FDA Approves Talazoparib/Enzalutamide for HRR Gene-Altered Metastatic Prostate Cancer

The FDA has approved talazoparib (Talzenna) in combination with enzalutamide (Xtandi) for the treatment of patients with metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer with homologous recombination repair (HRR) gene mutations, as detected by an FDA-authorized test, according to a press release from the agency.¹ The approval expands the combination's existing indication, which was previously limited to patients with HRR-mutated metastatic castration-resistant prostate cancer (CRPC).

What was the supporting data?

The approval was supported by data from the phase 3 TALAPRO-3 trial (NCT04821622), in which talazoparib plus enzalutamide reduced the risk of radiographic progression or death compared with placebo plus enzalutamide across patients with BRCA and non-BRCA HRR gene alterations.² In July 2026, the FDA granted priority review to the supplemental new drug application (sNDA) and set a PDUFA action date in the fourth quarter of 2026.³

Results from TALAPRO-3 were presented as a late-breaking abstract at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine.^4,5 The median radiographic progression-free survival (rPFS) in the talazoparib arm was not reached (NR; 95% CI, NR-NR) vs 45.8 months (95% CI, 37.7%-NR) with placebo (HR, 0.481; 95% CI, 0.357-0.647; P <.0001). In the BRCA-mutated subgroup, the median rPFS was NR (95% CI, NR-NR) vs 35.1 months (95% CI, 18.6-NR), respectively (HR, 0.368; 95% CI, 0.222-0.609; P <.0001); for the non-BRCA-mutated subgroup, the values were NR (95% CI, NR-NR) and NR (95% CI, 40.5-NR), respectively (HR, 0.567; 95% CI, 0.392-0.819; P = .0022).

An interim analysis at the time of the primary rPFS readout demonstrated a trend toward improved overall survival (OS; P = .0905), a key secondary end point, along with benefits in overall response rate (ORR), duration of response (DOR), and time to prostate-specific antigen (PSA) progression.

“When you look at the Kaplan-Meier curves for the intent-to-treat population, and for the BRCA subgroup vs the non-BRCA subgroup, the curves separate very early, within a matter of a few months,” Neal Shore, MD, FACS, medical director of the Carolina Urologic Research Center and primary investigator of the TALAPRO-3 trial, stated in an interview with CancerNetwork. “That is remarkably impactful in terms of showing efficacy against progression for these patients.”

Expert Perspective

"Current treatment approaches leave many patients with HRR gene-mutated metastatic [CSPC] vulnerable to early disease progression," said Neeraj Agarwal, MD, FASCO, professor and Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah and global lead investigator for TALAPRO-3, in a prior press release.² "The TALAPRO-3 results demonstrate that treatment with talazoparib in combination with enzalutamide earlier in the disease course significantly extends the time patients can live without their cancer worsening."

How was the TALAPRO-3 trial designed?

TALAPRO-3 was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 599 patients 18 years and older with metastatic CSPC at sites in the US, Canada, Europe, South America, and the Asia-Pacific region. Eligible patients had histologically or cytologically confirmed prostate adenocarcinoma without neuroendocrine, small cell, or signet cell features; a documented alteration in at least 1 of 12 HRR genes assessed by a dedicated gene panel; and no more than 3 months of prior chemical or surgical androgen deprivation therapy, with or without an approved androgen receptor pathway inhibitor, in the metastatic CSPC setting.

Patients were randomly assigned to receive talazoparib at 0.5 mg once daily plus enzalutamide at 160 mg once daily or placebo plus enzalutamide at 160 mg once daily. Those with moderate renal impairment at screening were treated with a reduced talazoparib or matching placebo dose of 0.35 mg once daily. Patients were stratified by de novo vs relapsed disease, high- vs low-volume disease, and BRCA vs non-BRCA mutational status.

The primary end point was investigator-assessed radiographic PFS, defined per RECIST v1.1 criteria in soft tissue or Prostate Cancer Working Group 3 (PCWG3) criteria in bone, or death, whichever occurred first. Secondary end points included OS, ORR, DOR, time to PSA progression, and patient-reported outcomes.

What was the safety profile in the TALAPRO trial?

The safety profile of the talazoparib/enzalutamide combination was consistent with the known profiles of each individual agent, and no new safety signals were identified. In the talazoparib arm, the overall incidence of anemia was higher compared with placebo (71% vs 22%), as was the grade 3 or higher incidence of anemia (51% vs 3%). Treatment-emergent hematologic adverse effects were reported to be manageable through dose modifications and other supportive measures, and patient-reported outcome data did not differ significantly between the treatment arms.

What Does the Updated Prescribing Information Say?

The FDA recommended talazoparib at a dose of 0.5 mg orally once daily with enzalutamide until disease progression or unacceptable toxicity. The prescribing information states that patients receiving talazoparib and enzalutamide should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.

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

References

1. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with HRR gene mutations. News release. FDA. October 26, 2026. Accessed October 26, 2026. https://tinyurl.com/4rvh4ndp
2. TALZENNA plus XTANDI significantly improves radiographic progression-free survival in metastatic prostate cancer. News release. Pfizer Inc. March 19, 2026. Accessed September 2, 2026. https://tinyurl.com/47jn4kwf
3. FDA grants priority review for Pfizer's TALZENNA plus XTANDI for the treatment of metastatic prostate cancer. News release. Pfizer Inc. July 22, 2026. Accessed September 2, 2026. https://tinyurl.com/3b77fwvx
4. Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007
5. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. Published online May 30, 2026. doi:10.1056/NEJMoa260412