FDA grants the first cancer approval guided by a resistance mutation found in circulating tumour DNA

The U.S. Food and Drug Administration granted accelerated approval on 4 September 2026 to Etcamah (camizestrant), used with a CDK4/6 inhibitor, for advanced breast cancer in which an ESR1 resistance mutation emerges in the blood during first-line therapy. It is the first time the agency has approved a cancer therapy triggered by a blood-based resistance mutation detected before scans show the disease is progressing.

Camizestrant is an oral next-generation selective oestrogen receptor degrader from AstraZeneca, dosed at 75 mg once daily with or without food. The approved indication covers adults with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer in whom an ESR1 mutation is detected during treatment with an aromatase inhibitor plus a CDK4/6 inhibitor. It is given in combination with abemaciclib, palbociclib or ribociclib. The companion diagnostic is the Guardant360 CDx assay, authorised to identify ESR1 mutations from circulating tumour DNA.

The registrational trial, SERENA-6, was randomised, double-blind, placebo-controlled and multicentre, and is registered on ClinicalTrials.gov as NCT04964934. It randomised 315 patients 1:1. Blood was sampled every two to three months and therapy was switched at the moment the mutation appeared, weeks to months before radiographic progression. Patients assigned to the control arm continued the aromatase inhibitor they were already receiving, alongside the same CDK4/6 inhibitor.

The design meant the change of treatment was made on a molecular signal alone. At the point of switching, imaging had not yet shown the disease to be progressing.

On the primary endpoint of progression-free survival, median survival without progression was 16 months (95% CI 12.7 to 18.2) for camizestrant plus a CDK4/6 inhibitor, against 9.2 months (95% CI 7.2 to 9.5) for continued aromatase inhibitor plus the same CDK4/6 inhibitor. The hazard ratio was 0.44 (95% CI 0.31 to 0.60), with P less than 0.00001, as stated in the approval notification issued by the FDA's Oncology Center of Excellence.

Dr Angelo de Claro, Director of the FDA's Oncology Center of Excellence, said: "This marks the first FDA approval of a cancer therapy guided by the detection of a resistance mutation in circulating tumor DNA (ctDNA) before imaging tests show that the disease is progressing." Acting FDA Commissioner Kyle Diamantas said: "Women living with metastatic breast cancer face an uphill battle as their tumors continuously evolve to escape treatment," and that "today's approval delivers a win to these patients by granting them a targeted therapy designed specifically to overcome resistance."

ESR1 mutations are the commonest acquired mechanism of resistance to aromatase inhibitors in hormone receptor-positive breast cancer. By sampling blood at fixed intervals and acting on the mutation as soon as it became detectable, SERENA-6 converted a reactive treatment paradigm, in which therapy changes once imaging shows growth, into a pre-emptive one. The FDA's Oncology Center of Excellence published a separate approval notification setting out the trial results.

The label carries a boxed warning for the risk of arrhythmia from QTc prolongation when camizestrant is combined with other QTc-prolonging drugs. Additional warnings cover bradycardia and embryo-foetal toxicity.

The clearance is an accelerated approval based on a surrogate endpoint, so confirmatory trials are required to verify clinical benefit. The open questions are whether pre-emptive switching on a molecular signal improves overall survival and not only progression-free survival, and whether the same serial circulating tumour DNA logic can be applied to resistance mutations in lung, colorectal and prostate cancer.