Abstract P5-03-01: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance to treatment. A large unmet medical need exists especially when resistance occurs following a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival ([PFS] median, 5.6 mos vs 3.7 mos; HR 0.669 [95% CI, 0.445-1.125]; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), and a favorable safety profile (Goetz MP, et al. Ann Oncol. 2023;34:1141-1151). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S, et al. Ann Oncol. 2023;34:1131-1140). Based on these promising earlier-phase data, the phase 3, registrational, ELAINE 3 trial was initiated. Other recent results from postMONARCH confirmed superior efficacy of fulv/Abema versus fulv/placebo (median PFS, 6.0 mos vs 5.3 mos; HR 0.73 [95% CI, 0.57-0.95], nominal P=0.02) in non-biomarker–selected mBC that progressed on a prior CDK4/6i and aromatase inhibitor (Kalinsky K, et al. J Clin Oncol. 2024;42[suppl 17]: abstract LBA1001 [slides]). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation–selected mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Study enrollment is currently underway at sites in the United States, Canada, France, Italy, Israel, and Spain, and is planned for expansion into Australia, Belgium, China, Germany, Hungary, Poland, Romania, Singapore, South Korea, Taiwan, and the United Kingdom. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM on days 1, 15, and 29, then once monthly plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. To achieve 90% power with a one-sided type I error rate of 0.025, the target sample size is 400 patients. Full recruitment is expected to occur over 18 mos. Citation Format: Matthew Goetz, Seth A Wander, Thomas Bachelot, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili Gal-Yam, Sarah L Sammons, Sherry Shen, Chris Twelves, Paul V Plourde, David J Portman, Senthil Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-03-01.