Abstract P4-13-03: Elacestrant (RAD1901) demonstrates anti-tumor activity in models resistant to CDK4/6 inhibitors

Abstract

Abstract Background: Approximately 75% of all breast cancers diagnosed are estrogen receptor-positive (ER+) and currently approved endocrine therapies rely heavily on blocking of the ER signaling pathway. In recent years, the combination of an endocrine agent with other targeted agents have been evaluated to address endocrine resistance and improve progression-free survival (PFS). Recently, it was demonstrated that the addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to an endocrine agent roughly doubles PFS, leading to the approval and use of certain CDK4/6 inhibitors in combination with either aromatase inhibitors in the first-line metastatic setting or in combination with the selective estrogen receptor degrader (SERD), fulvestrant, in the second-line metastatic setting. While combining CDK4/6 inhibitors and endocrine therapy can result in significantly increased PFS, patients eventually progressed on these combinations, and to date, there is no cure for patients with advanced metastatic ER+ breast cancer. Given the increased use of CDK4/6 inhibitors in the ER+ breast cancer treatment paradigm, it will be important to understand how treatment resistance to CDK4/6 inhibitors manifests in order to optimize therapeutic strategies to target this patient population. We have previously described elacestrant (RAD1901), a novel and orally bioavailable SERD, as an inhibitor of ER+ breast cancer growth in in vitro models and in in vivo patient-derived xenograft (PDX) models. Importantly, elacestrant inhibited the growth of PDX models that were derived from heavily pretreated patients, models harboring mutations in ESR1, and models insensitive to standard of care endocrine therapies. Given these results, we hypothesized that elacestrant would have anti-tumor activity in a CDK4/6 inhibitor-resistant setting. Herein, we describe elacestrant activity in multiple in vitro and in vivo models of CDK4/6 inhibitor resistance in both wild-type and mutant ESR1 backgrounds. Methods: In vitro models of estrogen-independent ER+ breast cancer, harboring either wild-type or mutant ER, were exposed to increasing concentrations of approved CDK4/6 inhibitors: palbociclib, ribociclib, or abemaciclib. ER expression/signaling, changes in cell cycle mediators, and the effects of elacestrant and other SERDs were examined in these representative models. Results: Despite prolonged exposure to CDK4/6 inhibitors, the resistant cell lines retained ER, ER signaling, and importantly, ER-driven proliferation. Elacestrant induced dose-dependent growth inhibition in CDK4/6 inhibitor-resistant cells, and this effect was independent of the CDK4/6 inhibitor used to generate resistance. Elacestrant also demonstrated in vivo tumor growth inhibition of CDK4/6 inhibitor-resistant ER+ PDX models. Conclusions: Our preclinical data demonstrate that elacestrant is a SERD that can inhibit tumor growth in a CDK4/6 inhibitor-resistant setting and provides rationale for examining elacestrant in patients that have progressed on a combination of endocrine therapy with a CDK4/6 inhibitor. Citation Format: Patel H, Tao N, Arlt H, Bihani T. Elacestrant (RAD1901) demonstrates anti-tumor activity in models resistant to CDK4/6 inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-03.