Abstract P4-13-02: Selective androgen receptor modulator RAD140 inhibits the growth of endocrine-resistant breast cancer models with defined genetic backgrounds
Authors: Yu Z , He S , Miller C , Saeh J , Hattersley G , O'Neill A 
Published: May 2019

Abstract
Estrogen receptor α-positive (ER+) breast cancer is routinely treated with therapies targeting the ER axis. However, de novo and acquired resistance to the standard-of-care treatment occur in a significant subset of patients. Multiple mechanisms have been proposed for the resistance, among which genetic alterations to the coding gene of ERα, ESR1, have been extensively studied. Notably, ESR1 hotspot mutations within the ligand binding domain (LBD), novel fusion proteins consisting of the N-terminal domain of ER and the C-terminal domain of a partner gene, and ESR1 gene amplification have been found to be enriched in endocrine-resistant, metastatic breast cancers. Together these ER gene alterations present new challenges in the management of ER+ breast cancer and call for the development of new agents to supplement the current standard-of-care. Around 90% of the ER+ breast cancer cases are also androgen receptor (AR) positive (AR+). Mounting preclinical evidence has demonstrated that AR agonists suppress AR and ER positive (AR/ER+) breast cancer cell growth, in line with clinical activity of androgens. We recently reported the oral selective androgen receptor modulator (SARM) RAD140 is a potent, tissue-selective AR agonist in breast cancer cells which significantly inhibited the growth of AR/ER+ patient-derived xenograft (PDX) models, partly via inhibiting ESR1 gene expression and ER signaling. It also elicited enhanced tumor growth inhibition when combined with a CDK4/6 inhibitor.
Here we further examine the activity of RAD140 in AR/ER+ breast cancer models that are endocrine-independent with a spectrum of ESR1 genetic alterations. In PDX models harboring ESR1 amplification or fusion, RAD140 inhibited tumor growth to a greater degree than fulvestrant, a standard-of-care selective ER degrader (SERD). These results are consistent with the clinical history of the donor patients whose diseases relapsed from or progressed rapidly on fulvestrant. In PDX models with ESR1 Y537S mutation, RAD140 showed anti-tumor activity comparable to that of fulvestrant. Notably, RAD140 treatment also led to substantial reduction of proliferation and colony formation in cell line models recapitulating resistance to the combination of estrogen deprivation and CDK4/6 inhibition.
In summary, RAD140 showed marked anti-tumor activity in AR/ER+, endocrine-resistant breast cancer models with defined genetic background. Importantly, in models with ESR1 amplification and fusion, the AR-targeting RAD140 exhibited more profound inhibitory activity compared with fulvestrant. In models with an ESR1 mutation, the efficacy of RAD140 and fulvestrant was comparable. These results lend support to a clinical hypothesis that AR/ER+, endocrine-resistant tumors with these genetic backgrounds may benefit from AR agonist-based treatment. RAD140 is currently being evaluated in hormone receptor positive (HR+) breast cancer patients (NCT03088527).
Citation Format: Yu Z, He S, Miller C, Saeh J, Hattersley G, O'Neill A. Selective androgen receptor modulator RAD140 inhibits the growth of endocrine-resistant breast cancer models with defined genetic backgrounds [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-02.