Talazoparib Tosylate

In a resounding 8-0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) rejected Pfizer’s combination of Talzenna and Xtandi for treating mCRPC patients without HRR mutations (non-HRRm). This decision deals a blow to one of Pfizer’s high-profile oncology strategies, despite notable improvements in survival outcomes reported in the TALAPRO-2 Phase III trial.   According to final data, the combination extended radiographic progression-free survival (rPFS) to 33.1 months compared to 19.5 months in the control group. Overall survival (OS) improved by nearly 9 months, reducing the risk of death by over 20%. Among HRRm-positive patients, rPFS nearly doubled, and OS was prolonged by 14 months. However, the core issue lay with non-HRRm patients, where regulators questioned whether the observed OS improvement was statistically credible or the result of confounding variables.   ODAC members raised concern that over a quarter of patients lacked confirmed HRR mutation status at randomization, and many of them were later found to be HRRm-positive. This undermined the reliability of the subgroup analysis. The FDA emphasized that biomarker-driven approvals must be rooted in prospective stratification, not retrospective data that might skew conclusions.   While Pfizer argued the mechanistic rationale was strong—citing synergy between PARP inhibition and androgen receptor blockade—and manageable safety signals, including anemia and absence of MDS/AML, the advisory panel stood firm. Regulators warned this could set a dangerous precedent by encouraging biomarker-independent use of PARP inhibitors, a direction unsupported by past trials with olaparib and rucaparib in similar settings.

iStock, JHVEPhoto The FDA’s independent advisors found Pfizer’s data lacked the precision needed to establish the efficacy of Talzenna in patients with prostate cancer who do not carry HRR mutations. The FDA’s Oncologic Drugs Advisory Committee unanimously declined to endorse a label expansion for Pfizer ’s PARP inhibitor Talzenna, which the pharma is proposing as a combination regimen with its drug Xtandi for first-line treatment of patients with metastatic castration-resistant prostate cancer carrying a certain biomarker profile. Voting 8–0 against the proposal, the external experts said Wednesday that Pfizer had not provided enough evidence to establish the efficacy of the Talzenna combo in men with non-homologous recombination repair mutated (non-HRRm) prostate cancer. “Precision oncology demands precision trials,” Neil Vasan, assistant professor at the Columbia University Medical Center, said at the end of the meeting explaining his no vote. “The study was not powered to test the efficacy in the patients without HRR mutations,” which in turn “weakened the strength of the conclusions that we can draw.” This problem extends “across all oncology” as well, Vasan added. “As a field, we need to commit to formally evaluating whether targeted therapies benefit patients with and without the biomarker.” To back its latest application, which seeks a broader prostate cancer label for Talzenna, Pfizer drew data from the Phase III TALAPRO-2 trial. The company announced in October 2024 that Talzenna plus Xtandi significantly and meaningfully improved overall survival (OS) versus Xtandi alone—an effect that was observed not only in those with HRR mutation but in all participants regardless of biomarker status. At the time, Roger Dansey, former chief oncology officer at Pfizer, said that Talzenna is the “first and only PARP inhibitor” to demonstrate a significant survival benefit, when used with an androgen receptor blocker, in mCRPC patients, “regardless of mutation status.” But in a briefing document published ahead of the advisory committee meeting, the FDA’s internal reviewers challenged Dansey’s claims. “While the statistically significant OS improvement in the all-comers population provided the impetus for this application, interpretation of the OS result and its applicability to current U.S. standard of care are unclear,” they wrote. “Consideration of the all-comers OS result may be misleading when interpreting efficacy in the non-HRRm population.” Talzenna, an oral drug, was first approved by the FDA in October 2018 for HER2-negative, germline BRCA-mutated breast cancer. Nearly five years later, in June 2023, the agency handed Talzenna a label expansion , this time in combination with Xtandi, an oral androgen receptor blocker, for patients with metastatic castration-resistant prostate cancer (mCRPC) who have HRR mutations.