FDA advisory committee votes against camizestrant combination for ESR1-mutant advanced breast cancer in a setback for AstraZeneca

The FDA’s Oncologic Drugs Advisory Committee has voted 3 to 6 against a favourable benefit-risk profile for AstraZeneca’s camizestrant in combination with a CDK4/6 inhibitor for the first-line treatment of patients with hormone receptor-positive, HER2-negative advanced breast cancer whose tumours carry an emergent ESR1 mutation. The FDA is not bound by the committee’s recommendation and will take it into consideration as it completes its review of the application, with AstraZeneca confirming it will continue working with the agency through that process.

The negative vote is a setback for a therapy that had received Breakthrough Therapy Designation in May 2025 and whose application was accepted based on compelling Phase III data. Results from the planned interim analysis of the SERENA-6 trial showed a highly statistically significant 56% reduction in the risk of disease progression or death with the camizestrant combination versus standard-of-care aromatase inhibitor plus CDK4/6 inhibitor, with median progression-free survival of 16.0 months versus 9.2 months in the comparator arm. Nearly a third of patients in the camizestrant arm showed sustained disease control at 24 months, compared with just 5.4% in the comparator arm. A subsequent pre-planned analysis also demonstrated a statistically significant progression-free survival 2 benefit of 25.7 months versus 19.1 months. Overall survival data continue to mature in favour of the camizestrant combination, and the trial will continue to assess this as a key secondary endpoint.

What makes SERENA-6 particularly notable from a scientific standpoint is its design. It is the first global, double-blind, registrational Phase III trial to use a circulating tumour DNA guided approach to detect emerging endocrine resistance via ESR1 mutations through routine blood tests, allowing a switch in therapy before disease progression occurs. This adaptive strategy aims to get ahead of resistance rather than wait for clinical deterioration.

Kevin Kalinsky, Division Director of Medical Oncology at the Winship Cancer Institute of Emory University and a trial investigator, expressed disappointment at the outcome given the patient need: “Patients with this specific form of breast cancer are in urgent need of new treatments that delay disease progression. Today’s recommendation by the ODAC is disappointing, as new options and innovative treatment strategies which address emerging resistance ahead of disease progression and deterioration in quality of life are needed in the first-line setting.”

Susan Galbraith, AstraZeneca’s Executive Vice President for Oncology Haematology R&D, pushed back on the outcome while reaffirming confidence in the data: “We strongly believe in the results of the SERENA-6 trial, and are encouraged that the Committee saw camizestrant as a safe and effective potential new medicine. We remain confident in the clinical benefit the combination can bring to patients by changing therapeutic strategy at the earliest opportunity, and are committed to challenging the status quo in the pursuit of innovation that optimises outcomes for patients.”

The safety profile of camizestrant across all three CDK4/6 inhibitor combinations was consistent with the known profile of each individual medicine, with no new safety concerns identified and discontinuation rates that were low and similar across both arms.

Regulatory applications for camizestrant in this setting remain under review in the EU, Japan and several other countries.

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Related Topics and Keywords

AstraZeneca, camizestrant combination, ESR1-mutant advanced breast cancer