Abstract P3-04-22: RAD1901 demonstrates anti-tumor activity in multiple models of ER-positive breast cancer treatment resistance

Abstract

Abstract Estrogen receptor positive (ER+) breast cancer makes up approximately 70% of all newly diagnosed breast cancers and ER remains the single most useful predictive and prognostic marker for these patients. In fact, dependence on ER signaling is retained in recurrent disease and even in disease treated with multiple lines of anti-endocrine agents. Indeed, inhibiting estrogen synthesis (e.g. with aromatase inhibitors) and modulating ER pathway activity (e.g. with tamoxifen) continue to be mainstays in the standard of care for ER+ breast cancer patients both in adjuvant and metastatic setting. While patients initially respond well to these agents, a majority of patients with metastatic disease will relapse. Therefore, it is critical to improve our understanding and model the specific mechanisms that can lead to treatment resistance. Mutations in the ligand binding domain of ESR1 have been described as a mechanism that contributes to clinical resistance to aromatase inhibitors. In addition, some ESR1 mutations can lead to a conformational change of the receptor, leading to decreased binding of tamoxifen, thereby reducing its activity. Recently, selective estrogen receptor degraders, or SERDs, have gained widespread attention as a novel treatment strategy for ER+ disease. Indeed, fulvestrant has been shown to degrade ER and cause tumor growth inhibition in many ER+ breast cancer models. However, in the clinic, fulvestrant appears to be limited by PK exposure properties and this, combined with its intramuscular route of administration underscore the need for an oral SERD with improved PK properties. Recently, we have described RAD1901, a novel, orally available, non-steroidal small molecule SERD that is able to degrade ER and effectively cause tumor growth inhibition in multiple patient-derived xenograft models (PDX) models, including two that harbor a Y537S mutation in ESR1. To further validate that RAD1901 has the potential to be used in the advanced disease setting, we tested its anti-tumor activity in preclinical models representing the most common ESR1 mutations (D538G, E380Q, S463P, Y537N/C). In addition, we have tested RAD1901 in multiple cell line models of anti-endocrine resistance. These include long-term estrogen deprived cells that model progression of disease on aromatase inhibitors, as well as tamoxifen-resistant models. Here, we present anti-tumor activity of RAD1901 both as a single agent and as part of rational clinical combinations (eg. CDK4/6, PI3K/Akt/mTOR inhibitors) in multiple models of anti-endocrine resistance. These results combined with previous studies demonstrating RAD1901 efficacy in treatment naïve models provide strong preclinical evidence for clinical testing of RAD1901 in both adjuvant and metastatic setting. RAD1901 is currently under clinical investigation for the treatment of ER+ breast cancers in post-menopausal women (NCT02650817, NCT02338349). Citation Format: Bihani T, Arlt H, Brechbuhl H, Patel H, Tao N, Purandare DM, Hattersley G, Kabos P, Garner F. RAD1901 demonstrates anti-tumor activity in multiple models of ER-positive breast cancer treatment resistance [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 P3-04-22.