazoparib plus enzalutamide to patients with HRR-mutated metastatic prostate cancer in the androgen pathway modulation-naïve or -sensitive setting, providing an additional targeted treatment option based on molecular testing.  

Based on results from the phase 3 TALAPRO-3 trial, the US Food and Drug Administration (FDA) has approved talazoparib (Talzenna; Pfizer) plus enzalutamide for the treatment of patients with metastatic androgen pathway modulation-naïve or -sensitive prostate cancer harboring HRR gene mutations, expanding the availability of targeted treatment for this molecularly defined patient population. 

In this double-blind, placebo-controlled trial, 599 patients were randomized 1:1 to receive once daily talazoparib plus enzalutamide or enzalutamide plus placebo. All patients were required to  receive continuous androgen deprivation therapy. 

HRR gene mutation status was determined prospectively using tumor tissue or ctDNA-based next-generation sequencing tests. Evaluated gene included ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

The primary end point was investigator-assessed radiographic progression-free survival (PFS), assessed via RECIST v1.1 and Prostate Cancer Working Group 3 criteria for bone disease. A key secondary end point was overall survival (OS). 

At analysis, median radiographic PFS was not reached in the talazoparib plus enzalutamide arm and 45.8 months in the enzalutamide plus placebo arm, reducing the risk of radiographic progression or death by 52% (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36 to 0.65; P < .0001). 

Although the findings demonstrated a statistically significant radiographic PFS benefit, OS data remained immature.

The recommended dose is 0.5 mg of talazoparib taken in combination with enzalutamide until disease progression or unacceptable toxicity. 

Patients receiving the combination should also receive a gonadotropin-releasing hormone analog or have previously undergone bilateral orchiectomy. Enzalutamide dosing should follow its prescribing information. 

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity.

The FDA previously approved FoundationOne CDx and FoundationOne Liquid CDx as companion diagnostic assays to identify patients with HRR gene alterations who may be eligible for treatment with talazoparib plus enzalutamide. 

Source: 

US Food and Drug Administration. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with HRR gene mutations. Accessed on: October 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-talazoparib-enzalutamide-metastatic-androgen-pathway-modulation-naive-or-sensitive