Early detection of an ESR1 mutation, leading to a switch of endocrine therapy, led to an almost doubling in progression-free survival in the SERENA-6 trial, the global registrational study in patients with metastatic breast cancer for the investigational oral selective estrogen receptor degrader (SERD) camizestrant, researchers reported during the Plenary Session at the 2025 ASCO Annual Meeting.¹ The study was concurrently published in TheNew England Journal of Medicine.² Based on these outcomes, camizestrant was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA).

Patients with hormone receptor–positive, HER2-negative advanced breast cancer who were responding to a first-line aromatase inhibitor and a CDK4/6 inhibitor underwent circulating tumor DNA (ctDNA) testing earlier than the standard time for testing. Upon detection of an ESR1 mutation, they were switched to camizestrant while continuing CDK4/6 therapy. This early intervention led to a median progression-free survival of 16.0 months, compared with 9.2 months in the control arm, who continued their original treatment—a highly significant 56% reduction in risk (hazard ratio [HR] = 0.44; P < .0001).

“SERENA-6 represents a milestone in precision oncology, providing concrete evidence for the benefit of early, ctDNA-guided intervention.”

— Nicholas C. Turner, MD, PhD, FRCP, FMedSci

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“SERENA-6 represents a milestone in precision oncology, providing concrete evidence for the benefit of early, ctDNA-guided intervention,” said Nicholas C. Turner, MD, PhD, FRCP, FMedSci, Director of Clinical Research and a consultant medical oncologist at the Royal Marsden Hospital and Institute of Cancer Research, London. “This treatment strategy has the potential to significantly enhance first-line therapy outcomes for patients with advanced breast cancer and optimize treatment decisions before clinical disease progression manifests.”

ASCO expert Eleonora Teplinsky, MD, Head of Breast and Gynecologic Medical Oncology at Valley–Mount Sinai Comprehensive Cancer Care in New Jersey, underscored the significance of these findings during an ASCO press briefing. “In this study, an early-switch approach, before we see disease progression on imaging, allows us to stay ahead of the curve and allows patients to remain on first-line endocrine therapy,” she said. “This is critical, because we know that outcomes worsen with subsequent lines of therapy. We will need to see data on progression-free survival 2 and overall survival to truly know we are improving long-term outcomes with this approach. The median time until deterioration in patient-reported quality of life improved with camizestrant. Maintaining quality of life is a key objective in the metastatic setting, where living well with disease is critical.”

Eleonora Teplinsky, MD

As Dr. Turner explained, approximately 70% of breast cancers express hormone receptors without HER2 amplification, placing significant clinical importance on therapies targeting estrogen receptor signaling. Although rare at initial diagnosis, ESR1 mutations commonly emerge during first-line treatment with an aromatase inhibitor combined with a CDK4/6 inhibitor, affecting up to 40% of patients by the time of disease progression. These mutations induce constitutive, estrogen-independent activation of the estrogen receptor, complicating treatment and accelerating disease progression.

About SERENA-6

SERENA-6 is the first global, registrational phase III trial explicitly designed to assess the clinical utility of ctDNA monitoring to detect these emerging ESR1 mutations ahead of overt clinical disease progression. The trial enrolled 3,256 patients who had been stable on a first-line aromatase inhibitor plus a CDK4/6 inhibitor for at least 6 months. Participants underwent routine ctDNA testing every 2 to 3 months using the Guardant360 CDx assay. ESR1 mutations were detected in 548 patients, of whom 315 met eligibility criteria for randomization.

These eligible patients were randomly assigned (1:1) in a double-blind manner either to continue their current regimen (aromatase inhibitor plus CDK4/6 inhibitor) with placebo for camizestrant or to switch to camizestrant with continued CDK4/6 inhibition and placebo. The trial’s primary endpoint was investigator-assessed progression-free survival, with key secondary endpoints including progression-free survival 2, overall survival, safety, and patient-reported outcomes.

A Doubling of Progression-Free Survival

At a planned interim analysis, the median progression-free survival was significantly extended, from 9.2 months in the control group to 16 months among patients switched early to camizestrant (HR = 0.44; P < .0001), effectively more than doubling the time spent in remission.

As Dr. Turner reported, the separation in the progression-free survival curves occurred early and remained pronounced over time. At 24 months, 30% of patients receiving camizestrant were progression-free vs 5.4% of those continuing their original aromatase inhibitor. And, he emphasized, the progression-free survival benefit remained consistent across multiple prespecified subgroups, including different CDK4/6 inhibitors and clinical characteristics.

Quality of Life and Safety Profile

Additionally, switching to camizestrant significantly delayed the time to deterioration in patient-reported global health status and quality of life. The median time to deterioration of quality of life was prolonged from 6.4 months in the control group to 23 months in the camizestrant group (HR = 0.53, P < .001). Moreover, patients receiving camizestrant experienced significantly delayed deterioration of pain symptoms.

Regarding safety, camizestrant demonstrated a favorable profile with minimal treatment discontinuation from adverse events, reported at 1%. Serious adverse event rates were similar between the camizestrant (10%) and control groups (12%).

Of note, increased neutropenia observed in the camizestrant arm was likely attributed to prolonged exposure to CDK4/6 inhibitors, said Dr. Turner, as adjusted incidence rates by treatment duration were comparable between the groups. Photopsia, characterized by brief peripheral visual flashes, was reported to be more frequent with camizestrant (20%), but these effects were predominantly mild (grade 1) and did not significantly affect daily activities.

Although secondary endpoints such as progression-free survival 2 suggested continued benefit (HR = 0.52, P = .0038, not statistically significant at this interim analysis), these data remain immature, said Dr. Turner, and require further follow-up. “That will be another very important piece of evidence from this study,” he commented. Overall survival data and molecular data (such as clearance of ESR1 mutations) were also immature and not yet presented.

Could Another Oral SERD Be Used?

Because camizestrant is not yet approved by the FDA, the study stimulated discussion among oncologists at the meeting. Could they currently use this strategy, substituting elacestrant for
camizestrant?

“This is a question that everyone’s thinking about, but we don’t have those data,” commented Dr. Teplinsky. “Not all oral SERDs are the same, and we don’t know if using the available oral SERD in this setting is going to have the same results. At this time, there are no robust data to support the use of another oral SERD following the SERENA-6 paradigm. This is really going to evolve as we have these data.”

Julie R. Gralow, MD, FACP, FASCO

Press briefing moderator and breast cancer expert Julie R. Gralow, MD, FACP, FASCO, Chief Medical Office and Executive Vice President of ASCO, shared these comments about the SERENA-6 findings: “In the real world, with the patient in front of me who is asking about this study, and because we do have an oral SERD approved that has shown efficacy in ESR1 mutations, I would probably be a little bit more liberal—although Dr. Teplinsky gave ‘the study-backed’ answer.” 

DISCLOSURE: The SERENA-6 trial was supported by research funding from AstraZeneca. Dr. Turner has served as a consultant or advisor to AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Inivata, Guardant Health, and Exact Sciences; and has received research funding from AstraZeneca, Pfizer, Roche/Genentech, Merck Sharp and Dohme, Guardant Health, Invitae, Inivata, Personalis, and Natera. For disclosures of the other study authors, visit coi.asco.org. Dr. Teplinksy has received honoraria from Sermo; has served as a consultant or advisor to Novartis, Daiichi Sankyo/AstraZeneca, Pfizer, ImmunoGen, and AbbVie; and has received reimbursement for travel expenses from OncLive/MJH Life Sciences. Dr. Gralow reported no conflicts of interest.

REFERENCES

1. Turner NC, Mayer E, Park YH, et al: Camizestrant + CDK4/6 inhibitor for the treatment of emergent ESR1 mutations during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer: Phase 3, double-blind ctDNA-guided SERENA-6 trial. 2025 ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2025.

2. Bidard FC, Mayer EL, Park YH, et al: First-line camizestrant for emerging ESR1-mutated advanced breast cancer. N Engl J Med. June 1, 2025 (early release online).

EXPERT POINT OF VIEW

Invited discussant of the SERENA-6 trial, Angela DeMichele, MD, MSCE, FASCO, the Mariann T. and Robert J. MacDonald Professor in Breast Cancer, and Director, Clinical/Translational Research, Solid Tumor Oncology at the Perelman School of Medicine, University of Pennsylvania, highlighted that the trial successfully demonstrated its primary endpoint: ctDNA-guided switching from aromatase inhibitors to camizestrant upon emergence of ESR1 mutations significantly extended progression-free survival.

Angela DeMichele, MD, MSCE, FASCO

According to Dr. DeMichele, this innovative approach could establish a regulatory path and potentially validate ctDNA testing for this specific mutation-drug combination. However, she cautioned, the clinical utility of serial ctDNA testing as a routine first-line management strategy remains uncertain. “Additional time and outcomes are needed to determine the true clinical utility of this strategy,” she said.

“Critical information is still needed regarding secondary outcomes, particularly progression-free survival and overall survival, as well as associated costs and health-care burden. Early interim analysis showed promising trends regarding progression-free survival 2 but did not reach statistical significance, partly due to imbalanced subsequent therapies,” Dr. DeMichele pointed out.

Cautious Optimism

“The absence of crossover to camizestrant in the control arm also limits the ability to verify the underlying biological hypothesis—that early intervention before anatomic disease progression is truly advantageous.” During the panel discussion, Dr. DeMichele added these comments: “There is a worry that starting early will cause us to use up our [most effective] drugs earlier without a patient living longer. So, we have to approach this discussion in a very balanced way with our patients until we truly know this strategy helps our patients live longer.”

Furthermore, Dr. DeMichele underscored practical considerations, including the burden of frequent ctDNA testing, psychological stress related to awaiting test results, and potential impacts on health-care systems. She also questioned the broader applicability of this strategy to other mutations, other ctDNA platforms, other selective estrogen receptor degraders, and other therapeutic contexts without further prospective validation. Of note, she questioned whether this strategy would lead to longer overall survival and demonstrate clinical utility.

“While SERENA-6 provides compelling evidence of improved first-line progression-free survival, ultimate endorsement of this strategy will depend on demonstrating clinical utility through sustained benefits across subsequent treatments, improved overall survival, manageable health-care implementation, and comprehensive cost-effectiveness analyses,” she noted.

Dr. DeMichele shared these closing comments: “I cannot yet recommend the SERENA-6 strategy, as camizestrant is not yet approved and the strategy is not validated for other mutations or drugs. If camizestrant is approved based on progression-free survival and quality of life, the conversation will be about goals and trade-offs,” she added. “And if, as we all hope, an overall survival benefit is ultimately seen with this strategy, we will need to make sure this strategy is manageable for patients and the health-care system.” 

DISCLOSURE: Dr. DeMichele reported financial relationships with Pfizer, Genentech, Inivata/NeoGenomics, and Novartis.