On January 27, 2023, elacestrant was approved by the U.S. Food and Drug Administration (FDA) 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.¹ The FDA also approved the Guardant360 CDx assay as a companion diagnostic to identify patients for treatment with elacestrant.

Supporting Efficacy Data

Approval was supported by findings in the open-label, phase III EMERALD trial (ClinicalTrials.gov identifier NCT03778931). In the trial, 477 postmenopausal women and men with disease progression on one or two prior lines of endocrine therapy, including a CDK4/6 inhibitor, were randomly assigned to receive oral elacestrant at 345 mg once daily (n = 239) or investigator’s choice of standard-of-care endocrine therapy (n = 239) with fulvestrant (n = 166) or an aromatase inhibitor (n = 73). Patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting. The population included 228 patients with ESR1 mutations (a stratification factor): 115 in the elacestrant group and 113 in the standard-of-care group.

Progression-free survival on blinded imaging review committee assessment was significantly improved with elacestrant in both the intention-to-treat population and the ESR1-mutation subgroup. In the ESR1-mutation subgroup, median progression-free survival was 3.8 months (95% confidence interval [CI] = 2.2–7.3 months) with elacestrant vs 1.9 months (95% CI = 1.9–2.1 months) with the standard of care (hazard ratio [HR] = 0.55, 95% CI = 0.39–0.77, P = .0005). The hazard ratio among patients without ESR1 mutation was 0.86 (95% CI = 0.63–1.19), indicating the improvement in the intention-to-treat population was primarily attributable to the outcome in the ESR1-mutated population.

How It Works

The recommended dose of elacestrant is 345 mg once daily until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification, including dose reduction, for adverse reactions and moderate hepatic impairment. Concomitant use with strong or moderate CYP3A4 inducers or inhibitors (eg, erythromycin, diltiazem, rifampicin) and use in severe hepatic impairment should be avoided.

Safety Profile

Among all 477 patients in the EMERALD trial, the most common adverse events of any grade in the elacestrant group were musculoskeletal pain (41% vs 39% in the standard-of-care group), nausea (35% vs 19%), and fatigue (26% vs 27%). The most common grade 3 or 4 adverse events included musculoskeletal pain (7% vs 1%) and nausea (2.9% vs 0.9%). The most common laboratory abnormalities of any grade were increased cholesterol (30% vs 17%), increased aspartate aminotransferase (29% vs 34%), and increased triglycerides (27% vs 15%); the most common grade 3 or 4 abnormalities were increased triglycerides (2%vs 1%).

Serious adverse events occurred in 12% of the elacestrant group, most commonly musculoskeletal pain (1.7%) and nausea (1.3%). Treatment was discontinued because of adverse events in 6%, most commonly because of musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse advents occurred in 1.7% of patients, consisting of cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).

Elacestrant has warnings/precautions for dyslipidemia and embryofetal toxicity. Patients should be advised not to breastfeed while receiving elacestrant. 

REFERENCE

1. Orserdu (elacestrant) tablets, for oral use, prescribing information, Stemline Therapeutics, Inc, a Menarini Group company. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639s000lbl.pdf. Accessed February 10, 2023.