Pfizer's bid to expand the use of its PARP inhibitor Talzenna (talazoparib) to a broader prostate cancer population has been rejected by the U.S. Food and Drug Administration's Oncologic Drugs Advisory Committee (ODAC), citing concerns over insufficient data in biomarker-negative patients.
The pharmaceutical giant had sought to broaden Talzenna's current first-line indication beyond castration-resistant prostate cancer (CRPC) patients with homologous recombination repair (HRR) gene mutations to include all CRPC patients regardless of biomarker status.
FDA Questions Subgroup Analysis Methodology
During the review, FDA officials expressed significant concerns about Pfizer's reliance on what the agency described as a "large, incompletely defined" subgroup of CRPC patients without known HRR gene alterations. The regulatory body questioned the rigor of the analysis in this biomarker-negative population.
Richard Pazdur, MD, the FDA's oncology chief, highlighted a fundamental issue with the application: "The lack of a formal analysis of efficacy in castration-resistant prostate cancer patients without HRR mutations." Pazdur emphasized that without such formal analysis, "chance cannot be ruled out" as an explanation for any observed benefits in this population.
Current Indication and Proposed Expansion
Talzenna, a poly (ADP-ribose) polymerase (PARP) inhibitor, is currently approved in combination with enzalutamide for adult patients with HRR gene-mutated metastatic CRPC. This approval was based on demonstrated efficacy in patients with specific genetic alterations that make their cancer cells more susceptible to PARP inhibition.
Pfizer's application aimed to remove the biomarker restriction, which would have significantly expanded the eligible patient population. However, the committee determined that the evidence presented was insufficient to support such a broad indication.
Clinical Data Considerations
The advisory committee's decision highlights the growing importance of biomarker-driven approaches in oncology drug development and approval. While targeted therapies often show impressive results in biomarker-positive populations, extending these benefits to biomarker-negative patients requires robust, pre-specified analyses.
The FDA's scrutiny focused on the methodological approach used by Pfizer, particularly questioning whether the observed effects in biomarker-negative patients represented a true treatment benefit or could be attributed to chance or other confounding factors.
Implications for Precision Medicine
This decision reinforces the FDA's commitment to evidence-based expansion of indications, particularly when moving from a biomarker-defined population to a broader patient group. It also underscores the challenges pharmaceutical companies face when attempting to broaden the reach of targeted therapies beyond their initial precision medicine indications.
For patients with CRPC who do not harbor HRR mutations, the search for effective treatment options continues, as Talzenna will remain restricted to the biomarker-positive population for the foreseeable future.
Market Impact
For Pfizer, the rejection represents a setback in its efforts to maximize Talzenna's market potential. The expansion to an all-comers CRPC population would have substantially increased the drug's eligible patient base and potential revenue.
The company will now need to evaluate whether additional clinical trials specifically designed to assess efficacy in biomarker-negative patients are warranted, or whether to focus resources on other development programs.
