medwireNews: SERENA-6 trial results point to the benefit of swapping first-line aromatase inhibitor (AI) treatment with camizestrant, an oral selective estrogen receptor degrader (SERD), at the first sign of emerging ESR1 mutations in patients with hormone receptor-positive, HER2-negative advanced breast cancer.
This approach, which relied on circulating tumor (ct)DNA to detect ESR1 mutations ahead of clinical disease progression, resulted in a significant 56% reduction in the risk for progression or death among patients who switched to camizestrant, reported Nicholas Turner, from the Royal Marsden Hospital in London, UK, at the 2025 ASCO Annual Meeting in Chicago, Illinois, USA.
He continued: “SERENA-6 is the first global registrational phase 3 study to demonstrate the clinical utility of ctDNA monitoring to detect and treat emerging resistance in breast cancer.
“And the findings from SERENA-6 have the potential to become a new treatment strategy in oncology, to optimize first-line patient outcomes.”
Giving the background to the trial, Turner explained that ESR1 mutations are rare at diagnosis of advanced breast cancer but emerge during first-line treatment with an AI plus CDK4/6 inhibitor, “to be detected in around 40% of patients at disease progression.”
Camizestrant – a next-generation SERD and complete ER antagonist – has shown antitumor activity in patients with and without detectable ESR1 mutations, and the study investigated whether using the drug to treat emerging mutations before clinical progression “could extend the duration of benefit of first-line therapy,” he added.
For the trial, 3256 patients who had been receiving an AI plus CDK4/6 inhibitor in the first line for at least 6 months underwent surveillance for ESR1 mutations via ctDNA testing with the Guardant360 CDx assay every 2–3 months, coinciding with routine staging scans. ESR1 mutations were detected in 548 patients, with just over half (51%) testing positive on the first test, 38% after two to five tests, and 11% after six or more tests.
In all, 315 of these ESR1 mutation-positive patients, none of whom had evidence of clinical disease progression, were randomly assigned to either switch to camizestrant 75 mg/day or to continue AI treatment, while continuing to receive the CDK4/6 inhibitor.
Turner presented the results of an interim analysis, conducted at a median follow-up of 12.6 months, which showed that the primary endpoint of investigator-assessed PFS was significantly prolonged for the participants who did versus did not switch to camizestrant, with median durations of 16.0 and 9.2 months, respectively, and the adjusted hazard ratio (HR) for progression or death was 0.44 in favor of the SERD.
The respective 12-month PFS rates in the camizestrant and AI groups were 60.7% and 33.4%, while the corresponding rates at 24 months were 29.7% and 5.4%.
The median time to deterioration in global health status, as assessed using the EORTC QLQ-C30 questionnaire, was significantly longer among patients who switched to camizestrant than those who continued the AI, at 23.0 versus 6.4 months, and an HR of 0.53.
Adverse events (AEs) of grade 3 or higher were more common in the camizestrant group than the AI group, at rates of 60% versus 46%, with the most frequently observed AE of this severity in both groups being neutropenia, occurring in 45% and 34% of patients, respectively.
The presenter pointed out that “neutropenia is a characteristic, asymptomatic [AE] of the companion CDK4/6 inhibitor,” and the higher incidence in the camizestrant arm “highly likely” reflected the longer duration of treatment. And indeed, after adjusting for exposure time, the rates were similar between the groups.
The incidence of symptomatic AEs was largely comparable among participants who switched to camizestrant and those who continued the AI, with one exception being a higher rate of any-grade photopsia (brief flashes of light in the peripheral vision) in the camizestrant group, at 20% versus 8%.
AE-related discontinuations were infrequent in both groups, with just 1% discontinuing camizestrant alone and 2% discontinuing AI, and 1% in each arm discontinuing both drugs.
Angela DeMichele (University of Pennsylvania, Philadelphia, USA), who discussed the presentation, said that the trial met its primary endpoint and “may represent a new path to regulatory approval.”
She added: “However, the clinical utility of serial ctDNA testing as a treatment strategy in first-line ER-positive metastatic breast cancer is not yet determined. We need information on other outcomes, including PFS2, overall survival, and the cost of the strategy, before adoption.”
The SERENA-6 findings were published simultaneously in The New England Journal of Medicine.
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2025 ASCO Annual Meeting; Chicago, Illinois, USA: 30 May–3 June
N Engl J Med 2025; doi:10.1056/NEJMoa2502929