ER-Positive

FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

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On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for 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.

FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with elacestrant.

Efficacy was evaluated in EMERALD (NCT03778931), a randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer of which 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting. Patients were randomized (1:1) to receive elacestrant 345 mg orally once daily (n=239) or investigator’s choice of endocrine therapy (n=239), which included fulvestrant (n=166) or an aromatase inhibitor (n=73). Randomization was stratified by ESR1 mutation status (detected vs. not detected), prior treatment with fulvestrant (yes vs. no), and visceral metastasis (yes vs. no). ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain.

The major efficacy outcome measure was progression-free survival (PFS), assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations.

In the 228 (48%) patients with ESR1 mutations, median PFS was 3.8 months (95% CI: 2.2, 7.3) in the elacestrant arm and 1.9 months (95% CI: 1.9, 2.1) in the fulvestrant or aromatase inhibitor arm (hazard ratio [HR] of 0.55 [95% CI: 0.39, 0.77], 2-sided p-value=0.0005).

An exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations showed a HR 0.86 (95% CI: 0.63, 1.19) indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1 mutated population.

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

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

Avoiding Chemotherapy in ER-Positive, Node-Positive Breast Cancer

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Postmenopausal women with 1 to 3 positive nodes and a recurrence score of ≤25 can avoid adjuvant chemotherapy without negative impact on invasive disease-free survival.

The prior TAILORx trial (NEJM JW Oncol Hematol Jul 2018 and N Engl J Med 2018; 379:111) showed that 21-gene recurrence score (RS) intermediate results (11–25) could be used to identify patients with estrogen-receptor (ER)-positive, node-negative breast cancer who could avoid adjuvant chemotherapy without any detrimental impact on outcome. Now, to provide similar guidance for patients with ER-positive, node-positive disease, investigators conducted a prospective, multicenter, randomized trial (RxPONDER), sponsored by the National Cancer Institute Cancer Therapy Evaluation Program.

The trial involved 5018 women (67% postmenopausal) from 632 sites in nine countries with ER-positive and HER2-negative, early-stage breast cancer with 1 to 3 involved axillary lymph nodes and an RS of ≤25. Participants were assigned to endocrine therapy with or without chemotherapy. Stratification factors included RS (0–13 or 14–25), menopausal status, and type of axillary surgery (sentinel-node biopsy or axillary lymph-node dissection).

Results at a median follow-up of 5 years were as follows:

  • Among postmenopausal women, invasive disease-free survival (iDFS; the primary objective) was similar with endocrine-only therapy or chemo-endocrine therapy (91.9% and 91.3%, respectively); no subgroup gained benefit from chemotherapy.
  • Among premenopausal women, iDFS was improved with chemo-endocrine therapy versus endocrine-only therapy (93.9% vs. 89.0%; hazard ratio, 0.60; P=0.002)
  • No chemotherapy benefit was observed in premenopausal women age ≥50 years; those age <50 years did achieve a benefit (HR, 0.48).
  • The chemotherapy benefit for premenopausal women remained significant (HR, 0.60), after adjustment for age, number of positive nodes, tumor grade, and tumor size; the benefit did not increase as RS increased.

Comment

The RxPONDER trial showed that postmenopausal women with ER-positive and HER2-negative, early-stage breast cancer with 1 to 3 involved axillary lymph nodes and an RS of ≤25 achieved similar outcomes with adjuvant endocrine therapy with or without chemotherapy. However, premenopausal women can continue to derive clinically meaningful benefit from the addition of chemotherapy to adjuvant endocrine therapy.

Source: NEJM