The updated median PFS was 16.6 months (95% CI, 14.7-19.4) with camizestrant (n = 157) vs 9.2 months (95% CI, 7.2-9.7) with the control (n = 158; HR, 0.46; 95% CI, 0.34-0.62; P < .00001). The time to first subsequent therapy also favored the camizestrant arm (HR, 0.47; 95% CI, 0.35-0.62).
“PFS results at data cutoff 2 were consistent with those at data cutoff 1. Switch to camizestrant with continuation of CDK4/6 inhibition at ESR1 mutation emergence and ahead of disease progression showed a clinically meaningful improvement of more than 7 months compared with continuing aromatase inhibition and CDK4/6 inhibition in patients with hormone receptor–positive, HER2-negative advanced breast cancer,” François-Clément Bidard, MD, lead study author, professor of medicine and head of the translational research group at the Institut Curie in Paris, France, said during the presentation.
What magnitude of benefit did camizestrant show in the first interim analysis?
Camizestrant is a next-generation oral selective estrogen receptor (ER) degrader and complete ER antagonist designed to block and degrade mutant and wild-type ER. Findings from the previously reported interim analysis demonstrated that the agent plus continued CDK4/6 inhibition led to a statistically significant improvement in PFS vs continued aromatase and CDK4/6 inhibition in the first-line setting ahead of disease progression in patients with ESR1-mutant hormone receptor–positive, HER2-negative advanced breast cancer.2 At a median follow-up of 12.6 months, the median PFS was 16.0 months (95% CI, 12.7-18.2) with camizestrant vs 9.2 months (95% CI, 7.2-9.5) with the control (HR, 0.44; 95% CI, 0.31-0.60; P < .0001).
Bidard noted that the investigational regimen also delayed time to deterioration and reduced the risk of deterioration in global health status/quality of life, and in patient-reported cancer symptoms and functioning. Few discontinuations due to adverse effects (AEs) also occurred, indicating favorable tolerability.
The study enrolled adult patients with ER-positive, HER2-negative advanced breast cancer who had received at least 6 months of an aromatase inhibitor in combination with palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio) as initial endocrine-based therapy for advanced disease.1 Also required was the presence of an ESR1 mutation in circulating tumor DNA and no evidence of disease progression.
A total of 315 patients were randomly assigned 1:1 to 75 mg of once daily camizestrant plus continued CDK4/6 inhibition and a placebo for the aromatase inhibition (n = 157) or continued aromatase inhibition plus CDK4/6 inhibition and a placebo for camizestrant (n = 158). Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death.
Tumor assessments were performed every 8 weeks for 18 months and then every 12 weeks until disease progression and circulating tumor DNA (ctDNA) was tested on day 1 of alternating cycles and at the end of treatment.
What other findings were reported in addition to updated PFS?
Bidard also shared that the median time to second progression (PFS2) was 25.7 months (95% CI, 20.3-28.9) with camizestrant vs 19.4 months (95% CI, 17.8-21.4) with control (HR, 0.56; 95% CI, 0.39-0.80; P = .00153). The time to second subsequent therapy also favored the camizestrant arm (HR, 0.57; 95% CI, 0.40-0.81). “The magnitude of benefit in time to first and second subsequent therapy was consistent with PFS and PFS2, respectively,” Bidard said.
Moreover, the median chemotherapy-free and antibody-drug conjugate–free survival was 22.7 months (95% CI, 20.3-31.5) in the camizestrant arm vs 18.7 months (95% CI, 16.7-24.7) in the control arm (HR, 0.69; 95% CI, 0.49-0.97).
Overall survival remained immature at just 22%, Bidard noted.
Did the use of camizestrant reduce mutant ESR1 in ctDNA?
In an exploratory ctDNA analysis, investigators found that the frequency of ESR1-mutant alleles was significantly reduced in the camizestrant arm vs the control arm (Wilcoxon nominal P < .00001). In the camizestrant arm (n = 126), the median change in small variant allele fraction (sVAF) from baseline to day 1, cycle 3, a period of 8 weeks, was –100% (IQR, –100% to –100%). In the control arm (n = 123), the change in sVAF from baseline to day 1, cycle 3 was +66.7% (IQR, –67.9% to +465.0%).
Bidard noted that ESR1-mutant allele frequency increased more than 500% from baseline in 24.4% of patients in the control arm vs 0.8% of those in the camizestrant arm.
Was the tolerability of the camizestrant regimen maintained with longer follow-up?
The exposure time-adjusted incidence rates were similar between treatment arms for hematologic AEs. AEs that occurred in at least 10% of patients in the camizestrant arm included neutropenia (grade 1/2, 32%; grade ≥3, 26%), decreased neutrophil count (28%; 23%), anemia (21%; 5%), decreased white blood cell count (11%; 8%), photopsia (21%; 1%), arthralgia (19%; 0%), fatigue (16%; 0%), back pain (12%; 1%), dry eye (12%; 0%), nausea (10%;, 0%), diarrhea (10%; 0%), and headache (9%;, 1%).
AEs that occurred in the control arm included neutropenia (grade 1/2, 25%; grade ≥3, 17%), decreased neutrophil count (21%; 17%), anemia (21%; 8%), decreased white blood cell count (7%; 1%), photopsia (8%; 0%), arthralgia (19%; 1%), fatigue (16%; 1%), back pain (11%; 0%), dry eye (7%; 0%), nausea (15%; 1%), diarrhea (13%; 1%), and headache (14%; 0%).
Notably, there were no additional AEs that led to discontinuation of camizestrant at the second data cutoff (n = 2; 1%), although 1 additional patient discontinued their aromatase inhibitor because of an AE (n = 4; 3%).
“Camizestrant and CDK4/6 inhibition was well tolerated, consistent with previous findings, and no new safety signals were observed,” Bidard stated.
“Switching first-line endocrine therapy to camizestrant, with continued CDK4/6 inhibition, significantly extends treatment benefit by delaying disease progression, prolonging chemotherapy/ADC-free survival and time to deterioration in quality of life, as well as profoundly and rapidly reducing ESR1-mutant allele frequency,” Bidard concluded.
Disclosures: Bidard made no disclosures.
References
- Bidard FC, Mayer EL, Park YH, et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA dynamics from SERENA-6, a phase 3 trial of camizestrant + CDK4/6 inhibitor for emergent ESR1m during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF7-03.
- Bidard FC, Mayer EL, Park YH, et al. First-line camizestrant for emerging ESR1-mutated advanced breast cancer. N Engl J Med. 2025;393(6):569-580. doi:10.1056/NEJMoa2502929
