Switching to camizestrant at ESR1 mutation emergence before disease progression during first-line treatment of hormone receptor-positive advanced breast cancer (SERENA-6): extended analysis of a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND

SERENA-6 is, to our knowledge, the first global registrational study to use prospective circulating tumour DNA (ctDNA) monitoring to identify the emergence of an acquired resistance mutation before clinical progression and then direct a change in therapy in patients with hormone receptor-positive advanced breast cancer. Switching to camizestrant from aromatase inhibitor with continued cyclin-dependent kinase (CDK) 4/6 inhibitor at ESR1 mutation emergence during first-line therapy significantly improved progression-free survival at interim analysis. We report comprehensive results from ESR1 mutation surveillance in SERENA-6, updated progression-free survival, final analysis of second progression-free survival with longer follow-up, and an exploratory analysis of ESR1 mutation ctDNA dynamics on treatment to give a comprehensive report of this new treatment strategy.

METHODS

This double-blind, placebo-controlled, randomised, phase 3 trial was conducted at 264 hospitals and cancer centres in 23 countries and enrolled women with any menopausal status, or men, aged 18 years or older who were receiving first-line treatment with aromatase inhibitor plus CDK4/6 inhibitor for at least 6 months for oestrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer. Patients were required to have an Eastern Cooperative Oncology Group performance status score of 0 or 1. Eligible patients were enrolled and had ctDNA tested for ESR1 mutation every 2-3 months, coinciding with routine clinical assessments, using the Guardant360 CDx assay. Patients with an ESR1 mutation in ctDNA and without radiological progression were randomly assigned (1:1) using block randomisation (stratified by disease site, time of ESR1 mutation detection, time from initiation of aromatase inhibitor plus CDK4/6 inhibitor to randomisation, and CDK4/6 inhibitor) to switch to camizestrant (75 mg orally once daily) with continued CDK4/6 inhibitor (orally at the same dose) or to continue receiving aromatase inhibitor (anastrozole 1 mg or letrozole 2·5 mg orally once daily) plus CDK4/6 inhibitor (orally at the same dose as was received during ESR1 mutation surveillance phase). Palbociclib and ribociclib were dosed, orally, once daily for 21 days and then 7 days with no treatment in 28-day cycles, while abemaciclib was dosed, orally, twice daily every day in 28-day cycles. The SERENA-6 sample size was determined to ensure sufficient power for both the primary endpoint (investigator-assessed according to RECIST 1.1 progression-free survival) and the key secondary endpoint of investigator-assessed second progression-free survival (time from randomisation to disease progression after first subsequent therapy or death). For patients who had experienced a first progression, scans to assess second progression-free survival were conducted every 8-12 weeks. Updated progression-free survival analysis at this data cutoff was descriptive. Efficacy analyses included all randomly assigned patients (intention to treat). This study is registered with ClinicalTrials.gov, NCT04964934, and is ongoing.

FINDINGS: From June 30, 2021, to June 14, 2024, 3325 patients were screened and 3256 patients received at least one ESR1 mutation test during first-line therapy and 548 patients had a positive ESR1 mutation test by the time of screening closure. 315 patients (312 [99%] female; 199 [63%] White, 73 [23%] Asian, six [2%] Black or African American, 37 [12%] other, not reported, or with missing race data) were randomly assigned: 157 to camizestrant plus CDK4/6 inhibitor and 158 to aromatase inhibitor plus CDK4/6 inhibitor. After a median follow-up of 23·5 months (IQR 17·9-32·1; data cutoff Jan 2, 2026), median progression-free survival was 16·8 months (95% CI 14·7-19·4) with camizestrant plus CDK4/6 inhibitor versus 9·2 months (7·2-9·7) with aromatase inhibitor plus CDK4/6 inhibitor (hazard ratio [HR] 0·45 [95% CI 0·34-0·59]; nominal p<0·0001); consistent with previous interim analysis. Median second progression-free survival was 25·7 months (95% CI 20·4-30·3) with camizestrant plus CDK4/6 inhibitor versus 19·1 months (16·8-21·0) with aromatase inhibitor plus CDK4/6 inhibitor; HR 0·63 (0·46-0·86; p=0·0037). The most common grade 3-4 adverse events were neutropenia (42 [27%] patients in the camizestrant plus CDK4/6 inhibitor group vs 27 [17%] patients in the aromatase inhibitor plus CDK4/6 inhibitor group) and neutrophil count decreased (35 [23%] vs 30 [19%] patients), while serious adverse events were reported in 24 (15%) versus 29 (19%) patients. There were three deaths considered by the trial investigator to be possibly related to treatment (camizestrant plus CDK4/6 inhibitor group: sudden death, possibly related to camizestrant; aromatase inhibitor plus CDK4/6 inhibitor group: sepsis, possibly related to abemaciclib, and ileus, possibly related to letrozole).

INTERPRETATION: Switching to camizestrant plus CDK4/6 inhibitor at ESR1 mutation emergence, versus continuing aromatase inhibitor plus CDK4/6 inhibitor, resulted in sustained progression-free survival benefit that translated into a statistically significant improvement in second progression-free survival. These results further support switching endocrine treatment to camizestrant from aromatase inhibitor upon detection of ESR1 mutation, with continuation of any of the globally approved CDK4/6 inhibitor, to extend first-line treatment benefit.

FUNDING: AstraZeneca.