Resistance to endocrine therapy (ET) is a common challenge in patients with estrogen receptor (ER)-positive metastatic breast cancer, particularly after treatment with a CDK4/6 inhibitor. A potential key driver of this resistance is the emergence of mutations in the ESR1 gene, which encodes Erα. Lasofoxifene, a next-generation oral ET and ER antagonist, has demonstrated promising results in 2 phase 2 trials involving female patients with ER-positive/HER2-negative metastatic breast cancer with an ESR1 mutation who had progressed on previous ET and a CDK4/6 inhibitor. In the ELAINE 1 trial, lasofoxifene monotherapy exhibited numerically superior progression-free survival (PFS; median 5.6 months vs 3.7 months), objective response rate (ORR; 13% vs 3%), and clinical benefit rate (CBR; 37% vs 22%) compared with fulvestrant, with a favorable safety profile. Meanwhile, the single-arm ELAINE 2 trial showed that lasofoxifene combined with abemaciclib achieved a median PFS of approximately 13 months, an ORR of 56%, and a CBR of 66%, with good tolerability. This article describes the ELAINE 3 trial that will evaluate the efficacy of lasofoxifene plus abemaciclib in a post–CDK4/6 inhibitor, ESR1-mutated metastatic breast cancer population.
ELAINE 3 (NCT05696626) is an open-label, international, multicenter, phase 3 trial designed to compare the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib in patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer harboring ESR1 mutations. The study is enrolling patients across 218 sites in 17 countries, including the United States, United Kingdom, France, China, and Australia. Eligible participants include pre- and postmenopausal female and male patients aged ≥18 years with ER-positive/HER2-negative locally advanced and/or metastatic breast cancer, at least 1 acquired ESR1 mutation, disease progression on an aromatase inhibitor (AI) plus palbociclib or ribociclib as 1L therapy, and no more than 1 prior line of chemotherapy in the advanced/metastatic setting. Participants will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg twice daily (BID), or fulvestrant 500 mg intramuscularly with abemaciclib 150 mg BID. Treatment will continue until progression, unacceptable toxicity, death, or withdrawal.
The primary endpoint is PFS as assessed by blinded independent central review per RECIST 1.1 criteria. Key secondary endpoints include ORR, overall survival, CBR, duration of response, and time to response. Additional analyses will assess safety, time to initiation of cytotoxic chemotherapy, and quality of life (including vaginal health). Blood samples for circulating tumor DNA will be collected at multiple time points for genomic analysis. Statistical comparisons of lasofoxifene/abemaciclib versus fulvestrant/abemaciclib will utilize a stratified Cox proportional hazards model and log-rank test, with an expected PFS hazard ratio of 0.68 at final analysis.
The ELAINE 3 trial aims to provide critical data on the efficacy and safety of lasofoxifene plus abemaciclib in patients with ESR1-mutated, ER-positive/HER2-negative metastatic breast cancer who have progressed on a previous AI or CDK4/6 inhibitor therapy.
Source: Goetz MP, Wander SA, Bachelot T, et al. 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. Presented at: San Antonio Breast Cancer Symposium 2025. December 12, 2025; San Antonio, TX. Presentation PS5-07-30.