Adrian Lee, Director of the Institute for Precision Medicine at UPMC, Professor at UPMC Hillman Cancer Center, and at the University of Pittsburgh, shared a post on LinkedIn:
“Last week’s FDA ODAC vote on camizestrant was, in my view, a step backwards for precision oncology.
I was genuinely excited when PADA-1 demonstrated that ctDNA-guided switching, detecting emergent ESR1 mutations and acting before radiographic progression, could improve outcomes in HR+/HER2− breast cancer.
Then SERENA-6 came along: a global, double-blind, placebo-controlled, registrational Phase III trial that rigorously validated exactly that approach. The hypothesis had become evidence.
Across oncology, the therapeutic benefit of intervention consistently erodes with disease advancement. For example, anti-estrogen therapy loses ground as tumor burden grows and resistance pathways diversify. The recurring story of breast cancer treatment, elucidated by research, is that earlier is better: tumor populations are smaller, clonal diversity is lower, the microenvironmental landscape more favorable.
Waiting for overt progression makes the challenge harder. And yet the argument is: wait for radiologic progression first.
The committee voted 6-3 against the SERENA-6 ctDNA-guided switching strategy, despite a 56% reduction in risk of progression or death, median PFS 16.0 vs. 9.2 months, a clean safety profile, and a discontinuation rate under 1%. PADA-1 pointed the way. SERENA-6 delivered the proof. The regulatory response was to ask for more.
On OS: this is a high bar in a disease where second-line options are numerous, patients cross therapy lines for years, and survival is measured in years. PFS was accepted as the primary endpoint for CDK4/6 inhibitor approvals in advanced disease. Why is the bar different when the intervention is guided by a blood test?
On crossover: if the trial had included one, it would have been called contaminated and uninterpretable. SERENA-6 was double-blind, placebo-controlled, randomized at ESR1 detection, which is the rigorous design. The absence of crossover isolates the effect of timing. If the control arm was disadvantaged by not switching at progression, that is an argument for acting on the ctDNA signal, not against it.
On precedent: molecular resistance monitoring is being held to an evidentiary standard that radiographic progression never was. We built entire screening programs on catching things early, long before OS data existed to prove it. SERENA-6 is that logic applied to acquired resistance. If that’s a precedent, it’s one worth setting.
No conflicts of interest with AstraZeneca or any company involved in camizestrant’s development. My own views as a breast cancer researcher, because this decision matters for patients and requires further deliberation.”
Other articles about FDA ODAC on OncoDaily.