The standard of care (SOC) for the management of estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) metastatic or advanced breast cancer (BC) involves the use of endocrine therapy (ET; i.e., either aromatase inhibitors [AIs] or fulvestrant, along with a cyclin-dependent kinase [CDK 4/6] inhibitor). Further disease progression while on this regimen is associated with ET resistance and poor progression-free survival (PFS).

On January 27, 2023, the FDA approved elacestrant, a first-in-class selective estrogen receptor (ER) degrader, indicated for the management of postmenopausal women or men with ER+, HER2- metastatic or advanced BC who have received at least one line of ET and who have an ESR1 mutation. The ESR1 gene encodes for the ER protein, and mutations in this gene can lead to resistance to aromatase inhibitor therapy by causing estrogen-independent ER activation. Elacestrant works by degrading estrogen-receptor alpha in a dose-dependent way and by inhibiting estradiol-dependent, ER-directed gene transcription and tumor growth.

Approval of elacestrant, which received Priority Review and Fast Track designation by the FDA, was based on the results of the EMERALD trial. EMERALD was an international, randomized, open-label, active-controlled, multicenter phase III trial conducted between February 2019 and October 2020 that enrolled 478 postmenopausal women and men aged 18 years or older (230 elacestrant-treated patients and 238 SOC-treated patients with a median age of 63 years) from 17 countries with ER+/HER2- advanced or metastatic BC and either locoregional recurrence or metastatic disease. Almost one-half (47.8%) of the patients enrolled in this study had an ESRI mutation. ESR1 mutations were defined as any missense mutation in codons 310-547. Patients were excluded if they had had symptomatic metastatic visceral disease or a cardiovascular even in the past 6 months.

Study participants were randomized to receive either elacestrant 400 mg orally once a day (with dose adjustments to 300 mg or 200 mg allowed in the event of toxicity) or SOC treatment (i.e., the clinician’s choice of fulvestrant, anastrozole, letrozole, or exemestane monotherapy with fulvestrant preferred if it had not been previously administered).

Study sites were blinded during treatment as to the ESR1 status of patients.

The primary endpoint of the study was PFS in all patients and in those with an ESR1 mutation. Key secondary endpoints included the use of blinded-independent central review, which employ criteria to assess for complete response, partial response, stable disease, or progressive disease, and the impact on PFS and overall survival in patients without an ESR1 mutation.

Over 43% of patients received two prior lines of ET, and 22% had received a prior course of chemotherapy. Almost 70% had visceral metastases. The median duration of follow-up for the study was 15.1 months.

Efficacy analyses found that PFS was significantly prolonged by 30% in the elacestrant group compared with the SOC group (hazard ratio [HR] = 0.70; 95% CI 0.55-0.88, P = .002); this effect even greater in group with an ESRI mutation (HR = 0.55; 95% CI 0.39-0.77). Similar trends were seen for the elacestrant and SOC groups at 6 months and 12 months, with 6-month PFS rates of 34.3% and 20.4% for all patients and 40.8% and 19.1% for patients with an ESRI mutation, respectively. At 12 months, the PFS rates were 22.3% and 9.4% in the elacestrant group versus SOC group for all patients; among those with an ESR1 mutation, the 12-month PFS was 26.8% and 8.2%, respectively.

The most common adverse events occurring in >10% of elacestrant-treated patients included nausea, fatigue, vomiting, decreased appetite, and arthralgias. The most common grade III/IIII adverse events were nausea, back pain, and increased ALT in the estrogen-receptor degrader group compared with nausea, fatigue, diarrhea, and increased AST in the SOC group. Treatment-related events occurred in 63.3% of elacestrant-treated patients versus 43.7% of SOC-treated patients, with grade III/IIII events occurring in 7.2% and 3.1%, respectively.

The authors concluded that elacestrant significantly improves PFS in those with advanced or metastatic ER+/HER2- BC compared with SOC in those with or without an ESR1 mutation. However, this drug’s approval was based on this one clinical trial and is only indicated for those ER+/HER2- patients who possess an ESRI mutation. Pharmacists will need to closely monitor patients on this drug for both efficacy and signs of adverse events.

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