Camizestrant Enhances PFS vs AI Inhibitor in ER+/HER2– Breast Cancer

In the camizestrant arm and aromatose inhibitor arms, the respective 12- and 24-month PFS rates were 60.7% vs 33.4% and 29.7% vs 5.4%

Camizestrant added to continued therapy with CDK4/6 inhibition vs continued therapy with an aromatase inhibitor (AI) plus CDK4/6 inhibitor enhanced progression-free survival (PFS) outcomes as a treatment for patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer who had emergent ESR1 mutations during endocrine therapy and whose disease progressed, according to phase 3 SERENA-6 trial (NCT04964934) findings presented in a press briefing at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

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/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 33.4% and 5.4% in the continued AI/CDK4/6 inhibition arm.

“SERENA-6 is the first global registrational phase 3 study to demonstrate the clinical utility of circulating tumor DNA [ctDNA] monitoring to detect and treat emerging resistance ahead of disease progression,” Nicholas C. Turner, MD, PhD, lead study author and director of The Royal Marsden and Institute of Cancer and National Institute for Health and Care Research Biomedical Research Centre in London, United Kingdom, said in the press briefing.

Echoing the significance of these findings, Eleonora Teplinsky, MD, stated, “When patients progress on scans, we’re already behind. We’re switching therapy, and we’ve already lost control [of the disease]. What this study does is [adopt] an early switch approach before we see disease progression on imaging, allowing us to stay ahead of the curve.” Teplinsky is head of Breast and Gynecologic Medical Oncology at Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, and a clinical assistant professor of medicine at The Icahn School of Medicine at Mount Sinai in New York, New York.

The Origin of the SERENA-6 Trial

Turner started the presentation by acknowledging the present unmet need for patients with ESR1-mutant, advanced hormone receptor–positive breast cancer. Although rare at diagnosis, comprising less than 5% of advanced cases, ESR1 mutations will develop in approximately 40% of cases, resulting in disease progression on frontline therapy with an AI and CDK4/6 inhibitor.

However, ESR1 mutations can be isolated in ctDNA approximately 6 months before progression.

Camizestrant is a next-generation oral selective ER degrader and complete ER antagonist that’s designed to inhibit and degrade the mutant and wild-type forms of the ER. Previously, the FDA granted fast track designation to the agent for the population enrolled in SERENA-6.2 By coupling the use of ctDNA with early integration of camizestrant ahead of disease progression, investigators theorized they could prolong the clinical benefit of frontline treatment.1

The randomized, double-blind, placebo-controlled SERENA-6 trial enrolled female and male patients with ER-positive, HER2-negative advanced breast cancer who had received at least 6 months of an AI in combination with a CDK4/6 inhibitor as initial endocrine-based therapy for advanced disease. Patients also needed to have a detectable ESR1 mutation in their ctDNA without evidence of disease progression.

A total of 3,325 patients who were receiving frontline therapy with an AI and CDK4/6 inhibitor for at least 6 months were screened. ESR1 mutation testing (n = 3,256) was evaluated in ctDNA with the Guardant360 CDx assay every 2 to 3 months at the time of routine staging scans. A total of 548 patients had detectable ESR1 mutations, 51% of whom were positive on the first test, 38% of whom were positive after 2 to 5 tests, and 11% of whom were positive after the fifth test. A total of 233 patients discontinued the study due to screening failure (n = 200) or consent withdrawal, lost follow-up, or other reasons (n = 33).

A total of 315 patients were randomly assigned 1:1 to 75 mg of camizestrant daily plus continued CDK4/6 inhibition and placebo for the AI or continued AI with anastrozole or letrozole plus CDK4/6 inhibition and placebo for camizestrant. Treatment was continued until disease progression, unacceptable toxicity, and patient withdrawal or death.

The primary end point was investigator-assessed PFS by RECIST 1.1 criteria. Secondary end points included time to second disease progression or death, overall survival, safety, and patient-reported outcomes.

Patients were stratified by visceral disease (yes vs no), detection of ESR1 mutation (mutation detected at first test vs a subsequent test), time from initiation of CDK4/6 inhibition plus an AI to randomization (<18 months vs ≥18 months), and choice of CDK4/6 inhibitor (palbociclib [Ibrance] vs ribociclib [Kisqali] vs abemaciclib [Verzenio]).

Secondary End Points and Trial Significance

Time to deterioration (TTD) in global health status/quality of life (QOL) was also presented. The median TTD according to the European Organization for Research and Treatment of Cancer 30-item QOL questionnaire was 23.0 months (95% CI, 13.8-not calculable) with camizestrant (n = 107) vs 6.4 months (95% CI, 2.8-14.0) with continued AI/CDK4/6 inhibition (n = 95; adjusted HR, 0.53; 95% CI, 0.33-0.82; nominal P < .001).

Turner noted that the camizestrant regimen also had a low rate of treatment discontinuations resulting from adverse effects.

“[These data highlight the] potential for a new treatment strategy in oncology to treat developing resistance before it causes progression,” Turner said in conclusion.

Elaborating on the novelty of the study design, Teplinsky explained, “Allowing patients to remain on first-line endocrine therapy for hormone receptor–positive, HER2-negative advanced breast cancer is critical, because we know that outcomes worsen with subsequent lines of therapy. Allowing that longer time on first-line endocrine therapy is significant, and it also improves QOL, as we’ve seen, and that’s a huge part of living with metastatic breast cancer. [The study] uses a technology, [which] is a liquid biopsy, that doesn’t pose risks of surgical biopsies, and it’s something that can be done and is available in our clinic now. Although camizestrant is not yet FDA approved, this likely will pave the way for a new treatment strategy in first-line hormone receptor–positive, HER2-negative metastatic breast cancer in patients with ESR1 mutations.”

Julie Gralow, MD, chief medical officer and executive vice president at ASCO, added, “We are using these liquid biopsies [to detect] ctDNA. We have whole sessions at this meeting, looking at using them in colon cancer, but using them to detect emerging resistance before we see evidence of tumor progression on scans is what’s novel about this study.”

Disclosures: No disclosures were presented for Turner.

References

1. 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
2. Camizestrant significantly improved progression-free survival vs faslodex in SERENA-2 phase II trial in advanced ER-positive breast cancer. News release. AstraZeneca. October 26, 2022. Accessed May 31, 2025. https://www.astrazeneca.com/media-centre/press-releases/2022/camizestrant-significantly-improved-progression-free-survival.html