The Phase 3 EMBER-3 trial (NCT04975308) presented at the 2025 ESMO Breast Congress found that combining the oral selective estrogen receptor degrader (SERD) LY3484356 with abemaciclib (Verzenio) significantly prolonged progression-free survival (PFS) in patients with ER-positive, HER2-negative advanced breast cancer, compared with LY3484356 alone. This benefit held across clinical and genomic subgroups, regardless of biomarker status or prior CDK4/6 inhibitor use.
Key PFS Improvements in Visceral and Bone-Only Metastases
Visceral Metastases
Doublet therapy (LY3484356 + abemaciclib; n = 119): median PFS 8.1 months (95% CI, 6.2–11.2)
LY3484356 alone (n = 120): median PFS 3.7 months (95% CI, 1.9–4.9)
Hazard ratio (HR): 0.55 (95% CI, 0.40–0.75)
Bone-Only Metastases
Doublet therapy (n = 51): median PFS 16.4 months (95% CI, 9.3–NR)
LY3484356 alone (n = 46): median PFS 10.4 months (95% CI, 5.6–13.9)
HR: 0.55 (95% CI, 0.30–1.02)
In patients previously treated with a CDK4/6 inhibitor, doublet therapy extended median PFS to 7.5 months (visceral) and 16.4 months (bone-only), versus 1.9 months and 9.5 months with monotherapy, respectively.
Benefits Seen Across Genomic Subgroups
ESR1 Mutations
Doublet (n = 67): median PFS 11.1 months (95% CI, 7.4–13.7)
Monotherapy (n = 92): median PFS 5.5 months (95% CI, 3.8–7.2)
HR: 0.53 (95% CI, 0.35–0.80)
PI3K Pathway Mutations
Doublet (n = 88): median PFS 7.6 months (95% CI, 5.6–11.0)
Monotherapy (n = 84): median PFS 3.8 months (95% CI, 3.1–5.5)
HR: 0.61 (95% CI, 0.42–0.87)
Both ESR1 and PI3K Mutations
Doublet (n = 40): median PFS 11.1 months (95% CI, 7.5–16.4)
Monotherapy (n = 47): median PFS 5.5 months (95% CI, 3.5–6.3)
HR: 0.48 (95% CI, 0.28–0.83)
Similar PFS gains appeared in patients who had prior CDK4/6 inhibitor treatment.
Study Design and Endpoints
EMBER-3 enrolled patients with ER-positive, HER2-negative advanced disease who progressed on or shortly after aromatase inhibitor therapy, with or without earlier CDK4/6 inhibitors. Participants were randomized 1:1:1 to receive:
LY3484356 400 mg daily
LY3484356 400 mg daily + abemaciclib 150 mg twice daily
Standard-of-care endocrine therapy (fulvestrant or exemestane)
Primary endpoints included investigator-assessed PFS comparisons of LY3484356 versus SOC in all patients and in those with ESR1 mutations, and PFS of the combination versus LY3484356 alone.
Expert Commentary
“EMBER-3 is the first Phase 3 trial to show the benefit of an oral SERD plus CDK4/6 inhibitor after progression on prior CDK4/6 therapy,” said Cristina Saura, MD, PhD, of Vall d’Hebron University Hospital, Barcelona. “It provides an effective, tolerable, all-oral targeted option for these patients.”
Follow-up for overall survival is ongoing.
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