On September 25, 2025, the Food and Drug Administration approved imlunestrant, an oestrogen receptor antagonist, for adults with oestrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative, oestrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with imlunestrant.

Full prescribing information for imlunestrant will be posted on Drugs@FDA. 

Efficacy and Safety

Efficacy was evaluated in EMBER-3 (NCT04975308), a randomised, open-label, active-controlled, multicenter trial that enrolled 874 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor either alone or in combination with a CDK4/6 inhibitor. Patients were excluded if they were eligible to receive a PARP inhibitor.

Patients were randomised 1:1:1 to imlunestrant, an investigator’s choice of endocrine therapy (fulvestrant or exemestane), or an additional investigational combination regimen. Randomisation was stratified by previous treatment with a CDK4/6 inhibitor, presence of visceral metastasis, and geographic region. ESR1 mutational status was determined by blood circulating tumour deoxyribonucleic acid (ctDNA) analysis using the Guardant360 CDx assay and was limited to specific ESR1 mutations in the ligand-binding domain.

The major efficacy outcome was investigator-assessed progression-free survival (PFS) (RECIST v1.1) comparing imlunestrant to the investigator’s choice of endocrine therapy in patients with ESR1 mutated tumours. Other efficacy outcome measures included overall survival (OS) and objective response rate (ORR). In the ESR1 mutated population (n=256), a statistically significant difference in investigator-assessed PFS for imlunestrant compared to investigator’s choice of endocrine therapy was observed. The median PFS was 5.5 months (95% CI: 3.9, 7.4) in the imlunestrant arm and 3.8 months (95% CI: 3.7, 5.5) in the investigator's choice arm (hazard ratio 0.62 [95% CI: 0.46, 0.82]; p-value 0.0008). The ORR was 14.3% in the imlunestrant arm and 7.7% in the investigator's choice arm. At the time of the PFS analysis, OS data was immature with 31% of deaths in the ESR1 mutated population.

The most common adverse events (≥10%), including laboratory abnormalities were decreased haemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhoea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.

Recommended Dosage

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

Source: FDA