FDA Advisory Committee unanimously votes against talazoparib plus enzalutamide for mCRPC

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in a unanimous 0-8 decision that the TALAPRO-2 data on talazoparib (Talzenna) in combination with enzalutamide (Xtandi) is not sufficient to conclude a favorable benefit-risk profile in adult patients with metastatic castration-resistant prostate cancer (mCRPC) unselected for homologous recombination repair (HRR) gene alterations.¹

The sNDA is supported by data from cohort 1 of the TALAPRO-2 trial.

In their decision, the committee expressed concerns over a trial design that did not specifically stratify for patients without HRR gene mutations. They also cited concerns over the toxicity of this regimen in this population.

Although the FDA relies on the ODAC meeting to inform their pending regulatory decisions, the agency is not bound by the consensus that the group reaches.

Background

The FDA previously approved talazoparib in combination with enzalutamide for patients with HRR-positive mCRPC on June 20, 2023.²

The approval was supported by data from cohort 2 of the TALAPRO-2 trial (NCT03395197), in which the combination demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) vs placebo plus enzalutamide in patients with HRR-gene mutated mCRPC. At the time of report, the median rPFS had not been reached in the talazoparib/enzalutamide arm and was 13.8 months in the placebo/enzalutamide arm (HR, 0.45; 95% CI, 0.33 to 0.61; P < .0001).

Overall, the study included 2 cohorts: patients unselected for HRR gene mutations (cohort 1) and patients selected for HRR gene mutations (cohort 2).

Updated data from the TALAPRO-2 trial were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.^3,4 At a median follow-up of 52.5 months, the median overall survival (OS) among patients in cohort 1 was 45.8 months in the talazoparib/enalutamide arm vs 37 months in the placebo/enzalutamide arm (HR, 0.80; 95% CI, 0.66 to 0.96; P = .015).

OS was also found to favor the combination of talazoparib/enzalutamide in patients who were HRR-deficient (n = 169; HR, 0.549; 95% CI, 0.364 to 0.826; P = .0035) or HRR–non-deficient/unknown (n = 636; HR, 0.878; 95% CI, 0.713 to 1.080; P = .218). Data from cohort 2 were consistent with the primary analyses.

Based on these data, Pfizer submitted an sNDA to the FDA seeking an expanded indication for talazoparib plus enzalutamide to include patients unselected for HRR gene mutations. If approved, this would mark the first approval of a PARP inhibitor in unselected mCRPC.

Please find live updates from the ODAC meeting below. These were recording live by the Urology Times® editorial team.

4:00pm update:

The committee proceeded to a discussion of the first task proposed by the FDA: Discuss whether efficacy should be formally evaluated in a biomarker-negative population when the biomarker is predictive of response and the prevalence of the biomarker-negative group is high.

Overall, the committee discussed the value that trials with a biomarker-negative subgroup has in understanding what therapies work in these patients. The committee also touched on the importance of defining what efficacy means, the need to consider toxicity in evaluating the impact of treatment, and the overall value of next-generation sequencing. They noted the benefit of conducting a trial specifically focused on efficacy assessments in biomarker-positive vs biomarker-negative subgroups.

The committee then voted on the question: “Are the results from TALAPRO-2 sufficient to conclude a favorable benefit-risk profile for adding talazoparib to enzalutamide in patients with non-homologous recombinant repair mutated (non-HRRm) metastatic castration-resistant prostate cancer (mCRPC)?

Overall, 0 committee members voted “yes,” and 8 committee members voted “no.”

2:30pm update:

Will Maguire, MD, PhD, of the FDA, walked through the main review issues with Pfizer’s sNDA. These are as follows:

• Large (~70%), incompletely-defined non-HRRm subgroup was not formally tested for efficacy
• Interpretation of the OS results and applicability to current US standard of care are unclear
• Addition of talazoparib increases hematologic toxicity vs enzalutamide alone
• Trials of other PARP inhibitors did not support an all-comers indication

Maguire explained that definitions of biomarker-negative varied in the trial, depending on the number of negative tests (ctDNA and tissue). He also noted that the trial did not formally control for false-positive conclusions (type 1 error).

He also questioned the acceptability of added toxicity with talazoparib given the questionable efficacy of the combination.

These concerns are all in the context of other trials of PARP inhibitor plus ARPIs, in which there was limited or no efficacy of PARP inhibitors in patients with non-HRRm mCRPC. He also suggested a broad understanding in the field that there is differential sensitivity to PARP inhibitors based on biomarker status given that many trials include only patients with HRR mutations. This restricted eligibility applies to Pfizer’s TALAPRO-3 trial in metastatic hormone-sensitive prostate cancer (mHSPC).

Thus, there is uncertainty if the benefit of the combination is sufficient given the flaws in the trial design.

2:00pm update:

Neeraj Agarwal, MD, principal investigator of TALAPRO-2 and urologist at the Huntsman Cancer Institute, offered his perspective on the value of this combination.

He reiterated the unprecedented OS data in this patient population. He also shared efficacy data in comparison with that seen in PROpel to reiterate that the benefit seen in the non-HRR mutation population is clinically meaningful, and is likely due to mechanism of action rather than chance.

Agarwal also noted that the most frequent adverse event, anemia, is expected and manageable in clinic. Given the prevalence of anemia, many physicians treating mCRPC are well-versed in managing this complication.

1:30pm update:

Johanna Bendell, MD, chief development officer of oncology research and development at Pfizer, delivered opening remarks on behalf of the company.

She introduced data from the TALAPRO-2 trial, noting that benefits in rPFS and OS were observed in patients with and without HRR gene mutations. These results are unlikely to be due to chance, and there is a rationale for the differentiated mechanism of action for the combination of talazoparib plus enzalutamide in mCRPC, according to Bendell.

Pedro Barata, MD, MSc, FACP, of Case Western Reserve University in Cleveland, Ohio, was then invited to offer a treatment landscape perspective. The began by emphasizing the need for options in this space, noting that the probability of being alive at 5 years following an mCRPC diagnosis is less than 40%. He also explained that the first-line of therapy offers the best chance to improve outcomes.

He also illustrated the biological rationale for benefit of talazoparib plus enzalutamide in patients with and without HRR gene mutations due to the cross-talk between the 2 pathways.

Dana Kennedy, PharmD, BCOP, of Pfizer, walked through the efficacy and safety data from the TALAPRO-2 trial. The study included 2 cohorts: patients unselected for HRR mutations (cohort 1) and those with HRR gene mutations (cohort 2). In each cohort, patients were randomly assigned 1:1 to the combination of talazoparib plus enzalutamide (cohort 1, n = 402; cohort 2, n = 200) or to placebo/enzalutamide (cohort 1, n = 403; cohort 2, n = 199).

In the unselected population, the primary results showed a 37% reduction in the risk of progression or death with the combination of talazoparib plus enzalutamide (HR, 0.627; 95% CI, 0.506 to 0.777; P < .0001). At 2 years of follow-up, this benefit was sustained (HR, 0.667; 95% CI, 0.551 to 0.807; P < .0001).

The median rPFS of the combination was 33.1 months with talazoparib plus enzalutamide vs 19.5 months with enzalutamide alone.

rPFS benefit was also consistent across relevant clinical subgroups.

Additionally, the combination led to a statistically significant benefit in overall survival among these patients, with a 20% reduction in the risk of death with talazoparib/enzalutamide. In the combination arm, the median OS was 45.8 months vs 37.0 months with enzalutamide alone arm (HR, 0.796; 95% CI, 0.661 to 0.958; P = .0155). OS benefit was also consistent across pre-specified subgroups.

Treatment effect was also shown across the study’s secondary end points of confirmed PSA50 response, confirmed ORR, time to PSA progression time to first subsequent therapy, and time to first cytotoxic chemotherapy.

There was also a demonstrated improvement in rPFS and OS in patients with no detectable HRR mutations on both ctDNA and tissue, the most rigorously defined non-HRR mutation subgroup. According to Kennedy, these results suggest that benefit of the combination is unlikely due to chance.

Kennedy then outlined the safety data from the TALAPRO-2 trial. The safety profiles for talazoparib and enzalutamide were consistent with their known risks. No new safety signals were observed over 24 months.

According to Kennedy, there were no significant differences between the safety data in those with HRR mutations or without. In the unselected cohort (cohort 1), any adverse events (AEs) were reported in 99% of patients in the combination arm vs 95.8% in the enzalutamide alone arm. The most common treatment-emergent AEs in the combination arm were hematologic.

The incidence of anemia generally occurred early in the treatment course and then decreased over time. Dose discontinuation due to anemia was 8.5% in the talazoparib/enzalutmide arm vs 1.5% in the enzalutamide alone arm.

Quality of life measures and function and symptom scores were not significantly different between arms.

1pm update:

Jaleh Fallah, MD, issued opening remarks on behalf of the FDA.

Fallah reviewed data from the TALAPRO-2 trial, which showed an improvement in rPFS in both all-comers and in patients with an HRR gene mutation. However, she said that the FDA did not feel that the improvement in the all-comer population was clinically significant.

Updated results on OS show that the benefit in all-comers may be largely attributed to those with HRR gene mutations, according to Fallah. It is possible, she noted, that the observed effect in the non-HRR population may be due to randomness/chance.

Fallah then explained the purpose of the ODAC meeting, which is to address the following:

• The lack of pre-specified formal statistical testing of efficacy in the non-HRR population
• The lack of supportive data from prior trials of PARP inhibitors for approval of non-HRR population

She also acknowledged that this approval decision would affect a large patient population (over 70% of patients with mCRPC).

An approval for this population would warrant a trial with the following design:

1. Separate pre-specified formal statistical analyses with adequate control of type I error in each biomarker-defined population
2. Adequate prospective diagnostic testing for determination of the biomarker status.

Thus, the FDA poses the following discussion topic to the committee: Discuss whether efficacy should be formally evaluated in a biomarker-negative population when the biomarker is predictive of response and the prevalence of the biomarker-negative group is high.

The FDA also posed the following voting question: Are the TALAPRO-2 results sufficient to conclude a favorable benefit-risk profile for adding talazoparib to enzalutamide in patients with non-HRRm mCRPC?

REFERENCES

1. May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee. US Food & Drug Administration. Accessed May 21, 2025. https://www.fda.gov/media/186530/download

2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. US Food & Drug Administration. 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 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 (suppl 5; abstr LBA18). doi:10.1200/JCO.2025.43.5_suppl.LBA18

4. Pfizer’s TALZENNA in combination with XTANDI improves survival outcomes in metastatic castration resistant prostate cancer. News release. Pfizer. February 13, 2025. Accessed May 21, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-improves-survival