FDA Approves Imlunestrant for Patients With ER-Positive, HER2-Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer

On September 25, 2025, the US Food and Drug Administration (FDA) approved imlunestrant for patients with estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer harboring estrogen receptor-1 (ESR1) mutations who progressed following at least 1 line of endocrine therapy. This approval was based on results from the EMBER-3 trial. 

In this multicenter, open-label trial, 874 previously treated patients (with an aromatase inhibitor either alone or in combination with a CDK 4/6 inhibitor) were randomized on a 1-to-1-to-1 basis to receive imlunestrant, investigator’s choice endocrine therapy (either fulvestrant or exemestane), or an additional investigational combination regimen. Patients were stratified based on prior treatment with a CDK 4/6 inhibitor, presence of visceral metastases, and geographic region. Patients eligible to undergo PARP inhibition were excluded from trial enrollment. ESR1 mutations (n = 256) were detected using the Guardant360 CDx assay using blood circulating tumor DNA (ctDNA) analysis targeting only ESR1 mutations in the ligand-bonding domain. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS), objective response rate (ORR), and safety. 

At analysis, median PFS was 5.5 months in the imlunestrant arm and 3.8 months in the investigator’s choice arm (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.46 to 0.82; P = .0008). The ORR was 14.3% in the imlunestrant arm and 7.7% in the investigator’s choice arm. OS data was immature, with 79 deaths in the ESR1 mutated population. The most common adverse events occurring in ≥ 10% of patients including laboratory abnormalities included hemoglobin decrease, musculoskeletal pain, calcium decrease, neutrophil decrease, AST increase, fatigue, diarrhea, ALT increase, triglyceride increase, nausea, platelet decrease, constipation, cholesterol increase, and abdominal pain.

The recommended dose of imlunestrant is 400 mg once daily on an empty stomach at least 2 hours before food or 1 hour after food, until disease progression or unacceptable toxicity. 

The FDA has additionally approved the Guardant360 CDx assay as a companion diagnostic tool to identify ESR1 mutations. 

Source: 

FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Accessed on September 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast