Elacestrant (Orserdu): A Comprehensive Monograph on the First-in-Class Oral SERD for ESR1-Mutated, ER+/HER2- Metastatic Breast Cancer

Abstract

Elacestrant, marketed under the brand name Orserdu, represents a significant advancement in the treatment of hormone receptor-positive breast cancer. As the first-in-class orally bioavailable Selective Estrogen Receptor Degrader (SERD), it addresses key limitations of previous endocrine therapies. This report provides a comprehensive analysis of Elacestrant, covering its physicochemical properties, pharmacology, clinical evidence, and regulatory status. Its mechanism of action is dual in nature, involving both competitive antagonism of the estrogen receptor alpha (ERα) and induction of its degradation through the proteasomal pathway. This dual action is particularly effective against tumors that have developed resistance to aromatase inhibitors via acquired mutations in the estrogen receptor 1 gene (ESR1). The pivotal Phase III EMERALD trial demonstrated Elacestrant's superiority over standard-of-care endocrine monotherapy in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−), advanced or metastatic breast cancer who had progressed on prior endocrine therapy, including a CDK4/6 inhibitor. The clinical benefit was most pronounced in the subgroup of patients with activating ESR1 mutations, leading to a statistically significant improvement in Progression-Free Survival (PFS) (Hazard Ratio 0.55; P=0.0005).[1] This finding established Elacestrant as a new standard of care for this specific patient population and led to its approval by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The safety profile of Elacestrant is well-characterized and manageable, with the most common adverse events being gastrointestinal effects (nausea, vomiting) and dyslipidemia (increased cholesterol and triglycerides), which are typicall