Talazoparib/Enzalutamide sNDA Receives FDA Priority Review in HRR+ CSPC

The FDA has accepted for priority review a supplemental new drug application (sNDA) for talazoparib (Talzenna) in combination with enzalutamide (Xtandi) in patients with homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (CSPC), according to a news release from the developer, Pfizer.¹ The FDA set a prescription drug user fee act (PDUFA) action date in the fourth quarter of 2026. If approved, the application would expand the combination's current indication beyond metastatic castration-resistant prostate cancer (CRPC) to CSPC, an earlier stage of the disease.

What data support the sNDA?

The filing is supported by data from the phase 3 TALAPRO-3 trial (NCT04821622), in which talazoparib plus enzalutamide reduced the risk of radiographic progression or death by 52% compared with placebo plus enzalutamide, with consistent benefit observed across patients with BRCA and non-BRCA HRR gene alterations. Results presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meetingand simultaneously published in the New England Journal of Medicine showed that the median radiographic PFS 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).^2,3 In the BRCA-mutated subgroup, the median radiographic PFS was NR (95% CI, NR-NR) and 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 radiographic progression-free survival (PFS) readout showed a strong 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.⁴

The safety profile of the combination was consistent with the known safety profiles of talazoparib and enzalutamide individually, 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 well as the grade 3 or higher incidence of anemia (51% vs 3%).

Investigators noted that treatment-emergent hematologic adverse effects were manageable through dose modifications and other supportive measures. Additionally, the patient-reported outcome data did not differ significantly between each treatment arm.

How was TALAPRO-3 designed?

TALAPRO-3 is a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 599 patients 18 years and older with metastatic CSPC at sites in the United States, Canada, Europe, South America, and the Asia-Pacific region.¹ Eligible patients had histologically or cytologically confirmed prostate adenocarcinoma without neuroendocrine, small cell, or signet cell features; an 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, and were stratified by de novo vs relapsed disease, high- vs low-volume disease, and BRCA vs non-BRCA mutational status.⁵

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

What does this mean for the existing metastatic CRPC indication?

"For men living with metastatic prostate cancer, intervening during the hormone-sensitive stage represents an important opportunity to delay progression before the disease becomes more difficult to manage," stated Jeff Legos, chief oncology officer of Pfizer, in the press release.¹ "If approved, [talazoparib plus enzalutamide] would offer patients with HRR-driven disease a new treatment option that could help them live longer without their cancer progressing. The data supporting this application also reinforce the importance of biomarker testing to inform treatment decisions as early as possible."

References

1. 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 July 23, 2026. https://tinyurl.com/3b77fwvx
2. Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer harboring homologous recombination repair gene alterations. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007
3. 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/NEJMoa2604126
4. TALZENNA plus XTANDI significantly improves radiographic progression-free survival in metastatic prostate cancer. News release. Pfizer Inc. March 19, 2026. Accessed July 23, 2026. https://tinyurl.com/47jn4kwf
5. Study of talazoparib with enzalutamide in men with DDR gene mutated metastatic CSPC (TALAPRO-3). ClinicalTrials.gov. Updated July 22, 2026. Accessed July 23, 2026. https://tinyurl.com/mpj8s5pj