Camizestrant Approval Paves the Way for ctDNA-Guided Switching in Emergent ESR1-Mutated HR+/HER2– Advanced Breast Cancer

An early switch to camizestrant (Etcamah) in combination with a CDK4/6 inhibitor once an ESR1 mutation has surfaced in circulating tumor DNA (ctDNA), before clinical progression, prolongs progression-free survival (PFS) and delays deterioration in quality of life (QOL) vs continuing an aromatase inhibitor in patients with hormone receptor–positive, HER2-negative advanced breast cancer whose tumors develop an ESR1 mutation while they are receiving an aromatase inhibitor and a CDK4/6 inhibitor, according to Erica L. Mayer, MD, MPH.

On September 4, 2026, the FDA granted accelerated approval to camizestrant plus abemaciclib (Verzenio), palbociclib (Ibrance), or ribociclib (Kisqali) for the treatment of adult patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer that acquires an ESR1 mutation during treatment with an aromatase inhibitor and CDK 4/6 inhibitor therapy, as identified by an FDA-approved test.¹ This regulatory decision was based on findings from the phase 3 SERENA-6 trial (NCT04964934). The study randomly assigned 315 patients with an emergent ESR1 mutation and no radiologic progression 1:1 to switch to camizestrant at 75 mg once daily while continuing their CDK4/6 inhibitor (n = 157) or continue to receive their aromatase inhibitor plus a CDK4/6 inhibitor (n = 158).^1,2 The median PFS values were 16 months (95% CI, 12.7-18.2) vs 9.2 months (95% CI, 7.2-9.5), respectively (HR, 0.44; 95% CI, 0.31-0.60; P < .00001). Additionally, QOL deteriorated at a median of 21.0 months with camizestrant vs 6.4 months with a continued aromatase inhibitor, based on patient-reported global health status (HR, 0.54; 95% CI, 0.34-0.84).

“The approval of this agent allows us to offer this regimen to patients whose cancers have developed the ESR1 resistance mutation and more broadly introduces this concept of monitoring patients for resistance mutations and intervening at the time of molecular progression as opposed to waiting for clinical progression,” Mayer said in an exclusive interview with OncLive®.

In the interview, Mayer discussed the significance of the approval, key efficacy findings from SERENA-6, considerations for integrating ctDNA screening into clinical practice, the study’s influence on future clinical trial design, and remaining unmet needs in hormone receptor–positive, HER2-negative breast cancer.

Mayer is director of Breast Cancer Research at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: How does the FDA approval of camizestrant address unmet needs in emergent ESR1-mutated, hormone receptor–positive, HER2-negative advanced breast cancer?

Mayer: The approval of camizestrant, based on the data from SERENA-6, is incredibly important, not only for the approval of the agent itself, the oral selective estrogen receptor degrader [SERD] camizestrant, but also for the overall platform and structure in which it was approved. Camizestrant is an oral SERD, and it joins 3 other novel endocrine agents that have recently been approved for advanced hormone receptor–positive, HER2-negative breast cancer. Camizestrant is well tolerated and highly active in combination with a CDK4/6 inhibitor.

However, perhaps the greater finding from SERENA-6 and part of the approval is the introduction of the concept of monitoring for the emergence of resistance mutations and then tailoring a patient’s treatment. In SERENA-6, patients underwent serial ctDNA monitoring during first-line therapy with an aromatase inhibitor and a CDK4/6 inhibitor. If they were found to have emergence of the resistance mutation ESR1 in the estrogen receptor, they were [randomly assigned] to either continue to receive their current therapy or switch to the oral SERD camizestrant with continuation of the CDK4/6 inhibitor. The patients who made the switch experienced a significant prolongation in PFS and a significant delay in deterioration in QOL. Additionally, there was a delay until the time when a patient needed to switch to chemotherapy, as well as an improvement in time to second progression [PFS2]. This approval will make a substantial difference in the lives of our patients and improve their outcomes.

What were the key efficacy findings from SERENA-6 that supported the FDA approval of camizestrant?

The study had 2 parts. Step 1 was a screening step where patients who had been receiving a first-line aromatase inhibitor plus a CDK4/6 inhibitor for at least 6 months entered a screening section of the trial where ctDNA was checked for the emergence of an ESR1 mutation approximately 4 times a year at the times of routine restaging. The trial was looking to identify patients whose cancers had developed the ESR1 mutation but clinically did not have evidence of disease progression, suggesting a window of time when an intervention could improve outcomes for patients and overcome resistance. Patients identified in step 1 with the emergence of the mutation in the absence of clinical progression moved to step 2, where they were [randomly assigned] to either switch to the oral SERD camizestrant with continuation of the CDK4/6 inhibitor or continue to receive their prior regimen of an aromatase inhibitor plus a CDK4/6 inhibitor.

The study met its primary end point of PFS, with an improvement from [9.2] months in the control arm to [16] months in the switch arm with camizestrant. This was a positive trial. Further follow-up from the trial has demonstrated prolongation in PFS2 and time to chemotherapy, as well as a substantial delay in the deterioration of QOL, which appears to be driven by a delay in symptoms suggestive of subclinical cancer progression, such as pain, fatigue, or shortness of breath.

Additionally, molecular analysis has shown dramatic reductions in the levels of the ESR1 variant allele frequency in ctDNA, and a substantial number of patients who made the switch to camizestrant had complete clearance of ctDNA. Overall, camizestrant is well tolerated with minimal additional AEs beyond [those associated with] the backbone CDK4/6 inhibitor. The study showed that this is an active, safe, and highly effective regimen for patients.

What is your advice to colleagues about integrating ctDNA screening and a camizestrant-based regimen into breast cancer clinical practice?

This is an exciting step forward for us to begin to consider how to incorporate ctDNA screening into regular practice. As a community, we all will need to think about which patients this approach will be best for, when to use it, how often to use it, and how to make decisions that will be appropriate for our clinics and our clinic structure, as well as our patients themselves. We’re all excited to begin trying the approach of ctDNA screening and bringing camizestrant into clinic for patients.

How might the SERENA-6 trial design influence future clinical trial design now that camizestrant is FDA approved?

This trial is at the forefront of trials that are using molecularly derived data to influence real-time treatment decisions. Similar trials exist for other solid tumor types and may begin to grow over time. As we learn more about mechanisms of resistance in cancers and [develop] the appropriate targeted partners for those mechanisms of resistance, that will set the stage for future trials that can look at dissecting the exact mechanism of resistance for each individual patient and then allow us to apply the correct targeted therapy to help overcome that resistance. SERENA-6 is a huge step forward for breast cancer medical oncology, offering a new therapy and a new paradigm for how to monitor and treat patients, but it also may have more widespread implications in medical oncology in general.

What unmet needs remain for patients with hormone receptor–positive, HER2-negative breast cancer that future research should address?

It’s exciting to talk about ESR1 mutations, but these occur in only approximately 40% of patients. There are many other mutations that can develop that can lead to resistance to endocrine-based therapies, including ones that we are familiar with, such as mutations in the PI3K pathway, and other mutations that still need to be further developed and understood. There remains great need to identify actual mutations, develop safe, tolerable, and effective therapies to target these mutations, and learn how and when to use them.

Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. FDA grants accelerated approval to camizestrant with a CDK4/6 inhibitor for ESR1-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer. FDA. September 4, 2026. Accessed September 4, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-camizestrant-cdk46-inhibitor-esr1-mutated-hr-positive-her2-negative?utm_medium=email&utm_source=govdelivery
2. Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4