Abstract OT-09-01: An open-label, multicenter study evaluating the safety of lasofoxifene in combination with abemaciclib for the treatment of pre and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and have an ESR1 mutation
Authors: Damodaran Senthil , Plourde Paul V , Tripathy Debu , Jenkins Simon N , Portman David J 
Published: February 2021

Endocrine therapy is the established treatment for metastatic breast cancer (MBC) in patients that express estrogen receptor (ER) and/or progesterone receptor (PR). Agents targeting the ER pathway such as aromatase inhibitors (AIs) and fulvestrant with or without additional biologic agents are effective, but not curative. Over the last several years, clinical studies have shown that adding a CDK 4/6 inhibitor (CDKi) to endocrine treatment (either AIs or fulvestrant) significantly increases time to progression for MBC patients. Unfortunately, resistance due to a number of causes eventually develops. Secondary mutations in estrogen receptor (ESR1), most frequently seen after AI treatment produce constitutive activation of ER and are associated with a worse disease prognosis. Treatment options for MBC patients with an ESR1 mutation are limited and currently there are no approved therapies. Additionally, limited data exist to justify whether cyclin dependent kinase 4/6 inhibitors (CDK4/6i) should be continued, substituted for another CDK4/6i or discontinued all together. Lasofoxifene is a third generation SERM previously investigated for the treatment of osteoporosis and vulvo-vaginal atrophy (VVA). Clinical data have shown a significant reduction in the incidence of ER+ breast cancer in postmenopausal women with osteoporosis treated with lasofoxifene. These results supported further studies which showed significant in vitro and in vivo efficacy in pre-clinical breast cancer models. Moreover, a significant benefit was seen in pre-clinical models with lasofoxifene either as monotherapy or in combination with a CDK4/6i over fulvestrant (with or without a CDK4/6i) in breast cancer cells expressing ESR1 mutations. The multicenter phase 2 (ELAINE 1) study is currently enrolling patients evaluating the activity of lasofoxifene monotherapy compared to fulvestrant. Also, studies have shown that abemaciclib has meaningful clinical activity in patients previously exposed to other CDK4/6i (palbociclib/ribociclib) and chemotherapy. The pre-clinical and clinical study results also provide a strong rationale to pursue a phase 2 clinical trial in BC patients with ESR1 mutations in combination with a CDK4/6i.The ongoing study (ElAINE 2) is an open-label, multi-center study evaluating the safety of the combination of lasofoxifene and CDK4/6i abemaciclib. Inclusion criteria include pre- and postmenopausal women with ER+ ESR1mutation-bearing advanced breast cancer who have progressed on prior hormonal treatment and a CDK4/6i (including abemaciclib); 24 patients with measurable or evaluable disease (i.e. bone only) will be recruited. The primary endpoint will be the safety of the combination. Secondary endpoints will include progression free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and time to response (TTR), with exploratory serial circulating tumor DNA landscape analysis. The study started in 2Q2020 and will complete recruitment in 1 year. Ten centers in the US will be participating. Recruitment status will be provided at the time of presentation.

Citation Format: Senthil Damodaran, Paul V Plourde, Debu Tripathy, Simon N Jenkins, David J Portman. An open-label, multicenter study evaluating the safety of lasofoxifene in combination with abemaciclib for the treatment of pre and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and have an ESR1 mutation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-01.