April 30, 2026
I’m Dr. Diana Zuckerman, president of the nonprofit National Center for Health Research. We do not accept funding from those with a financial interest in our work, so we have no conflicts of interest.
As a breast cancer survivor and epidemiologist, I know that overall survival is most important because treatments that kill cancer cells can sometimes kill patients due to toxicity, or have side effects that make their remaining days miserable.
SERENA-6 was not designed to demonstrate the clinical benefit of its experimental strategy, in which patients received a new therapy at ESR-1 detection rather than when progression is diagnosed later from scans. There is no other evidence to support that earlier switch. Detection of an ESR-1 mutation does not necessarily indicate that patients are clinically progressing or need an immediate change in therapy. That’s why we need clear evidence that the earlier intervention meaningfully extends patients’ lives.
We agree with the FDA that progression free survival rates from monotherapy trials can NOT be used to support this new experimental strategy – since patients will vary in other ways and because that would ignore the impact of a CDK inhibitor.
Although SERENA-6 met its PFS endpoint, it differs from other study results because it measured survival from an earlier start point and did not compare the switch strategy at biomarker detection vs. later radiographic progression.
FDA often does NOT require a statistically significant improvement in overall survival, but that’s needed here to establish whether patients benefit from switching therapy at ESR-1 detection.
Final overall survival data are not expected until 2028. But the study is probably not large enough to have the statistical power to evaluate OS even in 2028.
Although earlier treatment sounds good, using toxic therapies earlier may do more harm than good. If the treatment isn’t proven to extend life, earlier adverse events could harm patients’ quality of life during their final years. That’s why we share FDA’s concern that if it approves this treatment based on SERENA-6, that study design could be adopted by others despite the trial’s inability to demonstrate a clinical benefit of switching treatments earlier based on biomarker detection. That precedent would NOT be good for patients.
The later Progression Free survival outcome measure cited is irrelevant because patients received other therapies as well.
The patient reported outcome (PRO) results are unreliable due to infrequent events, poor data quality, uncertain clinical meaning, and minimal changes compared to an arbitrary baseline. And, the analysis did not statistically control for multiple comparisons.
Chemotherapy or ADC-free survival is a questionable endpoint because it could reflect clinical decisions, patient preference, or other variables rather than patient benefit.
In conclusion, this drug lowers heart rate and prolongs QT. That’s especially risky when combined with other QT-prolonging drugs, which the applicant proposes. Those risks would require additional monitoring, such as frequent ECGs.
Despite the unmet need, we agree with FDA that to support approval, clinical benefit must be established and the benefits must clearly outweigh the risks. Neither is true here.