Camizestrant Approval Introduces ctDNA-Guided Treatment Switching Before Radiographic Progression

Treatment sequencing in hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer now includes the option to act on molecular evidence of endocrine resistance before progression becomes visible on imaging.

On September 4, 2026, the FDA granted accelerated approval to camizestrant, an oral selective estrogen receptor degrader and antagonist, in combination with a CDK4/6 inhibitor. The indication covers adults with HR+, HER2- locally advanced or metastatic breast cancer upon detection of an ESR1 mutation during treatment with an aromatase inhibitor and a CDK4/6 inhibitor, based on an FDA-authorized test.

“We now have a third oral selective estrogen receptor degrader (SERD) available for patients,” Dr. Alberto Montero, Clinical Director, Breast Cancer Medical Oncology Program at University Hospitals Seidman Cancer Center, tells SurvivorNet Connect.

“While we have two other FDA-approved SERDs (elacestrant and imlunestrant), it is always good to have different options for patients,” Dr. Montero adds.

The approval establishes a new treatment point between clinical stability and radiographic progression. However, it also introduces practical questions about serial circulating tumor DNA testing, patient selection, and the long-term value of changing therapy at molecular progression.

Dr. Sonya Reid, associate professor of medicine in the Division of Hematology/Oncology at Vanderbilt-Ingram Cancer Center, calls the update a “paradigm-shifting treatment approach.”

“Patients will have the option to potentially switch to camizestrant earlier, rather than waiting for progression on scans. This is, however, not a one-size-fits-all decision,” Dr. Reid tells SurvivorNet Connect. “Patients should have a shared discussion with their medical oncology team, taking into account how well first-line treatment is being tolerated, current symptoms, and imaging results.”

Indication and Treatment Strategy

ESR1 mutations are acquired alterations in the gene encoding estrogen receptor alpha. They can activate estrogen receptor signaling despite estrogen deprivation, creating resistance to aromatase inhibitors such as anastrozole or letrozole.

These mutations may be detectable in circulating tumor DNA — tumor-derived DNA fragments found in plasma — before clinical symptoms or imaging demonstrate progression. The FDA concurrently approved Guardant360 CDx as a companion diagnostic for identifying eligible patients.

“This represents an important shift toward truly biomarker-driven treatment. Rather than waiting for clinical or radiographic progression, we can identify a specific mechanism of treatment resistance through circulating tumor DNA and use that information to select patients for a change in therapy while their disease is still controlled,” Dr. Jaime Alberty, director of the Comprehensive Breast Center at NYC Health + Hospitals/Kings County, tells SurvivorNet Connect.

Once an ESR1 mutation is detected, camizestrant replaces the aromatase inhibitor. The patient continues the same CDK4/6 inhibitor at the dose being administered when the mutation was identified. The recommended camizestrant dose is 75 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

The regulatory indication and the pivotal trial population should not be treated as identical. The FDA indication specifies mutation detection during aromatase inhibitor plus CDK4/6 inhibitor therapy but does not separately state the trial’s requirement for at least six months of first-line combination therapy.

SERENA-6 enrolled only patients receiving first-line aromatase inhibitor plus CDK4/6 inhibition for at least six months, without radiographic progression, and with an Eastern Cooperative Oncology Group performance status of 0 or 1. Therefore, evidence remains limited for patients with poorer performance status, shorter exposure to first-line therapy, an ESR1 mutation identified after radiographic progression, or use of the strategy beyond the first-line setting.

Dr. Bahar Moftakhar, Medical Oncologist, UH Seidman Cancer Center stresses, “this strategy is for a very specific group of patients- those who develop an ESR1 mutation while receiving an aromatase inhibitor and CDK4/6 inhibitor and whose cancer has not yet progressed on imaging.”

SERENA-6 Design and Efficacy

SERENA-6 was a global, double-blind, phase 3 trial in which patients underwent Guardant360 CDx testing every two to three months during routine clinical follow-up. The FDA approval does not establish a required testing interval, but the trial’s surveillance schedule provides the evidence base for the early-switch strategy.

Among 3,325 patients screened, 3,256 underwent at least one ESR1 mutation test and 548 had a positive result by the end of screening. A total of 315 eligible patients without radiographic progression were randomized: 157 switched from an aromatase inhibitor to camizestrant while continuing the same CDK4/6 inhibitor and 158 continued their aromatase inhibitor and CDK4/6 inhibitor.

• At the prespecified interim analysis, investigator-assessed median progression-free survival was 16.0 months with camizestrant versus 9.2 months with continued aromatase inhibition. The hazard ratio for progression or death was 0.44 (95% confidence interval, 0.31–0.60; P<0.00001).
• At 12 months, the estimated progression-free survival rates were 60.7% and 33.4%, respectively.
• At 24 months, they were 29.7% and 5.4%.
• An updated analysis after a median follow-up of 23.5 months showed consistent results: median progression-free survival was 16.8 versus 9.2 months, corresponding to a hazard ratio of 0.45.

Median second progression-free survival — the time from randomization to progression on a subsequent therapy or death — was 25.7 months with the camizestrant strategy and 19.1 months with continued aromatase inhibition (hazard ratio, 0.63; 95% confidence interval, 0.46–0.86).

Overall survival remains immature, and a survival advantage has not been demonstrated. Progression-free survival should therefore be presented as prolonged disease control after mutation detection, not evidence that patients live longer.

What SERENA-6 Does Not Answer

SERENA-6 compared an immediate switch to camizestrant with continued aromatase inhibitor therapy. It did not compare early switching with a strategy of continuing treatment until radiographic progression and then initiating camizestrant or another ESR1-directed therapy.

“The next big questions are whether switching earlier really helps people live longer, how it affects other treatments someone might need later, and whether patients can actually get both the repeated blood tests and the medicine easily,” Dr. Francisco Esteva, Chief of Hematology & Medical Oncology at Northwell’s Lenox Hill Hospital, tells SurvivorNet Connect. “This ‘accelerated approval’ means the drug is available now, but whether it stays approved might depend on more proof that it provides a clear clinical benefit.”

Crossover to camizestrant at first progression was not built into the control strategy. Consequently, the trial cannot determine whether using camizestrant immediately after molecular progression is superior to reserving an ESR1-directed agent until conventional progression.

This distinction is central to the accelerated approval. The FDA based the decision on progression-free survival measured from ESR1 mutation detection while acknowledging that the long-term clinical benefit of intervening at this point has not been confirmed. Continued approval may depend on confirmatory trials.

“While changing treatment early clearly delayed progression in this study, we do not yet know whether changing treatment at the time an ESR1 mutation appears is better in the long term than waiting until the cancer progresses and changing treatment then. We do not yet have enough follow-up to know whether this treatment strategy helps patients live longer. This is why this received accelerated approval and why additional studies and longer follow-up are important,” Dr. Moftakhar adds.

Safety and Monitoring

The safety profile reflects both camizestrant and continued CDK4/6 inhibition.

In the updated SERENA-6 analysis:

• Serious adverse events occurred in 15% of patients receiving camizestrant and 19% continuing an aromatase inhibitor.
• The most frequent grade 3 or 4 events included neutropenia, reported in 27% versus 17%, and decreased neutrophil count, reported as a separate laboratory term in 23% versus 19%.
• Visual disturbances — including photopsia, blurred vision, diplopia and light sensitivity — occurred in approximately one-third of camizestrant-treated patients. These events were usually low grade and rarely led to discontinuation, but persistent or function-limiting symptoms warrant treatment interruption and ophthalmologic assessment.

Cardiac monitoring requires particular attention. The prescribing information includes a boxed warning for potentially serious ventricular arrhythmias when camizestrant is administered with QT-prolonging medications. This is especially relevant with ribociclib, which can also prolong the QT interval.

In SERENA-6, bradycardia occurred in 8% of patients and QTc prolongation in 2.6%. The safety of camizestrant has not been established in patients with a baseline resting heart rate below 55 beats per minute because they were excluded from the trial.

Before initiation, clinicians should review all prescription drugs, over-the-counter medications and supplements; obtain an electrocardiogram; assess heart rate; and identify and correct electrolyte abnormalities. The prescribing information recommends electrocardiographic monitoring weekly during the first two weeks and periodically thereafter as clinically indicated. Concomitant medications that prolong the QT interval or reduce heart rate should be reassessed.

Implications for Practice

This approval makes serial ctDNA surveillance potentially actionable during first-line aromatase inhibitor plus CDK4/6 therapy. It does not establish an optimal testing frequency, demonstrate an overall survival benefit or show that every patient with an emerging ESR1 mutation should switch immediately.

Implementation should account for the patient’s current disease control, treatment tolerance, cardiovascular risk, access to companion testing and preferences regarding an early treatment change. The PFS improvement is clinically relevant, but the unresolved comparison is not camizestrant versus an ineffective aromatase inhibitor indefinitely. It is early camizestrant versus changing treatment after conventional progression—a question that SERENA-6 was not designed to answer.