SERENA-6 Introduces Potential New Paradigm of Early ESR1 Mutation Detection to Delay Progression in HR+ Breast Cancer

Erica L. Mayer, MD, MPH

Findings from the phase 3 SERENA-6 trial (NCT04964934) demonstrated the feasibility of guiding treatment decisions through early detection of ESR1 mutations through circulating tumor DNA (ctDNA) monitoring in patients with advanced hormone receptor–positive breast cancer, according to Erica L. Mayer, MD, MPH. She added that with the improved outcomes for patients who switched to a camizestrant-based regimen prior to radiographic progression, this may represent a new paradigm for identifying emerging treatment resistance to guide treatment decisions with the goal of delaying disease progression.

These data were presented at the 2025 ASCO Annual Meeting and showed that adding camizestrant to continued therapy with CDK4/6 inhibition significantly improved progression-free survival (PFS) vs continued therapy with an aromatase inhibitor (AI) and CDK4/6 inhibition in patients with a detected ESR1 mutation prior to radiographic progression on frontline therapy.

The median investigator-assessed progression-free survival (PFS) was 16.0 months (95% CI, 12.7-18.2) with camizestrant plus CDK4/6 inhibition (n = 157) vs 9.2 months (95% CI, 7.2-9.5) with continued AI plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001). The 12- and 24-month PFS rates in the camizestrant arm were 60.7% and 29.7%, respectively, vs respective rates of 33.4% and 5.4% in the continued AI plus CDK4/6 inhibition arm.

“These were exciting findings. [We] not only saw the efficacy of camizestrant, but also the greater new paradigm of using molecular progression as a moment when we can intervene with an effective therapy and make a difference for patients,” said Mayer, the director of clinical research at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

In an interview with OncLive®, Mayer expanded on how the SERENA-6 trial set out to address the development of endocrine resistance driven by ESR1 mutations in hormone receptor–positive, HER2-negative metastatic breast cancer; primary results from the study; and how these data could enable earlier detection of endocrine resistance and earlier treatment modifications to optimize patient outcomes in this disease setting.

OncLive: What challenges in disease management did SERENA-6 seek to address, and how might its findings influence the timing of ESR1 testing and subsequent treatment decisions in metastatic hormone receptor–positive, HER2-negative breast cancer?

Mayer: One of the most exciting abstracts we saw at ASCO 2025 this year is the SERENA-6 study. SERENA-6, which was presented in a plenary presentation, is a global phase 3 study that is looking at the oral selective estrogen receptor degrader camizestrant. SERENA-6 also explored a very novel paradigm in breast cancer. [We are starting to] think about what to do next when we define progressive disease. [Moreover], if we can define [when the] disease is becoming resistant, does early intervention help?

The concept behind SERENA-6 was that patients who have hormone receptor–positive, HER2-negative breast cancer develop resistance to endocrine therapy over time, which eventually leads to disease progression and the need to change treatments. One of the major drivers of resistance includes ESR1 mutations. ESR1 mutations are quite rare when patients initially begin therapy, but after they have been on first-line therapy in the metastatic setting, [which includes] an AI plus a CDK4/6 inhibitor, the rate of ESR1 mutations tends to go up significantly. This is thought to be one of the main reasons that patients develop resistance to their regimen.

The [thought process] in SERENA-6 was that if one could detect this molecular progression prior to the eventual development of clinical progression, then early intervention with an effective therapy to target the ESR1 mutation may help prevent or delay eventual progression and improve outcomes for patients.

What was the design and methodology of this study?

In SERENA-6, there were two steps. The first step was the screening step. Patients entered screening—there were several thousand patients who had serial ctDNA [testing] performed to look for the emergence of the ESR1 mutation. All of these patients had metastatic hormone receptor–positive, HER2-negative breast cancer and had already been on their first-line therapy with an AI and a CDK4/6 inhibitor for at least 6 months. Patients had ctDNA testing, usually timed with their restaging every 2 to 3 months.

If an ESR1 mutation was detected but there was no evidence of clinical progression, patients then moved to step 2, where 315 patients were randomly assigned to either continue on an AI plus CDK4/6 inhibitor with a placebo, or switch to camizestrant plus a CDK4/6 inhibitor with a placebo for an AI.

What were the primary efficacy and safety results from SERENA-6? How do these data add to the knowledge regarding the emergence of ESR1 mutations?

The PFS results from the study were highly significant, favoring the switch to camizestrant. Patients receiving an AI had a PFS of 9.2 months, and this significantly improved to 16.0 months with the switch to camizestrant, with a highly significant HR of 0.44. The curves separated early and stayed separated, showing early benefit in making this switch.

Additionally, a very important finding from the study was related to quality of life. Patients who switched to camizestrant had a substantially longer time until they experienced deterioration in quality of life—an improvement from 6.4 months to 23.0 months. This means those patients had an extra year and a half of living without substantial symptoms related to their cancer, which is incredibly clinically meaningful.

Other important end points from SERENA-6 included time to second progression [PFS2] and overall survival [OS]. We did see some early PFS2 data; [they were] still immature but trending in a favorable way, and we are waiting for OS data.

Camizestrant is extremely well tolerated. Very few patients had serious toxicities, and very few patients had to discontinue therapy. There is a unique toxicity of camizestrant called photopsia, which is like [seeing] flashing lights in low-light conditions. Patients who experience this do not seem bothered by it, it does not interfere with activities of daily living, there is no change to visual acuity, and it is very rapidly reversible and generally very mild.

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Reference

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