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Compared with standard of care, camizestrant in combination with a CDK4/6 inhibitor shows promise in enhancing progression-free survival (PFS) for patients with advanced breast cancer.
Camizestrant (AstraZeneca), used in combination with a CDK4/6 inhibitor, resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when used as a first-line treatment in patients with ESR1-mutated hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. These findings, which were presented at the 2025 American Society of Clinical Oncology in Chicago, Illinois, represent a potential new treatment strategy to improve and optimize patient outcomes in the first-line setting.1
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Trial Name: Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression (SERENA-6) (SERENA-6)
ClinicalTrials.gov ID: NCT04964934
Sponsor: AstraZeneca
Completion Date (Estimated): November 26, 2027
Camizestrant is an investigational, next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist intended for the treatment of HR+ breast cancer. In preclinical trials, it demonstrated anticancer activity across a range of preclinical models, such as those with ER-activating mutations.2 The double-blind, randomized SERENA-6 trial (NCT04964934)3 is the first global, registrational phase 3 trial that assesses a circulating tumor DNA (ctDNA)-guided approach to detect the emergence of ESR1 mutations during first-line treatment with an aromatase inhibitor combined with a CDK4/6 inhibitor to inform a switch in therapy prior to disease progression.1,3
Patients with HR+/HER2- advanced breast cancer who had received at least 6 months of first-line treatment with an aromatase inhibitor (anastrozole [Arimidex; AstraZeneca] or letrozole [Femara; Novartis]) in combination with a CDK4/6 inhibitor (abemaciclib [Verzenio; Eli Lilly and Company], palbociclib [Ibrance; Pfizer], or ribociclib [Kisqali; Novartis]) were enrolled and had ctDNA tested for ESR1 mutation every 2 to 3 months, coinciding with routine imaging. If ESR1 mutations were detected, patients who did not have evidence of disease progression were randomly assigned to switch to 75 mg of camizestrant with continued CDK4/6 inhibitor (type and dose maintained) in addition to placebo for aromatase inhibitor or continuing aromatase inhibitor with a CDK4/6 inhibitor and placebo for camizestrant.1,3
SERENA-6’s primary end point was investigator-assessed PFS. Secondary end points included overall survival (OS), chemotherapy-free survival, objective response rate (ORR), and clinical benefit rate. The prespecified interim analysis data cutoff was on November 28, 2024.1,3
A total of 3256 eligible patients were surveilled for ESR1 mutations using ctDNA until 315 eligible patients were randomly assigned to switch to camizestrant (n = 157) or continue with their original aromatase inhibitor (n = 158). All patients remained on the same CDK4/6 inhibitor. At the first ctDNA test, about 50% of randomly assigned patients had ESR1 mutations detected.
After 171 PFS events, the hazard ratio (HR) for PFS was about 0.44 (95% CI 0.31–0.60, p < .00001; median PFS: 16.0 vs 9.2 months), and the risk of disease progression or death was reduced by approximately 56% compared with standard-of-care treatment.1,2 The PFS benefit was consistent across subgroups. In addition, the PFS rate at 12 months was about 60.7% (95% CI 51.1–69.0) compared with 33.4% (95% CI 24.9–42.2) and was 29.7% (95% CI 19.0–41.2) compared with 5.4% (95% CI 0.7–18.2) at 24 months. At the time of these data, OS was considered immature (12%).1,2
“[The SERENA-6 findings] mark a pivotal moment in breast cancer care and redefine how we think about drug resistance in this type of breast cancer. The results of the innovative SERENA-6 trial show that switching from an aromatase inhibitor to camizestrant in combination with any of the 3 CDK4/6 inhibitors after emergence of an ESR1 mutation more than halved the risk of disease progression or death and delayed deterioration in quality of life by nearly 18 months. This proactive approach exemplifies a new treatment strategy in oncology; by treating developing resistance before it causes disease progression and deterioration in quality of life, we can extend the benefit of [first]-line treatment to optimize patient outcomes,” co-principal investigator Nicholas Turner, MD, PhD, professor of molecular oncology at the Institute of Cancer Research, London, said in a news release.2
Further, the investigators observed that camizestrant’s safety profile when in combination with a CDK4/6 inhibitor was consistent with the known safety profiles of each medicine. The majority of adverse events (AEs) were hematological events and consisted of neutropenia (camizestrant: 45%; standard of care: 34%), anemia (camizestrant: 5%; standard of care: 5%), and leukopenia (camizestrant: 10%; standard of care: 3%).2 Rates of treatment discontinuation due to adverse events were approximately 1.3% for camizestrant and 1.9% for other aromatase inhibitors, reported the investigators.1,2
“As the first pivotal trial to demonstrate the clinical value of monitoring ctDNA to detect emerging resistance and change therapy at the earliest opportunity; SERENA-6 is redefining the clinical paradigm in breast cancer. Camizestrant is the first and only next-generation oral SERD and complete estrogen receptor antagonist to demonstrate benefit in combination with widely approved CDK4/6 inhibitors in this [first]-line setting, and these results support its potential as a new standard of care endocrine therapy backbone in the treatment of HR+ breast cancer,” Susan Galbraith, executive vice president of oncology and hematology research and development at AstraZeneca, said.2
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