Evaluating Elacestrant in the Management of ER-Positive, HER2-Negative Advanced Breast Cancer: Evidence to Date

Abstract

Breast cancer remains the second leading cause of cancer mortality in women. Endocrine therapy is the backbone treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the most common subtype. Although several endocrine therapy agents are available, essentially all HR-positive metastatic breast cancers will become resistant to these drugs. ESR1 mutations represent an important mechanism of resistance to aromatase inhibitors. Elacestrant is a novel oral selective estrogen receptor degrader (SERD) that selectively binds to the estrogen receptor in breast cancer cells, inhibiting tumor growth. Preclinical data suggested greater efficacy of elacestrant in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/ 6i) or everolimus. In a Phase III clinical trial, elacestrant demonstrated a significant although modest improvement in median progression-free survival (PFS) compared to standard of care endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer. Importantly, there was also a significant benefit in patients with ESR1 mutations, which led to the FDA approval of elacestrant in this patient group. Elacestrant was generally well tolerated, with main side effects being upper gastro-intestinal symptoms. There are several ongoing clinical trials evaluating the efficacy of elacestrant in the early setting as well as in combination with other targeted agents in the treatment of metastatic breast cancer. Other novel oral SERDs are also currently being evaluated in the treatment of HR-positive breast cancer. Results of ongoing clinical trials with these drugs will help clinicians decide the best sequence and combination of endocrine therapy agents.