Targeting ESR1 Mutations: FDA Approves Innovative Therapy Imlunestrant

On September 25, 2025, the U.S. Food and Drug Administration granted approval to imlunestrant for adults with estrogen receptor (ER)–positive, HER2–negative, ESR1-mutated advanced or metastatic breast cancer who have progressed after at least one line of endocrine therapy.

To identify patients eligible for treatment, the FDA also approved the Guardant360 CDx assay as a companion diagnostic to detect ESR1 mutations.

The drug’s efficacy was demonstrated in the EMBER-3 trial, a randomized, open-label study of 874 patients previously treated with aromatase inhibitors, with or without CDK4/6 inhibitors. In patients whose tumors carried ESR1 mutations, imlunestrant showed a median progression-free survival (PFS) of 5.5 months, compared to 3.8 months in the standard endocrine therapy arm (hazard ratio 0.62; p = 0.0008). The objective response rate (ORR) was 14.3% vs. 7.7%. Overall survival data are not yet mature.

Common side effects (occurring in ≥10% of patients) included reduced hemoglobin, musculoskeletal pain, fatigue, gastrointestinal symptoms (such as diarrhea and nausea), elevated liver enzymes, increased triglycerides, and others.

The recommended dosage is 400 mg once daily, taken on an empty stomach until disease progression or unacceptable toxicity.

This approval was supported by expedited regulatory pathways: imlunestrant received Fast Track designation, and the FDA leveraged the voluntary Assessment Aid submission to facilitate review.

Learn more: FdaFDA approves imlunestrant