LAUSR

Antiestrogens are widely used to treat ER+, HER2- breast cancer however these may produce estrogen-like agonist effects in a cell and gene-specific manner. Furthermore, this partial agonism has been implicated in the development of tumor resistance. In contrast, a complete ER antagonist lacks agonist activity in all tissues. Given the high risk of recurrence in ER+ patients treated with endocrine therapies, we hypothesize that drugs that completely antagonize ER-mediated signaling will have a clinical advantage in treating resistant tumors, particularly in tumors for which the ER has acquired mutations conferring estrogen-independent growth. We previously identified OP-1250 in our laboratory as a complete antagonist and degrader of wild type and mutant ERalpha in breast and uterus cells. Here we explore the pharmacokinetic properties of orally administered OP-1250 and its ability to shrink breast tumors from xenograft models expressing both wild type and mutant estrogen receptors. Orally administered OP-1250 produced high and stable levels in multiple species, suggesting that once daily dosing may be sufficient to produce excellent drug exposure in patients. OP-1250 shrank ER+ tumors in multiple patient-derived tumor xenografts in mice at daily doses of 3 mg/kg, including in tumors expressing the Y537S allele of ERalpha that confers estrogen-independent growth and tumor resistance. Furthermore, OP-1250 accumulated within tumor specimens, indicating excellent target penetration was achieved with low daily doses. These preclinical studies indicate that OP-1250 has the potential to be a best-in-class antiestrogen due to its ability to complete antagonize ER, potent efficacy in shrinking tumors, and robust drug exposure. A Phase 1/2 dose escalation and expansion study in patients with ER+, HER2- metastatic or advanced BC previously treated with an endocrine therapy will be initiated this year. Citation Format: Leslie Hodges-Gallagher, Richard Sun, David C Myles, Pamela M Klein, Jo Anne Zujewski, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 shrinks tumors in xenograft models and has favorable preclinical pharmacokinetic attributes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-16.