ODAC Votes Against Talazoparib Combo for Patients With non-HRR mCRPC

The FDA's ODAC voted unanimously against the risk-benefit profile of talazoparib and enzalutamide for the treatment of mCRPC: © stock.adobe.com.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously (8 to 0) against the risk-benefit profile of talazoparib (Talzenna) combined with enzalutamide (Xtandi) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) lacking homologous recombination repair (HRR) mutations.¹

This decision was based on findings from the phase 3 TALAPRO-2 trial (NCT03395197), and the ODAC's decision was shared in a meeting hosted by the regulatory agency.

In June 2023, the FDA approved talazoparib plus enzalutamide for the treatment of patients with HRR gene–mutated mCRPC based on data from TALAPRO-2, which investigated the combination vs placebo plus enzalutamide in patients with first-line mCRPC receiving ongoing androgen deprivation therapy (ADT).^2,3 Notably, patients in cohort 1 of the trial (the all-comers population) were stratified by HRR gene alteration status (deficient vs non-deficient/unknown); however, patients in the non-deficient/unknown group were not separately stratified between non-HRR–mutated status and unknown status.⁴

The FDA has received a supplemental new drug application seeking the approval of talazoparib in combination with enzalutamide for the treatment of all-comer adult patients with mCRPC.⁵

Although TALAPRO-2 did not formally evaluate the HRR-negative subgroup of patients, findings from preclinical studies have supported the clinical evaluation of the combination in patients not harboring HRR mutations.⁴ The FDA noted that mechanistic rationale alone is not enough to support the regulatory approval of a regimen. However, the regulatory agency questioned whether the mechanistic rationale for using talazoparib plus enzalutamide in non-HRR–mutant mCRPC is enough to support the use of the combination for the all-comers indication despite flaws in the TALAPRO-2 design and findings from additional relevant clinical trials showing reduced or no efficacy of PARP inhibition in patients with non-HRR–mutated mCRPC.

TALAPRO-2 Background

TALAPRO-2 enrolled 1018 patients with first-line mCRPC who were asymptomatic or mildly symptomatic. Cohort 1 (n = 805) included patients who were unselected for HRR mutation status, and 169 patients in this group harbored HRR mutations. Patients in this cohort were randomly assigned 1:1 to receive enzalutamide plus talazoparib (n = 402; HRR-mutant, n = 85) or enzalutamide plus placebo (n = 403; HRR-mutant, n = 84). Cohort 2 enrolled 230 patients with HRR-mutated disease who were randomly assigned 1:1 to receive enzalutamide plus talazoparib (n = 115) or enzalutamide plus placebo (n = 115).

Data from the TALAPRO-2 that supported the 2023 FDA approval of talazoparib plus enzalutamide for patients with HRR-mutated mCRPC showed that in the combined HRR-mutated population (n = 399), a statistically significant radiographic progression-free survival (rPFS) benefit was seen with the combination. At the primary analysis, the median rPFS in this population was not reached (NR) with the combination vs 13.8 months with enzalutamide plus placebo (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).^2,4

In the HRR-unselected cohort 1 population at the primary analysis, the median rPFS was NR (95% CI, 27.5-NR) with the combination (n = 402) vs 21.9 months (95% CI, 16.6-25.1) with enzalutamide alone (n = 403; HR, 0.627; 95% CI, 0.506-0.777; P < .0001).⁶ At the final analysis, the rPFS benefit in the unselected population was maintained at 33.1 months (95% CI, 27.4-39.0) with the combination vs 19.5 months (95% CI, 16.6-24.7) with enzalutamide alone (HR, 0.667; 95% CI, 0.551-0.807; P < .0001). Additionally, the median overall survival (OS) in this population was 45.8 months (95% CI, 39.4-50.8) with the combination vs 37.0 months (95% CI, 34.1-40.4) with enzalutamide alone (HR, 0.796; 95% CI, 0.661-0.958; P = .0155).

Notably, an exploratory analysis in the non-HRR–mutated/unknown patients from cohort 1 (n = 636) showed an rPFS HR of 0.70 (95% CI, 0.54-0.89) and an OS HR of 0.93 (95% CI, 0.73-1.19).⁴

FDA’s Position

Gaps in Subgroup Definition

In the ODAC meeting, the FDA explained that although the biomarker-undetected population represented a high proportion of the all-comers population from cohort 1 of TALAPRO-2, this population was incompletely defined, not truly biomarker-negative, and not formally tested for efficacy in the trial. Therefore, the regulatory agency argued that the TALAPRO-2 data in the non-HRR–mutated/unknown population should be interpreted with caution, with the aim of preventing patients with non-HRR–mutated disease from unnecessary exposure to toxicity from talazoparib if they are expected to experience reduced efficacy with the agent compared with patients with HRR-mutated disease.

"This sequence underscores a very important regulatory and historical pattern where formally testing drugs in a biomarker-negative population not only answers the question [of efficacy], but it also spurs discovery to finding therapies that work in that population," Neil Vasan, MD, PhD, of the Perlmutter Cancer Center at New York University Langone Health, stated during a discussion regarding the necessity for formally evaluating therapies in biomarker-negative populations with a high prevalence when the biomarker is predictive of response.

Unclear Applicability of OS Data

Furthermore, the FDA noted that the OS benefit with talazoparib plus enzalutamide in TALAPRO-2 was primarily attributed to the HRR-mutated population and was not clearly established in the non–HRR-mutated/unknown population. A subgroup analysis of OS showed that although OS outcomes favored the combination in both populations, the benefit was greater among patients with HRR mutations (HR, 0.542; 95% CI, 0.361-0.814) vs those without HRR mutations/unknown HRR status (HR, 0.874; 95% CI, 0.711-1.076).⁶ Conflicting exploratory OS data have also been noted between the “double-negative” non-HRR–mutated population and the “single-negative”/unknown population, which the FDA defined based on the number of available tests that were used.

Added Talazoparib-Associated Toxicity

The regulatory agency also cited concern regarding the added toxicity associated with talazoparib plus enzalutamide vs enzalutamide alone. In the final OS analysis of cohort 1 of TALAPRO-2, any-grade treatment-emergent adverse effects (TEAEs) were reported in 99.0% of patients in the investigational arm (n = 398) vs 95.8% (n = 401) of patients in the placebo arm.⁶ The rates of treatment-related TEAEs were 90.5% vs 71.3%, respectively. Serious TEAEs and serious treatment-related TEAEs were reported in 45.7% and 21.4% of patients in the combination arm, respectively, vs 31.4% and 3.2% of those in the control arm, respectively. Grade 3/4 TEAEs were observed in 75.9% vs 44.6% of patients in the investigational and control arms, respectively. In total, 14 and 20 patients in these respective arms experienced grade 5 TEAEs, 1 and 2 of which were treatment-related, respectively.

Dose interruptions, reductions, or discontinuations of talazoparib or placebo due to AEs occurred in 65.3%, 54.5%, and 21.6% of patients in the combination arm vs 24.7%, 7.2%, and 13.0% of those in the placebo arm. Notably, in the talazoparib arm, 42.2% of patients received a red blood cell transfusion; among these patients, the median number of transfusions received was 2. The FDA also explained that myelodysplastic syndrome and acute myeloid leukemia, which are class effects of PARP inhibitors, were reported in 2 evaluable patients who received talazoparib in TALAPRO-2.⁵

Overall, the FDA argued that these safety data should be regarded within the context of certainty about the efficacy of talazoparib plus enzalutamide in the all-comer population of TALAPRO-2 to help determine whether the combination has an acceptable risk/benefit profile in this population.

Lack of PARP Inhibitor Benefit in Other mCRPC Trials

Finally, the FDA questioned the efficacy of talazoparib plus enzalutamide in a truly non-HRR–mutated mCRPC population in light of the limited efficacy observed with PARP inhibition in other non-HRR–mutated mCRPC trials. For instance, although the phase 3 MAGNITUDE trial (NCT03748641), which evaluated first-line niraparib (Zejula) plus abiraterone acetate (Zytiga) and prednisone in patients with mCRPC, was formally designed to evaluate the combination in a non-HRR–mutated cohort (cohort 2), it showed no added rPFS or OS benefit with the addition of the PARP inhibitor vs abiraterone acetate plus prednisone alone. Cohort 2 was stopped due to futility after 246 patients were treated.

Furthermore, the FDA noted that several completed and ongoing mCRPC clinical trials are only designed to enroll patients with HRR-mutated tumors, associating this with a trend toward the prostate cancer field’s broader understanding that PARP inhibitors are most effective in a biomarker-selected population. Notably, the ongoing phase 3 TALAPRO-3 trial (NCT04821622) of talazoparib plus enzalutamide has restricted enrollment to patients with HRR-mutated metastatic castration-sensitive prostate cancer.

References

1. May 21, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/5ecyDbK9ezc
2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastaic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed May 21, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
3. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3.
4. Talazoparib with enzalutamide for metastatic castration-resistant prostate cancer (mCRPC). FDA. May 21, 2025. Accessed May 21, 2025. https://www.fda.gov/media/186563/download
5. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Oncologic Drugs Advisory Committee (ODAC) Agenda. FDA. May 21, 2025. Accessed May 21, 2025. https://www.fda.gov/media/186520/download
6. 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.LBA1