Catching Resistance Early: Can New Breast Cancer Drug Help?

Medscape

05-06-2025

CHICAGO — Can spotting an emerging ESR1 mutation early and changing first-line drugs before progression improve outcomes in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2–negative advanced breast cancer?
Interim findings from the SERENA-6 trial suggest that may be the case.
Patients who switched from a first-line aromatase inhibitor to camizestrant, an investigational next-generation oral selective estrogen-receptor degrader, at the first signs of an emerging ESR1 mutation demonstrated significantly improved progression-free survival compared with those who continued their initial regimen.
Notably, circulating tumor DNA (ctDNA) testing allowed investigators to identify ESR1 mutations, which emerge at the time of disease progression in about 40% of patients on a first-line aromatase inhibitor and lead to treatment resistance.
Camizestrant, which has shown activity in patients who develop ESR1 mutations, helped improve first-line outcomes and has 'potential to become a new treatment strategy,' according to co-principal investigator Nicholas Turner, MD, PhD, professor and honorary consultant in medical oncology at the Institute of Cancer Research and Royal Marsden Hospital, London, England, who presented the findings at the American Society of Clinical Oncology (ASCO) 2025 annual meeting. Results were simultaneously published in The New England Journal of Medicine .
This trial also demonstrated 'the clinical utility of ctDNA monitoring to detect and treat emerging resistance in breast cancer,' said Turner.
While praising the findings, others were not convinced that the SERENA-6 results warrant a change in practice yet.
'Based on first-line progression-free survival alone, this could represent a new regulatory approval path,' said invited discussant Angela DeMichele, MD, of the University of Pennsylvania, Philadelphia. But, DeMichele cautioned, 'I cannot recommend the SERENA-6 strategy at this time.'
One key reason, DeMichele noted, is that it's too early to tell whether this strategy improves overall survival. If camizestrant is approved based on progression-free survival and quality of life, DeMichele wondered, is it worth going through the ctDNA testing process if the drug doesn't help patients live longer?
Paolo Tarantino, MD, a breast oncologist at Dana-Farber Cancer Institute and Harvard Medical School in Boston, echoed this sentiment in a tweet on X: 'Outstanding results, though not ready for clinical practice (yet),' adding that it will also be 'important to take into account financial, psychological, and systemic costs of the strategy.'
Using ctDNA to Track Resistance
In the study, 3256 patients who had received at least 6 months of treatment with aromatase inhibitors and CDK4/6 therapy (palbociclib, ribociclib, or abemaciclib) received ctDNA testing with Guardant360 CDx every 2-3 months at the time of routine staging exams.
Overall, 315 patients who had an ESR1 mutation detected and had no radiologic evidence of disease progression were randomly assigned to either switch from the aromatase inhibitor to 75 mg of camizestrant daily (n = 157) or continue their aromatase inhibitor/CDK4/6 regimen (n = 158). (An additional 233 patients who had an ESR1 mutation detected were not included for a variety of reasons, including disease progression and consent withdrawal.)
At the planned interim analysis, the median progression-free survival was 16.0 months in the camizestrant group and 9.2 months in the aromatase inhibitor group (adjusted hazard ratio [aHR], 0.44; P < .00001). At 24 months, only 5.4% of patients who had continued their initial first-line treatment had not progressed compared with 30% of patients on camizestrant. The progression-free survival findings were consistent across clinically relevant patient subgroups.
Patients who switched to camizestrant also showed improved time to deterioration in global health status and quality of life — a median of 23.0 months vs 6.4 months in the aromatase group (aHR, 0.53).
At the time of the interim analysis, overall survival data were immature, with 20 deaths in the camizestrant group and 19 in the aromatase inhibitor group (HR, 0.91; 95% CI, 0.48-1.73). As for time to second progression, there were 38 events in the camizestrant group and 47 events in the aromatase group, but the findings were also immature.
As for adverse events, 60% of patients in the camizestrant group had a grade 3 or higher event, 10% of which were deemed serious compared with 46% in the aromatase group, 12% of which were serious. Neutropenia (45% vs 34%, respectively) and anemia (5% in both groups) were the most common grade 3 or higher adverse events. Only 1% of patients on camizestrant discontinued treatment due to adverse events.
Overall, Turner concluded that 'for people with HR-positive advanced breast cancer, the results of SERENA-6 show that camizestrant plus CDK4/6 inhibitor could be a new treatment option to use at the point of ESR1 mutation detection during treatment with first-line aromatase inhibitor plus CDK4/6 inhibitor — but before the cancer grows.'
Despite the promising findings, DeMichele highlighted several key unanswered questions and challenges.
Notably, will this strategy lead to longer overall survival and demonstrate clinical utility?
Overall survival and time to second progression are currently not known, DeMichele said. The trial did not address whether first-line treatment gains would be lost if camizestrant was given in the second-line setting after anatomic progression.
DeMichele also noted the high cost and potential anxiety associated with serial ctDNA testing. Overall, 'the full complement of financial, psychological, and systemic costs is needed to fully assess utility and feasibility for implementation,' she added.
SERENA-6 was supported by AstraZeneca. Turner disclosed consulting or advisory roles with AstraZeneca, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Health, Inivata Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics, and Roche. DeMichele disclosed a consulting or advisory role with Pfizer.