FDA Approves Talazoparib Plus Enzalutamide for HRR-Mutated mHSPC

The FDA has approved talazoparib (Talzenna; Pfizer) plus enzalutamide (Xtandi; Pfizer and Astellas) for metastatic hormone-sensitive prostate cancer (mHSPC) with homologous recombination repair (HRR) gene mutations, moving the combination into an earlier disease setting, Pfizer announced in a news release.¹ HRR gene mutations must be detected by an FDA-authorized test for patients to be eligible for the treatment.²

Support for the expanded indication came from the phase 3 TALAPRO-3 trial (NCT04821622), in which adding the PARP inhibitor to enzalutamide produced a 52% lower risk of radiographic progression or death compared with placebo plus enzalutamide. Investigators reported the data at the American Society of Clinical Oncology 2026 Annual Meeting, with a simultaneous publication in the New England Journal of Medicine.^1,3

HRR Mutations in Hormone-Sensitive Metastatic Prostate Cancer

In mHSPC, the cancer has spread outside the prostate but still responds to androgen deprivation therapy. Until now, the talazoparib-enzalutamide regimen was approved in the US only for HRR-mutated metastatic castration-resistant disease, an indication granted in June 2023 on the strength of the TALAPRO-2 trial.⁴ In that study, the combination lowered the risk of progression or death by 55% in the HRR-mutated cohort (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).

The double-blind, placebo-controlled TALAPRO-3 study randomly assigned 599 patients 1:1 to talazoparib 0.5 mg or placebo once daily, each given with enzalutamide 160 mg daily alongside continued androgen deprivation therapy.^1,2 Eligibility required a mutation in at least 1 of 12 HRR genes, among them BRCA1, BRCA2, ATM, CDK12, and PALB2, identified prospectively by sequencing tumor tissue or circulating tumor DNA.² Randomization was stratified by disease status, disease volume, and BRCA status. Investigator-assessed radiographic progression-free survival (rPFS) served as the primary end point, with overall survival (OS) as the key secondary end point.³

Talazoparib Plus Enzalutamide Improves rPFS in TALAPRO-3

Median rPFS had not been reached in the talazoparib group, compared with 45.8 months in the placebo group (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).² At 3 years, 77% of patients receiving the combination were alive without radiographic progression vs 56% of those in the control group.³

“In the TALAPRO-3 trial, clinical benefits were consistent for patients with BRCA and non-BRCA HRR gene mutations, addressing a long-standing unmet need—and reinforcing the importance of biomarker testing at the time of diagnosis,” Neeraj Agarwal, MD, FASCO, the trial’s global lead investigator and first author of the published study, said in the Pfizer news release.¹ At an interim analysis, 3-year OS was 78% in the talazoparib group and 72% in the placebo group (HR, 0.77), a difference that did not meet the prespecified threshold for statistical significance.³

Safety, Monitoring, and Open Questions

Rates of grade 3 or higher adverse events (AEs) were 81% with talazoparib and 44% with placebo, and rates of serious AEs were 42% and 32%, respectively.³ Anemia was the most frequent grade 3 or higher AE, occurring in 51% of the talazoparib group vs 3% of controls, and 5% of patients discontinued talazoparib because of it.¹ The trial recorded 2 treatment-related deaths, both with talazoparib.³ Pfizer stated that the safety findings matched the established profile of each drug and that no new signals emerged.¹

The prescribing information includes warnings about embryo-fetal toxicity, myelosuppression, and myelodysplastic syndrome/acute myeloid leukemia, and it calls for monthly blood count monitoring during treatment.^1,2 In pooled data, 41% of patients treated with the combination needed a red blood cell transfusion.¹ FoundationOne CDx and FoundationOne Liquid CDx are the authorized companion diagnostics for selecting patients.²

When the rPFS analysis was conducted, OS data were still immature, and Pfizer acknowledged that it is not yet known whether TALAPRO-3 will meet its OS end point.^1,2 The FDA reviewed the application under priority review and Project Orbis, and the European Medicines Agency is evaluating a parallel application.^1,2

“This approval represents a critical advancement for patients with newly diagnosed metastatic prostate cancer with HRR gene mutations, who face a more aggressive disease, worse prognosis, and limited treatment options,” Agarwal said.¹

References

1. Pfizer’s Talzenna plus Xtandi FDA-approved for an earlier metastatic prostate cancer treatment setting. News release. Pfizer. October 26, 2026. Accessed October 26, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzenna-plus-xtandi-fda-approved-earlier

2. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naive or -sensitive prostate cancer with HRR gene mutations. News release. FDA. 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

3. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026;395(5):427-439. doi:10.1056/NEJMoa2604126

4. Pfizer’s Talzenna in combination with Xtandi receives US FDA approval. News release. Pfizer. June 20, 2023. Accessed October 26, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-receives-us-fda