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A switch to camizestrant upon emergence of an ESR1 mutation improved PFS2 in ER-positive, HER2-negative advanced breast cancer.
Switching to camizestrant in combination with a CDK4/6 inhibitor upon emergent ESR1 mutation detection prior to disease progression extended time to second progression (PFS2) compared with continued treatment with an aromatase inhibitor (AI) plus a CDK4/6 inhibitor in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to final PFS2 data from the phase 3 SERENA-6 trial (NCT04964934) presented at the
Findings showed that patients treated with camizestrant plus a CDK4/6 inhibitor (n = 157) experienced a median PFS2 of 25.7 months (95% CI, 20.4-30.3) compared with 19.1 months (95% CI, 16.8-21.0) for those who continued with an AI plus a CDK4/6 inhibitor (n = 158; HR, 0.63; 95% CI, 0.46-0.86; P = .00373). The 30-month PFS2 rates were 41.5% and 29.7%, respectively. Notably, a supplementary analysis using RECIST 1.1 criteria demonstrated a similar PFS2 benefit with switching to camizestrant (HR, 0.64; 95% CI, 0.46-0.90; nominal P = .0094).
“[With] PFS2, the difference between the 2 arms [was] 6.6 months, suggesting—with all the caveats related to PFS2—that PFS benefit is sustained beyond first progression,” presenting study author Francois-Clement Bidard, MD, PhD, said during the presentation. “Time to second subsequent treatment is also very aligned with [data] we got for PFS2.”
Bidard is a professor of medicine in the Department of Medical Oncology at Institut Curie & UVSQ/Université Paris-Saclay in France; co-coordinator of breast cancer research at Institut Curie; vice-chair of the French Breast Cancer research group UCBG; director of the Clinical Investigation Center at the Institut Curie; and medical director for Breast Oncology at the Women’s Cancer Institute.
In April 2026, the FDA’s Oncologic Drugs Advisory Committee reviewed data from SERENA-6 supporting a new drug application (NDA) seeking the approval of camizestrant in combination with a CDK4/6 inhibitor—either palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)—for the treatment of adult patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer upon emergence of ESR1 mutation during first-line endocrine-based therapy, based on the results of an FDA-approved test.2 The committee
Notably, the FDA attested that it was uncertain if the PFS2 data were clinically meaningful, since the switch to camizestrant in the experimental arm was initiated at the time of the detection of an ESR1 mutation. The regulatory agency communicated to AstraZeneca that PFS2 would not be acceptable as an efficacy end point to support potential approval.
The FDA’s decision on the application is still pending after the agency
At ASCO 2026, Bidard also presented updated PFS data, showing that at a median follow-up of 23.5 months, camizestrant plus a CDK4/6 inhibitor yielded a median PFS of 16.8 months (95% CI, 14.7-19.4) compared with 9.2 months (95% CI, 7.2-9.7) for an AI plus a CDK4/6 inhibitor (HR, 0.45; 95% CI, 0.34-0.59; nominal P < .00001).1
Notably, the PFS improvement was consistent in patients who harbored PIK3CA co-mutations (HR, 0.41, 0.26-0.64) and those harboring TP53 co-mutations (HR, 0.52; 95% CI, 0.31-0.88). PFS benefits were also similar among patients with a single ESR1 mutation (HR, 0.46, 95% CI, 0.34-0.62) and patients with multiple ESR1 mutations (HR, 0.48; 95% CI, 0.25-0.88).
SIDEBAR: Key Takeaways From SERENA-6 Final Analysis
SERENA-6 was a randomized, double-blind, placebo-controlled study that enrolled adult patients with ER-positive, HER2-negative advanced breast cancer who had received an AI plus a CDK4/6 inhibitor as their initial endocrine-based treatment for advanced disease with no evidence of progression. No prior chemotherapy for advanced breast cancer was allowed. To be eligible for random assignment, patients needed to have an ESR1 mutation detected via circulating tumor DNA (ctDNA) in the absence of disease progression.
Patients were randomly assigned 1:1 to switch to camizestrant at 75 mg once daily and continue their same CDK4/6 inhibitor with an AI placebo; or to continue their AI plus a CDK4/6 inhibitor in addition to a camizestrant placebo.
Tumor assessments per RECIST 1.1 criteria were performed every 8 weeks for 18 months, then every 12 weeks; to measure PFS2, scans were mandated every 8 to 12 weeks.
Investigator-assessed PFS served as the primary end point, with PFS2 and patient-reported outcomes (PROs) as key secondary end points.
Data on first subsequent therapy showed that 55.2% of evaluable patients in the camizestrant arm (n = 87) received endocrine-based therapy as their next line of treatment compared with 66.7% of patients in the control arm (n = 117). Cytotoxic therapy was given to 43.7% and 30.8% of patients, respectively. Other therapies were given at respective rates of 1.1% and 2.6%.
The PFS and PFS2 outcomes were consistent for the camizestrant regimen across prespecified subgroups.
Chemotherapy/antibody-drug conjugate (ADC)–free survival was also substantially extended, with the camizestrant regimen yielding a median of chemotherapy/ADC-free survival of 22.6 months (95% CI, 19.3-30.9) vs 18.7 months (95% CI, 15.8-22.1) with an AI plus a CDK4/6 inhibitor (HR, 0.64; 95% CI, 0.47-0.87; nominal P = .00375).
Overall survival (OS) data remained immature at the final analysis, but trends favoring camizestrant were observed at the first data cutoff (HR, 0.91; 95% CI, 0.48-1.73), the second cutoff (HR, 0.92; 95% CI, 0.57-1.48), and the final cutoff (HR, 0.87; 95% CI, 0.57-1.30).
Total ctDNA clearance was markedly higher with camizestrant plus a CDK4/6 inhibitor (n = 98), at 51.0% vs 1.9% for an AI plus a CDK4/6 inhibitor (n = 108). Pooled across arms, ctDNA clearance was associated with an OS benefit (HR, 0.39; 95% CI, 0.19-0.73), consistent with findings in other tumor types.
