AstraZeneca's New Drug Application for camizestrant in combination with a CDK4/6 inhibitor encountered a setback when the US FDA's Oncologic Drugs Advisory Committee (ODAC) voted 3 to 6 against the benefit-risk profile of the combination. AstraZeneca is seeking approval for the molecule as a first-line treatment in hormone receptor-positive, HER2-negative advanced breast cancer in patients whose tumors carry an emergent ESR1 mutation.
The May 1 vote reflects unease among advisers about whether data from the Phase III SERENA-6 trial are sufficient to support a shift in treatment before radiographic disease progression — a departure from established clinical practice. While the committee acknowledged the regimen’s activity and manageable safety profile, the majority ultimately concluded that the evidence did not yet establish a clear clinical benefit in this earlier intervention setting.
The advisory vote is non-binding, but typically informs the FDA’s final decision. AstraZeneca said it will continue to engage with the agency as the review proceeds.
The New Drug Application, accepted in July 2025 and supported by Breakthrough Therapy Designation granted in May 2025, seeks approval for a biomarker-driven approach in which patients receiving a first-line aromatase inhibitor plus a CDK4/6 inhibitor — such as palbociclib, ribociclib, or abemaciclib — are switched to camizestrant upon detection of an ESR1 mutation in circulating tumor DNA, prior to clinical progression.
That strategy sits at the center of the regulatory debate. SERENA-6 is the first registrational study to use ctDNA monitoring to trigger a treatment switch before progression, aiming to delay endocrine resistance. However, ODAC discussion focused on whether improvements in progression-free survival (PFS) in this context translate into meaningful long-term outcomes, particularly in the absence of mature overall survival data.
An interim analysis showed the camizestrant combination reduced the risk of disease progression or death by 56% versus continued aromatase inhibitor plus CDK4/6 inhibition (HR 0.44; 95% CI 0.31–0.60), with median PFS of 16.0 months compared to 9.2 months. A subsequent analysis showed a PFS2 benefit (25.7 vs 19.1 months; HR 0.63), while overall survival remained immature (HR 0.87).
Despite these results, several advisers questioned whether PFS gains driven by an early switch — before patients would otherwise meet progression criteria — could overstate clinical benefit, and whether the approach risks overtreatment in some patients who may not progress imminently.
Committee members also weighed the novelty of using ctDNA-detected ESR1 mutations as a trigger for intervention in routine practice, including questions around assay standardization, timing of testing, and generalizability outside the trial setting.