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Purpose

The U.S. Food and Drug Administration approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2–), estrogen receptor 1 (ESR1)–mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET).

Patients and Methods

Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2– advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239).

Results

In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228, hazard ratio [HR] 0.55, 95% CI 0.39-0.77, P value=0.0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR 0.90, 95% CI 0.63-1.30) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat (ITT) population (n = 478; HR 0.70, 95% CI 0.55-0.88]; P value=0.0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia.

Conclusion

The approval of elacestrant in ER+, HER2– advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

Read an interview about the FDA approval summary special article here.