On October 26, 2026, the U.S. Food and Drug Administration (FDA) approved talazoparib (Talzenna, Pfizer Inc.) in combination with enzalutamide for adults with metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer harboring homologous recombination repair (HRR) gene mutations, as detected by an FDA-authorized test.
The approval was supported by results from the Phase III TALAPRO-3 trial (NCT04821622), evaluating talazoparib plus enzalutamide compared with placebo plus enzalutamide.
What Was Behind the Approval?
TALAPRO-3 was a randomized, double-blind, placebo-controlled Phase III trial involving 599 patients with HRR gene-mutated mAPMN/S prostate cancer. Patients were randomly assigned 1:1 to receive:
- Talazoparib plus enzalutamide.
- Placebo plus enzalutamide.
Both regimens were administered daily, and all patients received continuous androgen deprivation therapy (ADT). HRR gene mutation status was determined prospectively using tumor tissue or circulating tumor DNA (ctDNA)-based next-generation sequencing. The evaluated genes included ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.
The major efficacy endpoint was investigator-assessed radiographic progression-free survival (rPFS), evaluated according to RECIST v1.1 and PCWG3 bone criteria. Overall survival (OS) was an additional efficacy endpoint.
What Were the Key Findings?
The trial demonstrated a statistically significant improvement in rPFS with talazoparib plus enzalutamide compared with placebo plus enzalutamide.
- Median rPFS: Not reached (95% CI: NR–NR) versus 45.8 months (95% CI: 37.7–NR).
- Hazard ratio: 0.48 (95% CI: 0.36–0.65; p<0.0001).
These findings represent a 52% relative reduction in the hazard of radiographic progression or death with talazoparib plus enzalutamide. At the time of the rPFS analysis, overall survival data remained immature, and an OS benefit had not yet been established.
TALAPRO-3 at ESMO 2026
At the ESMO Congress 2026, Arun A. Azad (Melbourne, Australia) presented a biomarker analysis from TALAPRO-3 during the Rapid Oral session (2219RO), evaluating the prognostic utility of baseline ctDNA tumour fraction and changes at Week 5 in patients with HRR gene-mutated metastatic castration-sensitive prostate cancer (mCSPC). The analysis included 454 patients evaluable for baseline ctDNA tumour fraction, excluding patients in China, with a data cutoff of February 18, 2026.
Conversion from ctDNA-positive to ctDNA-negative status at Week 5 occurred in:
- 82.1% (55/67) of patients receiving talazoparib plus enzalutamide.
- 68.2% (45/66) of patients receiving placebo plus enzalutamide.
Compared with persistent ctDNA positivity, conversion to ctDNA-negative status was associated with longer rPFS in both treatment arms:
- Talazoparib plus enzalutamide: HR 0.36 (95% CI: 0.14–0.93; nominal p=0.03).
- Placebo plus enzalutamide: HR 0.43 (95% CI: 0.22–0.83; nominal p=0.01).
Patients who remained ctDNA-negative at baseline and Week 5 also demonstrated favorable rPFS outcomes. These findings support further evaluation of ctDNA tumour fraction and early on-treatment changes as potential prognostic biomarkers in this setting. The biomarker findings were separate from the primary efficacy evidence supporting the FDA approval.
Safety and Recommended Dosage
The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. The recommended dose of talazoparib is 0.5 mg orally once daily, administered with enzalutamide until disease progression or unacceptable toxicity.
Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or have undergone bilateral orchiectomy. The FDA previously approved FoundationOne CDx and FoundationOne Liquid CDx as companion diagnostic assays to identify patients with HRR gene alterations for treatment with talazoparib plus enzalutamide.
Regulatory Review
The application received priority review and was evaluated under Project Orbis, an initiative of the FDA Oncology Center of Excellence that facilitates concurrent regulatory review among international partners.
The FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada. Reviews by the other regulatory agencies were ongoing at the time of the FDA announcement.
Takeaway
The FDA approval of talazoparib plus enzalutamide provides an additional treatment option for patients with HRR gene-mutated metastatic androgen pathway modulation-naïve or -sensitive prostate cancer.
The decision was supported by a statistically significant rPFS benefit in TALAPRO-3, with a 52% relative reduction in the hazard of radiographic progression or death compared with placebo plus enzalutamide.
The ESMO 2026 biomarker analysis additionally demonstrated associations between early ctDNA tumour fraction changes and rPFS. However, overall survival data from the pivotal trial remain immature, and further follow-up is needed to establish the combination’s effect on survival.
Sources:
U.S. Food and Drug Administration (FDA), October 26, 2026.
ESMO Congress 2026, Abstract 2219RO — TALAPRO-3 biomarker analysis, presented by Arun A. Azad.
