Elacestrant, an oral selective estrogen receptor degrader, has shown promising efficacy in the EMERALD trial, significantly improving progression-free survival (PFS) compared with standard-of-care endocrine therapy (ET) in patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (mBC) previously treated with ET plus CDK4/6 inhibitors. However, intrinsic and acquired resistance mechanisms can limit the effectiveness of ET, prompting the exploration of combination therapies to address these challenges.
ELEVATE (NCT05563220) is a phase 1b study investigating the safety and efficacy of elacestrant in combination with various targeted therapies, including everolimus, alpelisib, capivasertib, ribociclib, palbociclib, and abemaciclib, for patients with ER-positive/HER2-negative mBC. The primary objective of the study is to determine the recommended phase 2 dose (RP2D) for each combination. A separate trial, ELECTRA (NCT05386108), has already established the RP2D for the elacestrant plus abemaciclib combination. The phase 2 portion of ELEVATE will primarily focus on evaluating PFS in patients receiving elacestrant combined with each of the other study drugs at their respective RP2Ds. A recently presented abstract shows updated safety data from the phase 1b portions for the everolimus, alpelisib, ribociclib, and palbociclib arms, as well as preliminary efficacy data for the everolimus arm.
Updated safety data for the everolimus RP2D group (n=57) showed that the most frequent treatment-emergent adverse events (TEAEs) were nausea (n=29, 51%; 2% grade ≥3), diarrhea (n=23, 40%; 5% grade ≥3), and stomatitis (n=19, 33%; 4% grade ≥3). Other everolimus cohorts followed similar trends. Alpelisib also showed high rates of nausea across both its cohorts (n=8, 89%; 11% grade ≥3). Neutropenia was the most common TEAE in the ribociclib (n=11, 46%; 29% grade ≥3). The R2PD group for palbociclib also showed neutropenia as the most common TEAE (n=4, 57%; 43% grade ≥3), with its other cohorts having similar data. Preliminary efficacy data for the everolimus arm demonstrated a clinical benefit rate at 24 weeks of 81% and an objective response rate of 25%. Other combinations are still ongoing or are under evaluation.
The data presented here suggest that the elacestrant combinations with everolimus, ribociclib, or palbociclib have demonstrated manageable safety profiles in the phase 1b portion of the ELEVATE trial. Notably, the rate of grade ≥3 TEAEs was low. Furthermore, the elacestrant plus everolimus combination has shown promising efficacy, warranting further investigation in the phase 2 portion.
Elacestrant has the possibility to become the backbone of ET in combination with targeted therapies, potentially creating an option that includes all-oral treatment regimens that could replace fulvestrant-based combinations and potentially delay the need for infused chemotherapy or therapies based on antibody–drug conjugates. This highlights the potential of elacestrant to improve treatment options and outcomes for patients with ER-positive/HER2-negative mBC.
Rugo HS, et al. Elacestrant combinations in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): update from ELEVATE, a phase 1b/2, open-label, umbrella study. Presented at: San Antonio Breast Cancer Symposium. December 10, 2024; San Antonio, TX. Abstract SESS-1889.