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Elacestrant improves progression-free survival in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, especially in patients with estrogen receptor 1 gene mutations, according to the results of a recent literature review.

Endocrine therapy is the backbone of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treatment. Most cases of HR-positive metastatic breast cancer eventually become resistant to endocrine therapy agents. Estrogen receptor 1 (ESR1) gene mutations have been associated with resistance to aromatase inhibitors. 

Elacestrant is an oral selective estrogen receptor degrader (SERD) that selectively binds to the estrogen receptor and activates its degradation. A study in the journal OncoTargets and Therapy reviewed the available data regarding the efficacy and toxicity of elacestrant.

Rationale Provided by Preclinical Data for Testing Elacestrant

Preclinical evidence for elacestrant showed its effectiveness in decreasing estrogen receptor (ER)-positive cell proliferation and tumor growth in xenograft models and in cells having ESR1 mutation or resistance to cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i).

Phase I Trials Laying the Groundwork for Further Research on Elacestrant

Several studies have assessed the use of elacestrant in advanced breast cancer. RAD1901-106, a phase 1b clinical trial, evaluated the impact of elacestrant on ER availability in advanced ER-positive, HER2-negative breast cancer in patients with disease progression after endocrine therapy. A significant reduction was seen in FES uptake (89.1%) in tumor lesions after two weeks of continuous elacestrant administration. The overall objective response rate (ORR) was 11.1%, and the clinical benefit rate (CBR) was 30.8%. The median progression-free survival (PFS) was 5.3 months.

RAD1901-005, a phase 1 study, assessed the antitumor activity and safety of elacestrant in heavily treated postmenopausal women with advanced ER-positive, HER2-negative breast cancer. The ORR was 19.4%, and the CBR was 42.6%. The CBR was 56.5% in patients with an ESR1 mutation. The median PFS was 4.5 months, and 82% of patients with ESR1 mutation showed a reduction in the mutant allele fraction at the end of cycle 1. The most common side effects were nausea, increased triglycerides, and decreased serum phosphorus levels. No dose-limiting toxicities were observed.

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Elacestrant’s Superior Efficacy in ER-Positive, HER2-Negative Breast Cancer

The EMERALD phase III clinical trial evaluated elacestrant’s efficacy and safety against standard endocrine therapy. The study included 477 men and postmenopausal women with recurrent or metastatic ER-positive, HER2-negative breast cancer who had previously received one or two lines of endocrine therapy. Prior treatment with a CDK4/6i and no more than one prior line of chemotherapy were required. Participants were randomized to receive either elacestrant 400mg daily or endocrine treatment of the investigator’s choice (fulvestrant or an aromatase inhibitor). Elacestrant demonstrated prolonged PFS compared to standard of care in all patients, with a 30% relative reduction in disease progression or death.

Elacestrant Reduces ESR1 Disease Progression by 45 Percent

Notably, patients with ESR1 mutation treated with elacestrant showed a 45% relative reduction in disease progression or death. The 12-month PFS was 22.3% vs. 9.4% in patients treated with elacestrant vs. standard of care, and 26.8% vs. 8.2% in patients treated with elacestrant vs. patients with ESR1 mutation, respectively. 

The 12-month PFS was 22.3% vs. 9.5% in the elacestrant vs. fulvestrant group and 26.8% vs. 8.3% in patients with ESR1 mutation. Moreover, a longer duration of prior CDK4/6i therapy was associated with longer PFS on elacestrant vs. standard care, more so in patients with ESR1 mutation.

Adverse Events in Elacestrant Treatment

The most common side effects were nausea, vomiting, fatigue, decreased appetite, and arthralgia. Grade 3/4 adverse events occurred in 27% and 20% of patients on elacestrant and standard of care treatment, respectively.

Based on this trial, the FDA approved elacestrant for ER-positive, HER2-negative, ESR1-mutated, advanced or metastatic breast cancer with disease progression after endocrine therapy.

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Varella, L., & Cristofanilli, M. (2023). Evaluating elacestrant in the management of ER-Positive, HER2-Negative Advanced breast cancer: Evidence to date. OncoTargets and Therapy, Volume 16, 189–196. https://doi.org/10.2147/ott.s400563