Guardant Health, Inc (NASDAQ:GH) shares are trading lower on Tuesday after the U.S. Food and Drug Administration (FDA) announced a review of AstraZeneca Plc's (NASDAQ:AZN) application for camizestrant for advanced breast cancer.
In briefing documents, the agency panel appeared concerned about the trial design, measurement of progression-free survival (PFS), and immature overall survival (OS) results, which may not achieve statistical significance.
FDA Raises Concerns
The FDA has raised multiple concerns about the interpretation of results from the SERENA-6 trial evaluating camizestrant in HR-positive, HER2-negative advanced breast cancer, despite the study meeting its progression-free survival (PFS) endpoint.
Regulators said uncertainties remain around whether early treatment switching based on ESR1 mutation detection provides meaningful clinical benefit.
The study used Guardant Health’s FDA-approved Guardant360 CDx assay to detect ESR1 mutations detected in ctDNA.
The FDA did not approve the Guardant360 device for detecting ESR1m in patients with HR+HER2- ABC who are receiving an AI and a CDK4/6 inhibitor for ≥ 6 months (as used in SERENA-6).
A Premarket Approval (PMA) supplement for the Guardant360 device is under review in CDRH concurrently with the NDA for camizestrant.
Questions Around Early Treatment Strategy
A central issue flagged by the FDA is the lack of evidence supporting a strategy of switching therapy at ESR1 mutation detection rather than waiting for radiographic disease progression.
The agency noted that no clinical trials to date have demonstrated that initiating a new therapy earlier improves outcomes compared to the standard approach.
In SERENA-6, patients in the control arm continued on aromatase inhibitor (AI) and CDK4/6 inhibitor therapy for a median of 9.2 months before progression or death.
The FDA cautioned that switching treatments prematurely may limit the full benefit of existing therapies.
Uncertainty Over PFS Clinical Meaning
The FDA also questioned the clinical relevance of the PFS endpoint used in the trial. Unlike traditional trials, where PFS is measured after disease progression or diagnosis of advanced cancer, SERENA-6 measured PFS from the point of ESR1 mutation detection.
Regulators said the significance of this earlier measurement remains unclear, as it is not established how such improvements translate into long-term patient benefit.
Limitations Of Secondary Endpoints
The agency highlighted that PFS2, a secondary endpoint, does not provide reliable evidence of clinical benefit.
Variability in subsequent treatments and lack of crossover in the study design introduced subjectivity, making it difficult to isolate the effect of camizestrant.
Additionally, differences in treatment exposure between study arms further complicated interpretation, with patients receiving unequal numbers of therapies.
Safety Signals And Survival Data Concerns
Safety risks also emerged as a concern. Camizestrant has been associated with heart rate reduction and QT interval prolongation, raising the risk of cardiac arrhythmias, particularly when combined with certain CDK4/6 inhibitors. A reported case included severe cardiac complications.
Meanwhile, overall survival (OS) data remain immature, with final analysis expected around 2028. The FDA noted that the study may not achieve statistical significance for OS, further complicating the benefit-risk assessment.
GH Stock Price Activity: Guardant Health shares were down 5.24% at $83.86 at the time of publication on Tuesday, according to Benzinga Pro data.
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