Dr O’Shaughnessy on the Impetus for the ELEGANT Study in High-Risk Breast Cancer

“Is elacestrant going to salvage these patients who have very high–risk disease who have been [receiving] standard adjuvant endocrine therapy for 2 to 5 years? We’re worried there are resistance mechanisms emerging. Will elacestrant improve the outcomes of those patients?”

Joyce O’Shaughnessy, MD, co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at the Baylor-Sammons Cancer Center and The US Oncology Network, discussed ongoing research regarding the treatment of patients with estrogen receptor (ER)–positive, high-risk breast cancer, focusing on the phase 3 ELEGANT trial (NCT06492616).

ELEGANT is investigating the transition from standard adjuvant endocrine therapy to the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu) among patients with ER-positive, HER2-negative early breast cancer at high risk of recurrence. The study is evaluating the effect of switching therapy—regardless of ESR1 mutation status—among patients who are currently receiving aromatase inhibitors or tamoxifen, often following treatment with a CDK4/6 inhibitor.

The rationale for the study is centered on the fact that oral SERDs are not cross-resistant with standard adjuvant endocrine therapies and have proven effective in the metastatic setting post–CDK4/6 inhibition, according to O’Shaughnessy. She noted that although elacestrant is equally as effective as fulvestrant (Faslodex) in the ESR1 wild-type breast cancer populations, it is superior in ESR1-mutant populations. This is a critical distinction because aromatase inhibitors are essentially ineffective once ESR1 mutations emerge during the 2 to 5 years of antecedent therapy, she emphasized. By using elacestrant, the ELEGANT researchers aim to target the estrogen receptor in a way that addresses these emerging resistance mechanisms, she explained.

Furthermore, the ELEGANT trial is designed to address a very high–risk population, patterning its eligibility criteria after those from the phase 3 monarchE (NCT03155997) and NATALEE (NCT03701334) trials, O’Shaughnessy said. Notably, monarchE cohort 1 included patients with 4 or more positive nodes, or those with 1 to 3 nodes and additional high-risk features, such as grade 3 disease. O’Shaughnessy reported the importance of using the most effective agents in the curative setting to eliminate resistant clones. Therefore, the ELEGANT study aims to determine whether elacestrant can successfully salvage outcomes for patients at high risk of developing resistance to standard endocrine regimens, she concluded.