FDA ODAC Votes Against Clinical Benefit of Switching to Camizestrant in HR+ Breast Cancer After ESR1 Mutation Detection

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 6-3 that switching to camizestrant upon emergence of an ESR1 mutation during treatment with an aromatase inhibitor (AI) and a CDK4/6 inhibitor ahead of radiographic disease progression did not demonstrate clinically meaningful benefit for the treatment of patients with hormone receptor–positive, HER2-negative metastatic breast cancer.¹

The committee reviewed data from the phase 3 SERENA-6 trial (NCT04964934), which are the basis for a new drug application (NDA) seeking the approval of camizestrant in combination with a CDK4/6 inhibitor—either palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)—for the treatment of adult patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer upon emergence of ESR1 mutation during first-line endocrine-based therapy, based on the results of an FDA-approved test.²

“The data for changing the paradigm just isn’t there. There is a progression-free survival [PFS] benefit—if there was an overall survival [OS] benefit, I think I would have voted yes, for sure,“ Stanley Lipkowitz, MD, PhD, of the National Cancer Institute, said regarding his no vote. “Aside from OS, I don’t see how they can demonstrate [the benefit of] early vs late [treatment] at this point. [However,] I agree that the bar should be high here, because it’s changing fundamentally the way we do business, and I do agree with the FDA’s concern that all the [subsequent] trials will do exactly this, with no evidence that [early treatment switch] is improving outcomes.

“I want to make it clear, I’m excited about oral selective estrogen receptor degraders. They’re going to change the field because we can combine them in a way we could never do with fulvestrant [Faslodex]…But I couldn’t bring myself to say that we should fundamentally change the way we approach patients based on this data.”

Presentations on behalf of AstraZeneca, the developer of camizestrant, highlighted the efficacy, safety, and patient-reported outcome data from SERENA-6.¹ Kevin Kalinsky, MD, MS, FASCO, of Emory University School of Medicine, provided clinical perspectives on these data, highlighting that this switch could prolong time to chemotherapy or antibody-drug conjugate treatment, along with the ease of implementation.

“Since I was in training, patients have wanted an actionable blood marker to inform whether a treatment is working. With ESR1 mutations, we finally have a marker, and with camizestrant, a way to effectively target it,” Kalinsky said during the meeting. “In my view, SERENA-6 offers a novel, biomarker-driven approach that provides a positive benefit:risk ratio.”

Although the FDA agreed that the study met its PFS primary end point, the regulatory agency argued that it is uncertain if data for time to second progression (PFS2) were clinically meaningful, since switching the camizestrant in the experimental arm was initiated at the time of the detection of an ESR1 mutation. Given the design of SERENA-6, the FDA communicated to AstraZeneca that PFS2 would not be acceptable as an efficacy end point to support potential approval. Additionally, they highlighted that OS data remain immature and may not reach statistical significance to further support the PFS outcomes. They also acknowledged the potential for cardiac adverse effects (AEs) with camizestrant, particularly when combined with ribociclib

“The FDA is committed to advancing therapies for hormone receptor–positive, HER2-negative metastatic breast cancer…We support innovative trial design strategies and deeply appreciate the patients and caregivers who participate in trials like SERENA-6,” Joshua Donaldson, MD, PhD, a clinical reviewer in the Division of Oncology and Office of Oncologic Diseases at the FDA, said during the meeting. “However, our responsibility is to determine whether the trial evidence demonstrates clinical benefit for the intended patient population, according to regulatory standards.”

What data have been reported from the SERENA-6 trial?

Data presented at the 2025 ASCO Annual Meeting showed that switching to camizestrant plus CDK4/6 inhibition (n = 157) led to a median PFS of 16.0 months (95% CI, 12.7-18.2) per investigator assessment vs 9.2 months (95% CI, 7.2-9.5) continued treatment with an AI plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001).³

In updated data presented at the 2025 San Antonio Breast Cancer Symposium, the median PFS was 16.6 months (95% CI, 14.7-19.4) in the camizestrant arm compared with 9.2 months (95% CI, 7.2-9.7) in the control arm (HR, 0.46; 95% CI, 0.34-0.62; P < .00001).⁴

What was the design of SERENA-6?

The double-blind, randomized study enrolled patients at least 18 years of age with histologically confirmed estrogen receptor–positive/HER2-negative breast cancer whose disease was locoregionally recurrent or metastatic and not amenable to curative-intent resection or radiation.⁵ Active treatment with an AI in combination with a CDK4/6 inhibitor with or without luteinizing hormone-releasing hormone therapy as initial treatment in the advanced setting was required, and patients needed to have an ESR1 mutation detected via central circulating tumor DNA testing prior to radiographic progression. An ECOG performance status of 0 or 1, along with adequate organ function, were required.

Patients with emergent ESR1 mutations were randomly assigned to receive camizestrant in combination with the same CDK4/6 inhibitor they were previously receiving and an AI placebo; or a camizestrant placebo in combination with the same CDK4/6 inhibitor and an AI. In the experimental arm, camizestrant was administered orally at 75 mg per day.

Along with the primary end point of investigator-assessed PFS per RECIST 1.1 criteria, secondary end points included PFS2, OS, chemotherapy-free survival, objective response rate, clinical benefit rate at 24 weeks, quality of life, and pharmacokinetics.

What safety data were reported from SERENA-6?

Safety data presented at SABCS 2025 were consistent with earlier findings.⁴ Results showed that the most common any-grade adverse effects (AEs) reported in at least 10% of patients included neutropenia (camizestrant arm, 32%; control arm, 25%), decreased neutrophil count (28%; 21%), anemia (21%; 21%), decreased white blood cell count (11%; 7%), photopsia (21%; 8%), arthralgia (19%; 19%), fatigue (16%; 16%), back pain (12%; 11%), dry eye (12%; 7%), nausea (10%; 15%), diarrhea (10%; 13%), and headache (9%; 14%).

References

1. April 30, 2026 meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed April 30, 2026. https://www.youtube.com/live/taCx7enN7hk
2. April 30, 2026 meeting of the Oncologic Drugs Advisory Committee. Draft agenda. FDA. Accessed April 30, 2026. https://www.fda.gov/media/192151/download
3. Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4
4. Bidard FC, Mayer EL, Park YH, et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA dynamics from SERENA-6, a phase 3 trial of camizestrant + CDK4/6 inhibitor for emergent ESR1m during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF7-03.
5. Phase III study to assess AZD9833+ CDK4/​6 inhibitor in HR+/​HER2-MBC with detectable ESR1m before progression (SERENA-6). ClinicalTrials.gov. Updated April 21, 2026. Accessed April 30, 2026. https://clinicaltrials.gov/study/NCT04964934