Switching to Camizestrant Upon ESR1 Mutation Detection Improves Outcomes in ER-Positive Breast Cancer

Data from the phase 3 SERENA-6 trial (NCT04964934), presented at the 2026 ASCO Annual Meeting, showed that patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer who proactively switched to camizestrant in combination with a CDK4/6 inhibitor upon detection of an emergent ESR1 mutation achieved a longer time to second progression (PFS2) than those who remained on an aromatase inhibitor (AI) plus a CDK4/6 inhibitor.¹

Patients in the camizestrant plus CDK4/6 inhibitor arm (n = 157) had a median PFS2 of 25.7 months (95% CI, 20.4-30.3), compared with 19.1 months (95% CI, 16.8–21.0) in those who continued AI-based therapy (n = 158; HR, 0.63; 95% CI, 0.46-0.86; P =.00373). The 30-month PFS2 rates were 41.5% and 29.7%, respectively. A supplementary analysis applying RECIST 1.1 criteria yielded a comparable PFS2 benefit for the camizestrant switch (HR, 0.64; 95% CI, 0.46–0.90; nominal P =.0094).

"With PFS2, the gap between the 2 arms was 6.6 months, suggesting—with all the caveats inherent to PFS2—that the PFS benefit is maintained beyond first progression," said presenting author Francois-Clement Bidard, MD, PhD. "Time to second subsequent treatment is also very well aligned with what we observed for PFS2."

Bidard is a professor of medicine in the Department of Medical Oncology at Institut Curie & UVSQ/Université Paris-Saclay in France, co-coordinator of breast cancer research at Institut Curie, vice-chair of the French Breast Cancer research group UCBG, director of the Clinical Investigation Center at Institut Curie, and medical director for Breast Oncology at the Women's Cancer Institute.

Regulatory Status of Camizestrant

In April 2026, the FDA's Oncologic Drugs Advisory Committee reviewed SERENA-6 data in support of a new drug application (NDA) seeking approval of camizestrant in combination with a CDK4/6 inhibitor (palbociclib [Ibrance], ribociclib [Kisqali], or abemaciclib [Verzenio]) for adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who develop an ESR1 mutation during first-line endocrine-based therapy, as identified by an FDA-approved test.² The advisory committee voted 6-3 that the available data did not establish a clinically meaningful benefit for this population.

The FDA expressed uncertainty about whether the PFS2 results were clinically meaningful, given that the switch to camizestrant in the experimental arm was initiated at the time of ESR1 mutation detection rather than at progression. The agency informed AstraZeneca, the sponsor, that PFS2 would not be considered an acceptable efficacy end point to support approval. A final regulatory decision remains pending after the FDA extended the Prescription Drug User Fee Act target action date to allow for review of additional data.³

Updated PFS Results

Also presented at ASCO 2026, updated PFS data at a median follow-up of 23.5 months showed that camizestrant plus a CDK4/6 inhibitor produced a median PFS of 16.8 months (95% CI, 14.7-19.4) vs 9.2 months (95% CI, 7.2–9.7) for AI plus a CDK4/6 inhibitor (HR, 0.45; 95% CI, 0.34-0.59; nominal P <.00001).

The PFS benefit was consistent across key subgroups, including patients with PIK3CA co-mutations (HR, 0.41; 95% CI, 0.26-0.64) and those with TP53 co-mutations (HR, 0.52; 95% CI, 0.31-0.88), as well as patients harboring a single ESR1 mutation (HR, 0.46; 95% CI, 0.34-0.62) and those with multiple ESR1 mutations (HR, 0.48; 95% CI, 0.25-0.88).

Trial Design

SERENA-6 was a randomized, double-blind, placebo-controlled study enrolling adults with ER-positive, HER2-negative advanced breast cancer who were receiving an AI plus a CDK4/6 inhibitor as their initial endocrine-based therapy for advanced disease without evidence of disease progression. Prior chemotherapy for advanced breast cancer was not permitted. Patients were eligible for randomization upon detection of an ESR1 mutation via circulating tumor DNA (ctDNA) in the absence of clinical progression.

Participants were assigned 1:1 to either switch to camizestrant 75 mg once daily while continuing their existing CDK4/6 inhibitor with an AI placebo, or to continue their AI plus CDK4/6 inhibitor with a camizestrant placebo.

Tumor assessments per RECIST 1.1 were conducted every 8 weeks for the first 18 months and every 12 weeks thereafter; for the purpose of measuring PFS2, imaging was required every 8 to 12 weeks.

Investigator-assessed PFS was the primary end point, with PFS2 and patient-reported outcomes (PROs) as key secondary end points.

Among evaluable patients receiving first subsequent therapy, 55.2% of those in the camizestrant arm (n = 87) went on to receive endocrine-based treatment, compared with 66.7% in the control arm (n = 117). Cytotoxic therapy was used as the next line in 43.7% and 30.8% of patients, respectively, while other treatments were administered in 1.1% and 2.6%, respectively.

Other Key Efficacy Results

PFS and PFS2 outcomes were consistent across all prespecified subgroups in the camizestrant arm.

Chemotherapy/antibody-drug conjugate (ADC)–free survival was also meaningfully prolonged. The camizestrant regimen yielded a median chemotherapy/ADC-free survival of 22.6 months (95% CI, 19.3–30.9) versus 18.7 months (95% CI, 15.8-22.1) with AI plus a CDK4/6 inhibitor (HR, 0.64; 95% CI, 0.47-0.87; nominal P =.00375).

Overall survival (OS) data were not yet mature at the time of the final analysis; however, trends consistently favored camizestrant across all 3 data cutoffs: HR, 0.91 (95% CI, 0.48-1.73) at the first cutoff; HR, 0.92 (95% CI, 0.57-1.48) at the second; and HR, 0.87 (95% CI, 0.57-1.30) at the final cutoff.

Exploratory ctDNA Analysis

Total ctDNA clearance was substantially greater with camizestrant plus a CDK4/6 inhibitor (n = 98) at 51.0%, versus just 1.9% among patients continuing AI plus a CDK4/6 inhibitor (n = 108). When analyzed across both treatment arms combined, ctDNA clearance was associated with an OS benefit (HR, 0.39; 95% CI, 0.19–0.73), consistent with observations seen in other tumor types.

REFERENCES

1. Bidard F-C, Mayer E, Park YH, et al. First-line camizestrant for emergent ESR1 mutations in advanced breast cancer: final progression-free survival results 2 from the phase III SERENA-6 trial. J Clin Oncol. 2026;44(suppl 17):LBA1007. doi:10.1200/JCO.2026.44.17_suppl.LBA1007

2. April 30, 2026 meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed June 2, 2026. https://www.youtube.com/live/taCx7enN7hk

3. US FDA decision date extended for SERENA-6 filing of camizestrant to enable review of additional data. News release. AstraZeneca. May 27, 2026. Accessed June 2, 2026. https://tinyurl.com/3kzatcua