Abstract 5776: Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft models

Abstract

Abstract Breast cancer is the most common form of cancer in women in the developed world, with estrogen receptor-positive (ER+) breast cancer accounting for 70-80% of all breast cancers. Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of ER+ breast cancer patients, either alone or in combination with CDK4/6 inhibitor (palbociclib or abemaciclib). However, due to poor pharmacokinetic property, fulvestrant has to be given via intramuscular injection. In addition, patients relapsed after prolonged endocrine therapy with aromatase inhibitors such as letrozole and anastrozole due to emergence of ER mutations. Here, we report the discovery of D-0502, an orally bioavailable SERD with potent activity in various ER+ breast cancer cell lines and xenograft models. In addition, combination of our SERD candidates and palbociclib in both MCF-7 xenograft model and ESR-1 mutated (Y537S) patient-derived breast cancer xenograft model resulted in further tumor growth inhibition or regression. Comparison of various SERD molecules showed our candidate has more potent antitumor activity in MCF-7 xenograft model than GDC-0810, AZD9496 and fulvestrant. More importantly, drug metabolism and pharmacokinetic (PK) studies both in vitro and in vivo demonstrated that our SERD molecule D-0502 exhibits superior PK profiles suitable for clinical development. Citation Format: Yaolin Wang, Zhe Shi, Yueheng Jiang, Xing Dai. Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft 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 5776.