Dr Damodaran on the ELAINE-3 Trial in Patients With ESR1-Mutated ER+/HER2– Metastatic Breast Cancer

Senthil Damodaran, MD, PhD, associate professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale for the phase 3 ELAINE-3 trial (NCT05696626) in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations.

Dr Damodaran on Identifying ESR1 Mutations in ELAINE-3

ELAINE-3 will enroll patients with ER-positive, HER2-negative breast cancer with ESR1 mutations. Several platforms can identify ESR1 mutations in circulating tumor DNA, Damodaran says. The earlier phase 2 ELAINE-1 (NCT03781063) and ELAINE-2 (NCT04432454) trials tested for ESR1 mutations using a smaller panel with approximately 6 genes, Damodaran notes.

The ELAINE-3 trial is using the Guardant360^® CDx liquid biopsy next generation sequencing–based test, which was approved by the FDA on January 30, 2023, as a companion diagnostic for patients with ESR1-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer. This is a broad panel that sequences for alterations in 90 genes, so although the ELAINE-3 investigators will focus on finding ESR1 mutations, the assay results will provide supplemental information about additional genes, Damodaran explains.

Dr Damodaran on Lasofoxifene Plus Abemaciclib in ELAINE-2 and ELAINE-3

The ELAINE-3 trial is supported by findings from the single-arm phase 2 ELAINE-2 trial, which investigated the efficacy and safety of lasofoxifene plus abemaciclib (Verzenio). The ELAINE-2 investigators hypothesized that patients with ER-positive, HER2-negative metastatic breast cancer with ESR1 mutations may derive more benefit from combination regimens than monotherapies, Damodaran says. Since lasofoxifene-containing combinations had shown preclinical activity in patients with ESR1 mutations, the investigators decided to combine lasofoxifene with other agents, Damodaran notes. Preclinical studies at institutions such as The University of Texas MD Anderson Cancer Center showed that abemaciclib is still active in patients who had have previously progressed on CDK4/6 inhibitors such as palbociclib (Ibrance) and ribociclib (Kisqali), according to Damodaran.

Based on these preclinical data, ELAINE-2 investigated the combination of lasofoxifene and abemaciclib, the findings from which were presented at the 2022 ASCO Annual Meeting. ELAINE-2 evaluated the safety of the combination and demonstrated a median progression-free survival of 13.9 months with the regimen, which is not typically expected in patients who have progressed on prior CDK4/6 inhibitors, Damodaran explains. As ELAINE-2 was a small trial, its findings need to be confirmed in the larger, randomized ELAINE-3 trial, in which the investigational combination of lasofoxifene plus abemaciclib is being compared with standard-of-care fulvestrant (Faslodex) plus abemaciclib, Damodaran concludes.