Talazoparib/enzalutamide approved for HRR-mutated mAPMN/S prostate cancer

The FDA has approved talazoparib (Talzenna) plus enzalutamide (Xtandi) for adults with homologous recombination repair (HRR) gene-mutated metastatic prostate cancer.¹ The October 26, 2026, approval applies to androgen pathway modulation-naïve or -sensitive (mAPMN/S) disease, with HRR mutations detected by an FDA-authorized test.¹

For urologists managing metastatic disease, the indication ties eligibility for this regimen directly to HRR genotyping.¹ The FDA previously approved the FoundationOne CDx and FoundationOne Liquid CDx assays as companion diagnostics to identify patients eligible for talazoparib plus enzalutamide.¹ Qualifying alterations span 12 HRR genes, so eligibility extends beyond BRCA1 and BRCA2 alone.¹

Efficacy was established in TALAPRO-3 (NCT04821622), a randomized, double-blind, placebo-controlled trial enrolling 599 patients with HRR gene-mutated mAPMN/S prostate cancer.^1,2 Patients were randomly assigned 1:1 to daily enzalutamide plus either talazoparib or placebo, and all patients received continuous androgen deprivation therapy.¹ HRR mutation status was determined prospectively with tumor tissue or circulating tumor DNA (ctDNA)-based next-generation sequencing.¹

The 12 qualifying genes were ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.¹ The major efficacy outcome was investigator-assessed radiographic progression-free survival (rPFS) per RECIST version 1.1 and Prostate Cancer Working Group 3 (PCWG3) bone criteria.¹

Talazoparib plus enzalutamide produced a statistically significant rPFS improvement vs placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).¹ Median rPFS was not reached (95% CI, NR-NR) in the talazoparib arm vs 45.8 months (95% CI, 37.7-NR) in the placebo arm.¹ Both arms received daily enzalutamide with continuous androgen deprivation therapy, making placebo plus enzalutamide the active comparator.¹

Overall survival, safety warnings, and dosing for talazoparib plus enzalutamide in HRR-mutated metastatic prostate cancer

Overall survival (OS) served as an additional efficacy outcome in TALAPRO-3.¹ At the time of the rPFS analysis, OS data were immature, and the FDA announcement does not report OS estimates.¹ The agency also did not report adverse reaction rates or discontinuation data; full prescribing information for talazoparib will be posted to Drugs@FDA.¹

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), myelosuppression, and embryo-fetal toxicity.¹ The recommended talazoparib dose is 0.5 mg orally once daily with enzalutamide until disease progression or unacceptable toxicity, with enzalutamide dosed per its own prescribing information.¹

Patients receiving the combination should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have undergone bilateral orchiectomy.¹ The application received priority review.¹

The review was conducted under Project Orbis, an FDA Oncology Center of Excellence framework for concurrent submission and review of oncology drugs among international partners.¹ For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada, where reviews remain ongoing.¹ The FDA also used the Assessment Aid, a voluntary applicant submission intended to facilitate the agency’s assessment.¹

For urologists treating metastatic prostate cancer, the approval makes HRR gene testing a prerequisite for this regimen in the mAPMN/S setting.¹ Testing can draw on tumor tissue or a liquid biopsy through the approved FoundationOne companion diagnostics.¹

REFERENCES

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

2. TALAPRO-3. ClinicalTrials.gov identifier: NCT04821622. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT04821622