Abstract P3-04-05: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models

Abstract

Estrogen receptor positive (ER+) breast cancer accounts for 70% of all breast cancers and is primarily treated with endocrine therapy. Approximately 40% of patients on endocrine therapy will become resistant via a number of mechanisms. There is evidence that in many cases ER continues to play a central role, including mutations in ER leading to a constitutively active receptor. Estrogen receptor degraders like fulvestrant are effective in shutting down ER signaling; however, poor pharmaceutical properties limit fulvestrant clinical activity and prevent it from achieving maximum receptor blockade. We describe the discovery of SAR439859, a novel, orally bioavailable SERD that is a potent antagonist and degrader of ER both in vitro and in vivo. SAR439859 has robust activity in multiple ER+ breast cancer cell lines including cells that are resistant to tamoxifen as well as cell lines harboring ER mutants. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity than most SERDs undergoing clinical testing. This leads to a profound inhibition of ER signaling, better inhibition of cell growth and results in improved in vivo efficacy. SAR439859 demonstrated tumor regression in all ER+ BC models including MCF7-ESR1 mutant-Y537S model, as well as patient-derived xenograft model that is resistant to endocrine therapies. Furthermore, SAR439859 displays limited cross-resistance with other class of SERDs. Taken together, these results suggest that SAR439859 would be of therapeutic benefit in metastatic BC setting for patients harboring wild type or mutant ER. SAR439859 is being advanced toward the clinic. Citation Format: Shomali M, Cheng J, Koundinya M, Weinstein M, Malkova N, Sun F, Hebert A, Cindachao M, Hoffman D, McManus J, Levit M, Pollard J, Vincent S, Besret L, Adrian F, Winter C, El-Ahmad Y, Halley F, Hsu K, Lager J, Garcia-Echeverria C, Bouaboula M. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-05.

G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

“…For decades, estrogen has been recognized to be the major driver of ER-positive breast cancers through the activation of ERα [ 9 ]. This has led to FDA approval of several ERα-targeting drugs, such as tamoxifen and fulvestrant, and the development of various next-generation ERα-targeting antagonists in various stages of clinical development [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

“…However, its clinical efficacy is limited by poor solubility and oral bioavailability (Wardell et al, 2013a; van Kruchten et al, 2015). Consequently, new complete antiestrogens are being examined for their activities in breast cancers harboring Y537S and D538G ERα that all demonstrate improved oral bioavailability and pharmacokinetics, including G1T48, AZD9496, GDC-0927, RAD1901, SAR439859, and LSZ102 (Wardell et al, 2017; De Savi et al, 2015; Weir et al, 2016; Toy et al, 2017; Dickler et al, 2018; Wardell et al, 2015b; Bihani et al, 2017; Tria et al, 2018; Shomali et al, 2017). Other non-traditional ERα degraders including H3B 6545, which covalently binds to the ERα LBD, and an ER PROTAC from Arvinas are currently in development.…”

Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader

“…In nude mice bearing the ERαpositive MCF-Y537S tumor model, a single oral administration of SAR439859 over 2.5-25 mg/kg dose range induced a dose-dependent intra-tumoral degradation of ERα. At 12.5 mg/kg, SAR439859 decreased ERα by 90% for at least 8 h [9]. In vivo efficacy data obtained against MCF7-Y537S demonstrated that the tumor growth inhibition induced by SAR439859 was correlated with ERα intra-tumoral degradation.…”

“…Dose range was chosen considering in vivo antitumor activity observed at 12.5 mg/kg bi-daily (bid) with caliper measurements. FES-PET imaging was performed 4 h post-treatment, a time at which the maximum of ERα degradation was previously documented by western blot measures [9].…”

“…SAR439859 not only antagonizes the binding of estradiol to ER but also promotes the transition of ERα to an inactive conformation that leads to as up to 98% receptor degradation at nanomolar concentrations in cellular assays. These dual properties of SAR439859 translate in a robust inhibition of ERα pathways and a more effective anti-proliferative activity in ERα-dependent breast cancer cell lines driven by mutant or wild-type ERα compared to other ERα inhibitors [9]. SAR439859 induces ERα degradation and inhibits in a dose-dependent manner the cell proliferation of MCF7 cells harboring wildtype ERα or mutant ERα.…”