Abstract P4-04-17: Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model

Abstract

Abstract Background: Breast cancer is subdivided into categories based on tumor receptor status, with estrogen-receptor positive (ER+) breast cancer making up approximately two-thirds of all breast cancers diagnosed. In advanced or metastatic disease, dependence on ER signaling is often retained even after multiple rounds of endocrine therapy, supporting the use of ER targeting agents for several lines of treatment prior to chemotherapy. Selective estrogen receptor degraders (SERDs) have gained recent attention as ER antagonists given their ability to target and degrade ER. Fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of more potent and orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable SERD, as an inhibitor of ER+ breast cancer growth in preclinical patient-derived xenograft (PDX) models, including those that are insensitive to fulvestrant. Here, we describe elacestrant activity in an ER+ PDX model that had been treated with multiple rounds of fulvestrant treatment. Methods: An ER+/PR+ PDX model, MAXF-713, derived from a treatment-naïve patient, was passaged multiple times in the presence of fulvestrant over the course of a year. After each round of fulvestrant treatment, elacestrant or fulvestrant were evaluated for anti-tumor activity. Pharmacodynamic endpoints including changes in ER and ER target gene expression were also evaluated. Results: Despite repeated exposure to fulvestrant, the PDX model retained sensitivity to elacestrant. In fact, regardless of the number of prior rounds of fulvestrant treatment, elacestrant produced consistent tumor growth inhibition within every passage, while the effects produced by fulvestrant exhibited a high degree of variability. Conclusions: Our data demonstrate that elacestrant is a SERD that can inhibit tumor growth in a fulvestrant-resistant preclinical setting and provides rationale for examining elacestrant in the clinical setting in patients that have progressed on fulvestrant treatment. Citation Format: Arlt H, Garner F, Bihani T. Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-17.