16 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

16 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

Background

Patients with estrogen receptor–positive (ER+) metastatic breast cancer may develop resistance to endocrine therapy (ET), particularly after a CDK 4/6 inhibitor, potentially driven by a mutation in the ESR1 gene. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, was evaluated in 2 phase 2 studies of women with ER+/HER2-negative (HER2–), ESR1-mutated metastatic breast cancer that progressed on previous ET and CDK4/6 inhibitors. The phase 2 ELAINE 1 trial showed numerically greater progression-free survival (PFS; median about 6 vs 4 months; P = .138), objective response rate (ORR; 13% vs 3%; P = .124), and clinical benefit rate (CBR; 37% vs 22%; P = .117) with lasofoxifene alone vs fulvestrant, and a favorable safety profile. In the phase 2 ELAINE 2 trial, lasofoxifene plus abemaciclib was well tolerated with a median PFS of close to 13 months, an ORR of 56%, and a CBR of 66%. Thus, the registrational, phase 3 ELAINE 3 trial was initiated.

Methods

ELAINE 3 is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib vs fulvestrant plus abemaciclib. Women were pre-/postmenopausal, and men were aged 18 years or older; and had ER+/HER2–, locally advanced and/or metastatic breast cancer; 1 or more acquired ESR1 mutations; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal therapy for advanced and/or metastatic breast cancer; and 1 or fewer chemotherapy lines in the advanced/metastatic setting. Patients will be randomly assigned 1:1 to lasofoxifene at 5 mg/day plus abemaciclib at 150 mg twice a day, or fulvestrant at 500 mg through intramuscular injection on days 1, 15, and 29, then monthly, plus abemaciclib at 150 mg twice daily, until progression, death, unacceptable toxicity, or study withdrawal. End points include PFS (primary), ORR, overall survival, CBR, duration of response, time to response, time to cytotoxic chemotherapy, quality of life, and safety. Circulating tumor DNA will be analyzed at screening, at weeks 4 and 8, every 8 weeks thereafter, and at the final visit. Outcomes with lasofoxifene/abemaciclib vs fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified log rank test. Expected PFS is at least 10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (HR, 0.68 at final analysis). Target sample size is 400 to provide 90% power with a 1-sided type I error rate of 0.025 after 285 PFS events.