Elacestrant Receives FDA Approval for ESR1-Mutated Breast Cancer

For hormone-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer progressing after at least one line of hormonal therapy in postmenopausal women or adult men, the FDA (US Food and Drug Administration) approved elacestrant (Orserdu, Stemline Therapeutics) on January 27, 2023.

Elacestrant is an oral tablet in the selective estrogen receptor degrader (SERD) class. This is the first FDA approval of an oral SERD. Another commonly used drug in this class, fulvestrant (Faslodex), is administered by intramuscular injection into the buttock.

The FDA also approved Guardant360 CDx to identify ESR1 mutations in patients with breast cancer. Thus, for the first time ESR1 -targeted treatment received FDA approval.

What Is an ESR1 Mutation?

ESR1 is the gene encoding the estrogen receptor. Hormonal therapy in metastatic hormone receptor-positive breast cancer often leads to changes in the ESR1 gene, known as mutations . ESR1 mutations are most common in breast cancers progressing during aromatase inhibitor therapy.

FDA Approval Based on EMERALD

Approval was based on a study in which approximately half the patients had ESR1 mutations. The phase 3 EMERALD trial included 478 postmenopausal women and men with hormone-positive, HER2-negative advanced or metastatic breast cancer.

ESR1 status was determined from circulating tumor DNA (ctDNA), limited to ligand-binding-domain ESR1 missense mutations.

Patients had received one or two lines of hormonal therapy, including a CDK4/6 inhibitor . They could also have received one chemotherapy line for advanced or metastatic disease.

Patients were randomized 1:1: 239 received elacestrant 345 mg orally once daily, and 239 received investigator-selected hormonal therapy, either fulvestrant or an aromatase inhibitor.

Results

Of patients, 62% had received 1 hormonal therapy line. All had received a CDK4/6 inhibitor, 24% fulvestrant and 25% chemotherapy.

• ESR1 mutations were present in 228 patients (48%). Median progression-free survival with elacestrant was 3.8 months versus 1.9 months with fulvestrant or an aromatase inhibitor (hazard ratio, 0.55; P =0.0005).

No statistically significant PFS difference was observed between treatment arms in patients without the mutation.

Blood Lipids Require Monitoring

With elacestrant, the most common (occurring in 10% or more) adverse effects were musculoskeletal pain, nausea, increased cholesterol, AST and triglycerides, fatigue, reduced hemoglobin, vomiting, increased ALT, reduced sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flashes and dyspepsia (stomach discomfort).

The label warns of elevated lipids, termed hypercholesterolemia and hypertriglyceridemia. Monitor the lipid profile before treatment and regularly afterward.

The recommended elacestrant dose is one 345 mg tablet orally once daily with food until progression or unacceptable adverse effects.

How Does Elacestrant Work?

Elacestrant is a hormone-suppressing SERD (selective estrogen receptor degrader). It binds estrogen receptors and targets them for degradation, reducing receptor-controlled processes and aiming to inhibit cancer cell growth.

Compared with fulvestrant, it offers oral administration and stronger estrogen receptor suppression. It also crosses the blood-brain barrier more readily, suggesting potential suitability for patients with brain metastases.