Originally published by our sister publication Clinical Oncology News

In patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer, switching part of first-line treatment from an aromatase inhibitor (AI) to camizestrant (AstraZeneca) if an ESR1 mutation is detected before disease progression, while continuing with a CDK4/6 inhibitor, can slow cancer growth, extend the benefit of first-line therapy and improve quality of life. This conclusion comes from the SERENA-6 study presented at the 2025 annual meeting American Society of Clinical Oncology (LBA4), held in Chicago. 

Camizestrant is a next-generation oral selective estrogen receptor degrader that was designed to inhibit and degrade the mutating ESR1 mutations as well as wild-type estrogen receptor.

Lead study author Nicholas C. Turner, MD, PhD, from the Royal Marsden Hospital, in London, pointed out that approximately 70% of breast cancers are HR-positive and HER2-negative. “The estrogen receptor is encoded by the ESR1 gene. Activating ESR1 mutations are rare at diagnosis of advanced breast cancer but emerge during first-line treatment with aromatase inhibitors and CDK4/6 inhibitors in about 40% of patients and cause disease progression,” Dr. Turner said. “ESR1 mutations can be detected in circulating tumor [ct]DNA liquid biopsies many months prior to clinical progression on AI and CDK4/6 inhibitors.”


SERENA-6 recruited 3,256 patients into ESR1 mutation testing. All patients had been on a first-line AI and CDK4/6 inhibitor for at least six months. Patients had ESR1 mutation surveillance in their circulating tumor DNA every two to three months; 548 patients had ESR1 mutations detected and 315 were randomized to two groups. The first group switched from treatment with an AI to camizestrant, continuing with the CDK4/6 inhibitor and adding placebo in place of the AI (157 patients). The second group continued treatment with an AI and CDK4/6 inhibitor, adding placebo in place of camizestrant (158 patients). 

The median progression-free survival (PFS) was 16 months for those who switched to camizestrant and 9.2 months for those who continued treatment with an AI (hazard ratio, 0.44; 95% CI, 0.31-0.60; P<0.00001). All different subgroups of patients benefited from camizestrant. The PFS rate at 12 months was 60.7% (95% CI, 51.1%-69.0%) in the camizestrant arm versus 33.4% (95% CI, 24.9%-42.2%) and at 24 months was 29.7% (95% CI, 19.0%-41.2%) in the camizestrant arm versus 5.4% (95% CI, 0.7%-18.2%). 

“Importantly, we also looked at quality of life. In the control arm, continuation of AI the time to deterioration of quality of life was six months, but this was improved to 23 months by switching to camizestrant,” Dr. Turner said. Camizestrant and a CDK4/6 inhibitor had a very low rate, 1%, of treatment discontinuation due to adverse events. 


“We are looking to define a new treatment strategy in oncology. We have shown that switching to camizestrant and continuing the CDK4/6 inhibitor guided by the emergence of ESR1 mutations during first-line therapy ahead of disease progressions significantly improved the PFS,” Dr. Turner said. “Camizestrant plus a CDK4/6 inhibitor is a potential new treatment option.” 

Dr. Turner pointed out that SERENA-6 is the first global registration phase 3 trial to demonstrate the clinical utility of ctDNA monitoring to detect and treat emerging resistance ahead of disease progression and, therefore, presents a potential new treatment strategy in oncology to treat developing resistance before it causes progression.

At a press conference at the meeting, Eleonora Teplinsky, MD, the head of breast and gynecologic medical oncology at Valley-Mount Sinai Comprehensive Cancer Care in Paramus, N.J., and an ASCO expert in breast cancer, provided perspective on the study. “This study is significant for a number of reasons, the most important being that when patients progress on a scan, we are already behind. We are switching therapy and we have already kind of lost control,” Dr. Teplinsky said. “What this study does is an early-switch approach before we see disease progression on imaging, allowing us to essentially stay ahead of the curve. Allowing patients to remain on first-line endocrine therapy for HR-positive, HER2-negative advanced breast cancer is critical because we know that outcomes worsen with subsequent lines of therapy. So, allowing that longer time on first-line endocrine therapy is significant. [Camizestrant] also improves quality of life as we have seen, and that is a huge, huge part of living with metastatic breast cancer.”


Dr. Teplinsky said although camizestrant is not yet approved by the FDA, it likely will pave the way for a new treatment strategy in first-line HR-positive, HER2-negative metastatic breast cancer in patients with ESR1 mutations.

—Kate O’Rourke


Dr. Teplinsky reported honoraria from Sermo as well as a consulting or advisory role with AbbVie, Daiichi Sankyo/AstraZeneca, Immunogen, Novartis and Pfizer. Dr. Turner reported a consulting or advisory role with AstraZeneca, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Health, Inivata, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics and Roche.