Abstract 5775: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models
Authors: Shomali Maysoun , El-Ahmad Youssef , Halley Frank , Cheng Jane , Weinstein Michael , Wang Muchun , Sun Fangxian , Malkova Natalia , Levit Mikhail , Koundinya Malvika , Gou Zhuyan , Hebert Andrew , McManus Jessica , Hoffman Dietmar , Cao Hui , Jung Joonil , Pollard Jack , Vincent Sylvie , Ackerson Timothy , Adrian Francisco , Winter Chris , Richon Victoria , Chen Hong , Hsu Karl , Lager Joanne , Courjaud Albane , Arrebola Rosalia , Besret Laurent , Abecassis Pierre-Yves , Schio Laurent , McCort Gary , Tabart Michel , Certal Victor , Thompson Fabienne , Filoche-Rommé Bruno , Debussche Laurent , Cohen Patrick , Garcia-Echeverria Carlos , Bouaboula Monsif 
Published: August 2018

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 the ER that drive a constitutively active receptor. Fulvestrant, an estrogen receptor degrader, is effective at shutting down ER signaling. However, fulvestrant efficacy studies report insufficient blockade of ER signaling in patients that may be a consequence of poor pharmaceutical properties.

Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradative properties against ER both in vitro and in vivo. SAR439859 has robust inhibition of ER signaling activity in multiple ER+ breast cancer cell lines including tamoxifen resistant lines harboring ER mutations. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity as compared to other SERDs including improved inhibition of ER signaling and inhibition of cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ BC models including MCF7-ESR1 mutant-Y537S model and endocrine therapy resistant patient-derived xenograft tumor transplantation.

Collectively, these results showed that SAR439859 is an oral, nonsteroidal, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. SAR439859 is currently being evaluated in a phase I clinical trial.

Citation Format: Maysoun Shomali, Youssef El-Ahmad, Frank Halley, Jane Cheng, Michael Weinstein, Muchun Wang, Fangxian Sun, Natalia Malkova, Mikhail Levit, Malvika Koundinya, Zhuyan Gou, Andrew Hebert, Jessica McManus, Dietmar Hoffman, Hui Cao, Joonil Jung, Jack Pollard, Sylvie Vincent, Timothy Ackerson, Francisco Adrian, Chris Winter, Victoria Richon, Hong Chen, Karl Hsu, Joanne Lager, Albane Courjaud, Rosalia Arrebola, Laurent Besret, Pierre-Yves Abecassis, Laurent Schio, Gary McCort, Michel Tabart, Victor Certal, Fabienne Thompson, Bruno Filoche-Rommé, Laurent Debussche, Patrick Cohen, Carlos Garcia-Echeverria, Monsif Bouaboula. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5775.