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The FDA the selective estrogen receptor (ER) degrader elacestrant (Orserdu) for the treatment of postmenopausal women or adult men with 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 test to identify patients for treatment with elacestrant. As many as 40% of ER-positive, HER2-negative breast cancers are associated with ESR1 mutations.

"Advanced or metastatic ER-positive, HER2-negative breast cancer pretreated with endocrine-based therapy remains an area of unmet medical need," said Aditya Bardia, MD, MPH, of Mass General Cancer Center in Boston, from Stemline Therapeutics/Menarini Group, the maker of elacestrant. "The last endocrine therapy approved was about 20 years ago, and effective endocrine options for this patient population are needed."

"ESR1 mutations are a known driver of resistance to standard endocrine therapy, and so far, have been difficult to treat," she added. "The approval of elacestrant is welcomed, as it offers a novel option for patients with ER-positive/HER2-negative metastatic breast cancer."

Support for the approval came primarily from the phase III, randomized, multicenter EMERALD trial, which included 478 patients with ER-positive, HER2-negative advanced or metastatic breast cancer, 228 of whom had ESR1 mutations. Patients had to have experienced disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor.

Patients were randomized 1:1 to receive elacestrant 345 mg orally once daily or investigator's choice of endocrine therapy, which included fulvestrant or an aromatase inhibitor.

An intention-to-treat analysis showed that elacestrant significantly improved progression-free survival (PFS) versus standard-of-care endocrine therapy.

The benefit in the overall population was driven by improvement in the subgroup with ESR1 mutations, wherein the risk of disease progression or death decreased by 45% (median PFS 3.8 vs 1.9 months; HR 0.55, 95% CI 0.39-0.77, P=0.0005). Among patients treated for at least 12 months with a CDK4/6 inhibitor, the median PFS was 8.6 months with elacestrant versus 1.9 months for the control group. An exploratory analysis showed a nonsignificant 14% improvement in PFS among patients with ESR1 mutations.

The most common adverse events (affecting ≥10% of patients) with elacestrant included musculoskeletal pain, nausea, increased cholesterol, increased liver enzymes, hyponatremia, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flushes, and dyspepsia.

The Menarini Group obtained worldwide licensing rights for elacestrant in June 2020 from Radius Health, which sponsored the EMERALD trial.

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