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

Turner NC, Mayer EL, Park YH, Janni W, Ma C, Cristofanilli M, Bianchini G, Kalinsky K, Iwata H, Chia S, Brufsky AM, Fasching P, Nowecki Z, Pascual J, Karadurmus N, Gal-Yam E, Chung WP, Im SA, Zambelli A, Dalenc F, Oliveira M, Ishiguro H, Huang CS, Klinowska T, Fox S, Morrow C, Robert L, Huang-Bartlett C, Bidard FC (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 27

Pages Range: 941-958

Journal Issue: 8

DOI: 10.1016/S1470-2045(26)00287-1

Abstract

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.

Authors with CRIS profile

Involved external institutions

Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust United Kingdom (GB) Dana-Farber Cancer Institute United States (USA) (US) Sungkyunkwan University (SKKU) Korea, Republic of (KR) Universitätsklinikum Ulm Germany (DE) Washington University in St. Louis United States (USA) (US) Weill Cornell Medicine United States (USA) (US) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) Emory University United States (USA) (US) Nagoya City University / 名古屋市立大学 Japan (JP) British Columbia Cancer Agency Canada (CA) University of Pittsburgh Medical Center (UPMC) United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Hospital Universitario Virgen de la Victoria Spain (ES) Gülhane Training and Research Hospital / Gülhane Eğitim ve Araştırma Hastanesi (GEAH) Turkey (TR) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) National Cheng Kung University Hospital (NCKU) / 國立成功大學醫學院附設醫院 Taiwan (TW) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Humanitas Research Hospital / IRCCS Istituto Clinico Humanitas Italy (IT) Toulouse Oncopole Cancer University Institute (IUCT-O) / Institut universitaire du cancer de Toulouse Oncopole (IUCT-O) France (FR) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Saitama Medical University International Medical Center / 埼玉医科大学国際医療センタ Japan (JP) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) AstraZeneca UK Limited United Kingdom (GB) AstraZeneca, Spain Spain (ES) AstraZeneca (United States) United States (USA) (US) Institut Curie France (FR)

How to cite

APA:

Turner, N.C., Mayer, E.L., Park, Y.H., Janni, W., Ma, C., Cristofanilli, M.,... Bidard, F.C. (2026). 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. Lancet Oncology, 27(8), 941-958. https://doi.org/10.1016/S1470-2045(26)00287-1

MLA:

Turner, Nicholas C., et al. "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." Lancet Oncology 27.8 (2026): 941-958.

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