About the Discussion
The Committe discussed 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.
ODAC Rejects Label Expansion for Talazoparib in Non-HRRm mCRPC
The ODAC deemed the results from TALAPRO-2 are not sufficient to conclude a favorable benefit-risk profile for adding talazoparib to enzalutamide in non-HRRm mCRPC.
US FDA
The FDA’s Oncologic Drugs Advisory Committee (ODAC) deemed the results from TALAPRO-2 (NCT03395197) insufficient to conclude a favorable benefit-risk profile for adding talazoparib (Talzenna) to enzalutamide (Xtandi) in patients with nonhomologous recombination repair mutated (non-HRRm) metastatic castration-resistant prostate cancer (mCRPC). The vote was 8 to 0.1
Committee members expressed concerns over the lack of a prespecified, statistically powered analysis in the non-HRRm subgroup, which represents the majority of the target population. The panel emphasized that without prospective biomarker stratification, the reliability of the survival benefit in non-HRRm patients remains uncertain.
Additionally, concerns were raised regarding the increased hematologic toxicity and the precedent such an approval might set for biomarker-unselected use of PARP inhibitors absent definitive evidence.
The FDA convened an ODAC meeting on May 21, 2025, to evaluate Pfizer's request to expand the current indication for talazoparib in combination with enzalutamide to include all patients with mCRPC, and not just those with HRR gene mutations. Pfizer's application hinges on the final overall survival (OS) results from TALAPRO-2, a phase 3 trial which demonstrated a statistically significant OS benefit in the overall population.2,3
In June 2023, the FDA approved the talazoparib/enzalutamide combination for the treatment of HRRm mCRPC, supported by data from TALAPRO-2.4 The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.33-0.61; P <.0001).4 The median radiographic progression-free survival (rPFS) at the time was not reached (NR, 95% CI, 27.5 months-not reached) with talazoparib and enzalutamide vs 21.9 months (range, 16.6-25.1) with placebo plus enzalutamide.
“Ultimately, the review team concluded that the benefit-risk evaluation for the non-HRRm/unknown subgroup was not sufficiently favorable in the context of a broad indication, increased toxicity of the combination vs enzalutamide monotherapy, and immature OS. Therefore, the initial approval was limited to patients HRR-mutant mCRPC,” Will Maguire, MD, PhD, clinical reviewer, Genitourinary Malignancies, Division of Oncology I, Office of Oncologic Diseases, explained in the meeting regarding the initial approval of the combination.
The FDA team presented this application for the following issues: lack of prespecified formal statistical testing of the non-HRR population and lack of support from prior trials of PARP inhibitors for approval in the non-HRR population.
“Granting an approval... rewards inadequate methodology and sends the wrong message by promoting flawed practices,” explained Jaleh Fallah, MD, of the FDA stated in her presentation. “The lack of support... from other trials... raises our concern that any apparent efficacy... may just be due to chance.”
However, Pedro Barata, MD, MSc, FACP, associate professor at University Hospitals Seidman Cancer Center, during the meeting noted, “Our first chance to treat these patients is actually our best chance to improve outcomes. This combination has the potential to provide a meaningful breakthrough for [patients with] mCRPC.”
Pfizer’s Central Argument
The applicant is advocating for the approval of talazoparib with enzalutamide for all-comers with mCRPC, arguing that the TALAPRO-2 study showed clinically meaningful benefits in both rPFS and OS, including in the non-HRRm subgroup.1 They stated that although patients with HRR mutations derived the greatest benefit, patients without HRR mutations also appeared to benefit, and this benefit justifies access to the drug regardless of HRR mutant status.
This proposed label expansion would mark the first FDA approval of a PARP inhibitor in prostate cancer for patients not selected by HRR biomarker status, a precedent Pfizer supports based on TALAPRO-2 efficacy and mechanistic rationale.
“This was a robust study design with prospective HRR status testing and stratification—a key strength of TALAPRO-2,” added Dana Kennedy, PharmD, BCOP, vice president, GU therapeutic area head, oncology research and development, Pfizer Inc., during her presentation.
Clinical Evidence Supporting the sNDA
The TALAPRO-2 trial design consisted of 2 cohorts:
- Cohort 1: All-comers (regardless of HRR status)
- Cohort 2: HRRm population
The study randomly assigned patients 1:1 to receive talazoparib plus enzalutamide vs placebo plus enzalutamide. The primary end point was rPFS, and a key secondary was OS.
In the overall population, the HR for rPFS with the talazoparib and enzalutamide combination vs placebo was 0.667 (95% CI, 0.551-0.807; 2-sided P <.0001). Patients treated with talazoparib plus enzalutamide had a median rPFS of 33.1 months (95% CI, 27.4-39.0), vs 19.5 months with enzalutamide alone (95% CI, 16.6-24.7). The median OS was 45.8 months vs 37.0 months (HR, 0.796; P = .0155), representing a 20.4% reduction in risk of death.
“TALAPRO-2 met its primary end point, with a statistically significant and clinically meaningful improvement in rPFS of over a year,” said Johanna Bendell, chief development officer, Pfizer Oncology, during her presentation at the ODAC meeting. “We observed a 20% reduction in the risk of death... and a median survival of 45.8 months with the combination.”
In the HRRm subgroup, patients treated with talazoparib plus enzalutamide had a median rPFS of 30.7 months (95% CI, 24.3-38.5), vs 12.3 months (95% CI, 11.0-16.5) with enzalutamide alone. The HR in the HRR-deficient population was 0.468 (95% CI, 0.359-0.612; P <.0001). A 38% reduction in the risk of death was observed, translating to a 14-month OS improvement. In this group, the median OS with talazoparib plus enzalutamide was 45.1 months (95% CI, 35.4-not reached) and 31.1 months (95% CI, 27.3-35.4) in the placebo and enzalutamide arm. The HR was 0.622 (95% CI, 0.475-0.814; P =.0005). However, the benefit extended beyond patients who were HRR-deficient, as those without DNA repair mutations also saw an OS gain of approximately 9 months.
“The efficacy results seen in the non-HRR-mutated subgroup... reflect a true treatment effect that is unlikely due to chance,” said Bendell.
Pfizer argues that these findings demonstrate consistent treatment benefit across subgroups, supported by biological rationale involving PARP inhibition in combination with androgen receptor blockade.
With 2 additional years of follow-up from the primary analysis from TALAPRO-2, the combination therapy was associated with expected hematologic toxicities, notably anemia. These events were generally manageable with dose modifications and supportive care.
“Quality of life remained similar for patients who experienced grade 3 to 4 anemia and those who did not. There was no impact on patients’ ability to receive subsequent therapies,” Kennedy added. “Patients remained on enzalutamide longer when used in combination with talazoparib.”
Despite added toxicity, the duration of disease control (~20 months) supports tolerability in this setting. Additionally, there have been no new cases of myelodysplastic syndrome or acute myeloid leukemia reported at the final analysis, from the 1 case each previously reported at the primary analysis of TALAPRO-2.
“Overall, the safety profile supports an acceptable benefit-risk assessment for the proposed indication,” said Kennedy.
Pfizer concluded that the TALAPRO-2 trial demonstrated a favorable benefit-risk profile for talazoparib with enzalutamide in all patients with mCRPC, regardless of tumor HRRm status. They emphasized that the combination offers a new, effective first-line option for a large population of patients and that the OS benefit observed in the all-comers group is statistically significant, meaningful, and unprecedented for a PARP inhibitor in prostate cancer.
“This unique combination shows efficacy even in HRR-deficient tumors. This life-prolonging therapy should be an option available to all patients with mCRPC and their physicians,” said Neeraj Agarwal, MD, professor of medicine; Presidential Endowed Chair, Cancer Research; director, Genitourinary Oncology Program; and director, Center of Investigational Therapeutics at Huntsman Cancer Institute, University of Utah.
FDA’s Stance
The FDA expressed significant reservations about expanding the label based on TALAPRO-2 data.
“The proposed indication for talazoparib plus enzalutamide would mark the first-ever FDA approval of a PARP inhibitor for biomarker-unselected prostate cancer. This presents a major concern,” said Maguire.
First, they explained that TALAPRO-2 was not powered or prospectively designed to assess efficacy in the HRRm-negative population, which represents 70% to 80% of patients with mCRPC.
“Over 70% of patients with mCRPC do not have an HRR gene mutation,” said Fallah. “The FDA considers the OS results in the all-comers population in TALAPRO-2 to be potentially misleading and not directly applicable to the non-HRR population.”
There was no prespecified statistical plan to assess efficacy outcomes in HRRm-negative patients, which raises the risk that the observed improvements in rPFS and OS in this subgroup are due to chance.
“A primary regulatory risk is that, by approving this therapy for all-comers, we may be approving treatment for patients unlikely to benefit—which carries the consequence of exposing them to unnecessary toxicity without meaningful therapeutic gain,” explained Maguire.
“In the absence of formal statistical testing... it is challenging to determine whether there is truly a treatment effect in the non-HRR population,” Fallah said.
The trial also stratified randomization by HRR mutational status, but 26% of enrolled patients had unknown HRR status at randomization, with nearly a third of these patients later identified as HRRm-positive only after postrandomization testing. The FDA notes that this undermines the reliability of subgroup analyses and clouds interpretation of the true biomarker-negative population’s outcomes. The absence of prospective biomarker determination prior to randomization violates key principles in precision oncology, particularly when biomarker status is known to be predictive of treatment effect.
“This concern is not hypothetical. At least 70% of patients with mCRPC lack detectable HRR mutations. Therefore, a decision to approve or not approve this sNDA will directly impact the majority of mCRPC patients,” Maguire added.
While the OS analysis in the all-comers population showed a statistically significant improvement, the FDA was also concerned that this benefit may be driven primarily by the HRRm-positive subgroup, where the benefit is already well established. Moreover, the observed OS advantage may be inflated due to an underuse of postprogression PARP inhibitors in the control arm, a practice inconsistent with current US treatment standards. Only 7% to 9% of patients with HRR or BRCA mutations in the control group received subsequent PARP inhibitor therapy, potentially inflating the apparent OS benefit in the investigational arm.
Furthermore, prior trials of other PARP inhibitors, such as olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula), have consistently shown reduced or no clinical benefit in patients without HRRm. The FDA cautions against setting a precedent that weakens precision oncology standards.
Safety considerations also weigh heavily against broadening talazoparib’s indication. While the overall safety profile was consistent with the known effects of talazoparib and enzalutamide, the combination regimen was significantly more toxic than enzalutamide alone. The FDA noted severe anemia and other cytopenias in a substantial proportion of patients, where around 40% required transfusions.
Given that patients with mCRPC are often minimally symptomatic at treatment initiation and are expected to remain on this regimen for nearly 20 months, these toxicities may impose a meaningful burden, especially in patients without a clearly defined benefit from the drug. The clinical threshold for acceptable risk is understandably higher in such patients, and the evidence fails to demonstrate a favorable benefit-risk profile in this population.
“Granting an approval... rewards inadequate methodology and sends the wrong message by promoting flawed practices,” explained Fallah. “The lack of support... from other trials... raises our concern that any apparent efficacy... may just be due to chance.”
The ODAC’s Decision
The FDA’s ODAC voted againstagainst TALAPRO-2 data’s sufficiency, citing concerns about insufficient efficacy data in biomarker-negative patients and patient-centered toxicity outcomes.
“Though the drug is very effective, we want to be very sure that we’re treating the appropriate patient population with the drug... I would want to be very confident that we’re treating the right patient population with the drug in question today,” said ODAC member William J. Gradishar, MD, Feinberg School of Medicine at Northwestern University.
“There was concern on my part, as well as many others, for the full characterization of the nonmutant population, the statistical assumptions that went into making the case that there was a benefit, and I think the toxicity data really demonstrated that oncologists can take care of toxicity. It did not really necessarily get to the patient experience with the doublet,” added Gradishar.
“Testing whether a biomarker-directed therapy works in patients without the biomarker is a very scientifically valid question but because it's a counter hypothesis, it just demands a high level of rigor. Because this powerful study was not powered to test efficacy in the patients without HRR mutations, I thought this weakened the strength of the conclusions that we can draw,” said Neil Vasan, MD, PhD, physician-scientist in the Department of Medicine and the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center.
“Coming from the community oncology setting, that we have a lot of room for improvement to adhere to the recommendations for biomarker testing so that we can truly be confident that we're finding the patients that will benefit from biomarker-driven therapy. And yet, we look into the community to a well done clinical trial that’s designed well, where the patients are tested as they should be, so that we can be confident of the results from a statistical perspective and efficacy perspective,” said Heidi McKean, MD, director of the GI Oncology Program and community oncologist at Avera Medical Oncology and Hematology.
“Toxicity is a big part of this conversation. I don’t think we’d be at ODAC if this was a nontoxic component to the method of management. Just because grade 3 and 4 toxicities are deemed ‘manageable,’ they still can impact patients in ways that, probably, it’s hard for us to fully understand with our questionnaires and things. And I do think that the impact on appetite—nausea and decreased appetite in patients—is especially important. I think that’s where it becomes challenging, when there are questions about the statistical planning and even the relative trends that we’re seeing here. I think the safety part, which is very patient-centric, is really at the heart of all of this,” said Ravi A. Madan, MD, ODAC member and senior clinician at the National Cancer Institute.
REFERENCES:
1. Meeting of the Oncologic Drug Advisory Committee. FDA. May 21, 2025. Accessed May 21, 2025. https://tinyurl.com/5n7mwvjt
2. Fizazi K, Azad A, Matsubara N, et al. Presentation on Abstract LBA 141 Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA359
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. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA185.
4. Pfizer’s TALZENNA® in combination with XTANDI® receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed May 21, 2025. https://tinyurl.com/bdh36t4s
Recent Videos
Related Content
