Elacestrant Approved for ER-Positive, HER2-Negative, ESR1-Mutated Breast Cancer

Invasive breast cancer tumor.

The FDA has approved elacestrant (Orserdu™, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative, estrogen receptor 1 (ESR1)–mutated advanced or metastatic breast cancer with disease progression subsequent to at least one line of endocrine therapy. Additionally, the FDA approved the Guardant360 CDx assay, a companion diagnostic test, to identify breast cancer patients eligible for treatment with elacestrant.

“Current treatment guidelines recommend sequential endocrine therapy in the absence of visceral crisis or until all endocrine therapy options have been exhausted,” wrote Francois-Clement Bidard, MD, Professor of Medicine and Co-Coordinator of Breast Cancer Research at the Institut Curie in Paris, France, and colleagues, in their published results of the EMERALD trial (NCT03778931), on which approval was based. “However, the clinical activity of endocrine monotherapy in patients who have received prior cyclin-dependent kinase 4 and 6 (CDK4/6) or mammalian target of rapamycin inhibition is limited, with a median progression-free survival of approximately two months, highlighting a major unmet clinical need in the field.”

Safety and efficacy were evaluated in the phase 3, open-label, active-controlled, international, multicenter trial in which 478 men and postmenopausal women with ER-positive, HER2-negative advanced or metastatic breast cancer were randomized 1:1 to receive either 345 mg of elacestrant or investigator-chosen endocrine therapy, including fulvestrant or an aromatase inhibitor. Stratification for randomization was based on ESR1 mutation status, of which 228 of the total patients had a detected ESR1 mutation, as well as on prior treatment with fulvestrant and visceral metastasis. All patients had disease progression following one or two prior lines of therapy, including one line containing a CDK4/6 inhibitor.

The primary end point measured was progression-free survival as assessed by a blinded imaging review committee (BICR). Of the patients with a confirmed ESR1 mutation, progression-free survival was seen at a median of 3.8 months in the elacestrant arm compared with 1.9 months in the fulvestrant or aromatase inhibitor arm. Both the intention-to-treat and the ESR1-mutation subgroup saw a statistically significant difference in progression-free survival.

The most common adverse events experienced in ≥10% of patients, including laboratory abnormalities, were musculoskeletal pain, nausea, increased cholesterol, increased aspartate aminotransferase (AST), increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased alanine aminotransferase (ALT), decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

“Elacestrant is the first oral selective estrogen receptor degrader (SERD) that demonstrated a significant improvement in progression-free survival versus standard-of-care therapy in a randomized phase 3 study in patients with ER-positive/HER2-negative advanced or metastatic breast cancer in the second- or third-line setting,” concluded Dr. Bidard and colleagues. “Elacestrant showed a predictable and manageable safety profile consistent with other endocrine therapies. These data represent a long-awaited opportunity to potentially offer second- or third-line, including heavily pretreated, patients with breast cancer a new effective option and further advance toward precision medicine in the ER-positive/HER2-negative subtype.”

The recommended dosage is 345 mg of elacestrant dose orally with food, once daily until disease progression or unacceptable toxicity.

For More Information

Bidard FC, Kaklamani VG, Neven P, et al (2022). Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol, 1;40(28):3246-3256. DOI:10.1200/JCO.22.00338

Clinicaltrials.gov (2022). Phase 3 trial of elacestrant vs. standard of care for the treatment of patients with ER+/HER2- advanced breast cancer (EMERALD). NLM identifier: NCT03778931.

Orserdu™ (elacestrant) prescribing information (2023). Stemline Therapeutics. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639s000lbl.pdf

US Food and Drug Administration (2023). FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer 

Image credit: Sshah74. Licensed under CC BY 4.0

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