Abstract 3452: Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859

Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in ER that drive a constitutively active receptor. SAR439859 is a novel next generation SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity against ER both wild type and mutant and currently evaluated as a single agent and in combination with palbociclib in a Phase I/II clinical trial (NCT03284957). Here we describe the preclinical development of this molecule in multiple xenografts and demonstrated significant anti-tumor efficacy/regression in ER+ BC models including MCF7-ESR1 mutant-Y537S and endocrine therapy resistant patient-derived xenograft tumor models. The molecule also demonstrated strong synergistic activity with CDK4 inhibitor palbociclib. SAR439859 has a favorable safe profile and no uterotrophic activities. Collectively, these results show that SAR439859 is an oral, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. In conclusion, SAR439859 demonstrates broad anti-tumor activity in ER+ breast cancer cell line/PDX models. Anti-tumor efficacy correlates with PK exposure/PD modulation in target tissue. SAR439859 also has synergistic activity with CDK4 inhibitor Palbociclib. Citation Format: Fangxian Sun, Jane Cheng, Amy Sullivan, Natalia Malkova, Maysoun Shomali, Jesseca McManus, Mikhail Levit, Dinesh Bangari, Youssef El-Ahmad, Sukhvinder Sidhu, Laurent Debussche, Monsif Bouaboula. Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3452.