ODAC Votes 8-to-0 Against First-Line Talazoparib/Enzalutamide in mCRPC

In June 2023, the FDA approved talazoparib/enzalutamide for patients with HRR–mutant metastatic CRPC, with supporting data for the decision coming from the phase 3 TALAPRO-2 trial.

The FDA’s Oncologic Advisory Drug Committee (ODAC) voted 8-0 against the favorability of talazoparib (Talzenna) plus enzalutamide (Xtandi) as frontline therapy for all-comer patients with non-homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (CRPC).¹

“There was concern about full characterization of the non-mutant population, the statistical assumptions that went into making the case that there was a benefit, and the toxicity data demonstrated that oncologists can take care of toxicity, but it did not get to the patient experience with [talazoparib plus enzalutamide],” William Gradishar, MD, Betsy Bramsen professor of Breast Oncology at Northwestern University, said at the ODAC meeting.¹ “For all those reasons, I voted no.”

In June 2023, the FDA approved talazoparib/enzalutamide for patients with HRR–mutant metastatic CRPC.² Supporting data for the decision came from the phase 3 TALAPRO-2 trial (NCT03395197).

Developers proposed expanding the indication for the talazoparib combination to include all patients regardless of their HRR mutation status.³ The ODAC convened to discuss and vote on whether findings from TALAPRO-2 were sufficient to support a favorable risk/benefit profile for combining talazoparib with enzalutamide for patients with metastatic CRPC who do not have HRR gene mutations.

TALAPRO-2 Data

According to results from the final prespecified overall survival (OS) analysis of the phase 3 TALAPRO-2 trial, among 805 unselected patients, the median OS was 45.8 months (95% CI, 39.4-50.8) with the talazoparib/enzalutamide combination vs 37.0 months (95% CI, 34.1-40.4) with placebo/enzalutamide (HR, 0.796; 95% CI, 0.661-0.958; 2-sided P = .0155), meeting the threshold for statistical significance (P ≤ .022).⁴

Additionally, subgroup analyses revealed a pronounced OS benefit in those with HRR-deficient disease (HR, 0.542; 95% CI, 0.361-0.814), and trends in OS improvement were noted in those without a detectable BRCA mutation (HR, 0.749; 95% CI, 0.582-0.963; P = .0237) and those without a detectable HRR deficiency (HR, 0.782; 95% CI, 0.582-1.050; P = .1008).

The OS data complemented previously reported radiographic progression-free survival (rPFS) data that directly resulted in the June 2023 FDA approval of talazoparib and enzalutamide in HRR-mutant metastatic CRPC. The final data confirmed a statistically significant improvement rPFS with talazoparib vs placebo at 33.1 months (95% CI, 27.4-39.0) vs 19.5 months (95% CI, 16.6-24.7), respectively (HR, 0.667; 95% CI, 0.551-0.807; P <.0001).

Furthermore, another notable benefit observed with talazoparib included an increase in median time to cytotoxic chemotherapy; for the combination arm, it was not reached (NR; 95% CI, NR-NR) vs 56.1 months (95% CI, 32.7-NR) in the placebo arm (HR, 0.568; 95% CI, 0.446-0.772; P <.0001). Furthermore, an additional benefit was an increase in the median time to definitive deterioration in patient quality of life at 41.5 months (95% CI, 36.0-48.8) vs 34.1 months (95% CI, 27.9-45.2) in each respective arm (HR, 0.878; 95% CI, 0.704-1.096; P = .2487).

The phase 3 TALAPRO-2 trial included 2 cohorts, the first of which enrolled 805 unselected patients with newly diagnosed metastatic CRPC regardless of HRR status. Cohort 2 enrolled 399 patients with confirmed HRR alterations in BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, and/or CDK12. The goal in each cohort was assessing whether a synergistic tumor cell killing effect was achieved through the combination of PARP inhibition and androgen receptor pathway inhibition.

Patients in the talazoparib arm received 0.5 mg of daily talazoparib plus 160 mg of daily enzalutamide. Those in the control arm received matching placebo plus 160 mg of daily enzalutamide.

The primary end point of the trial was blinded independent central review–assessed rPFS in all comers and those with HRR deficiencies. Secondary end points included time to cytotoxic chemotherapy, objective response rate, and patient-reported outcomes.

No new safety signals were observed during follow-up; the most common grade 3/4 treatment-emergent adverse effects (TEAEs) observed in the combination and placebo arms, respectively, included anemia (49.0% vs 4.5%) and neutropenia (19.3% vs 1.5%). Toxicity led to dose interruptions in 65.3% vs 24.7% of the respective arms, dose reductions in 54.5% vs 7.2%, and drug discontinuations in 21.6% vs 13.0% of each arm.

Additionally, 49.0% of patients treated with talazoparib developed grade 3/4 anemia at a median time to onset of 3.3 months.Of these patients, 42.2% received a red blood cell transfusion at a median of 2 transfusions over a median talazoparib treatment duration of 19.7 months. Treatment discontinuation due to anemia was observed in 8.5% of patients.

References

1. May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee (ODAC) - Day 2. Streamed live May 21, 2025. Accessed May 21, 2025. https://tinyurl.com/3dwnev5z
2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. June 20, 2023. Accessed May 20, 2025. https://bit.ly/3pcuSTH
3. Oncologic Drugs Advisory Committee (ODAC) Meeting May 21, 2025. NDA# 211651/Supplement 13 . FDA. Accessed May 21, 2025. https://tinyurl.com/ym576r9u
4. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA18