On January 27, the U.S. Food and Drug Administration (FDA) approved elacestrant (Orserdu) for postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. The FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with elacestrant.
Efficacy was evaluated in EMERALD (ClinicalTrials.gov identifier NCT03778931), a randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer; in this group, 228 patients had ESR1 mutations. Patients were required to have had disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting.
Patients were randomly assigned 1:1 to receive elacestrant at 345 mg orally once daily (n = 239) or investigator’s choice of endocrine therapy (n = 239), which included fulvestrant (n = 166) or an aromatase inhibitor (n = 73). Random assignment was stratified by ESR1 mutation status (detected vs not detected), prior treatment with fulvestrant (yes vs no), and visceral metastasis (yes vs no). ESR1 mutational status was determined by blood circulating tumor DNA using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain.
The major efficacy outcome measure was progression-free survival, assessed by a blinded imaging review committee. A statistically significant difference in progression-free survival was observed in the intention-to-treat (ITT) population and in the subgroup of patients with ESR1 mutations.
In the 228 (48%) patients with ESR1 mutations, median progression-free survival was 3.8 months (95% CI confidence interval [CI] = 2.2–7.3) in the elacestrant arm and 1.9 months (95% CI = 1.9–2.1) in the fulvestrant or aromatase inhibitor arm (hazard ratio [HR] = 0.55, 95% CI = 0.39–0.77, two-sided P-value = .0005).
An exploratory analysis of progression-free survival in the 250 (52%) patients without ESR1 mutations showed a hazard ratio of 0.86 (95% CI = 0.63–1.19), indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1-mutated population.
The most common adverse events (≥ 10%), including laboratory abnormalities, were musculoskeletal pain, nausea, increased cholesterol, increased aspartate aminotransferase, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased alanine transaminase, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.
The recommended elacestrant dose is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review and Fast Track designation.