Abstract 3608: RAD140, an orally available selective androgen receptor modulator, inhibits the growth of AR/ER positive breast cancer cell line- and patient-derived xenograft models

Abstract

Abstract Breast cancer is the most frequently diagnosed malignancy for women in the US with 246,660 new cases predicted in 2016. Histological and molecular characterization of breast cancer has led to improved understanding of the heterogeneity of this disease and development of therapeutic modalities tailored for each disease subtype. Hormone receptor positive breast cancers, which represent 75% of breast cancer cases, are routinely treated with therapies targeting the estrogen receptor (ER) axis, including aromatase inhibitors or anti-estrogens, either alone or in combination with other agents. Recent studies have shown that the androgen receptor (AR) is widely expressed across all subtypes of breast cancer, with AR detected in 75-95% of ER positive tumors. Mounting preclinical evidence from has demonstrated that AR agonists can suppress AR and ER positive (AR/ER+) breast cancer cell growth. Furthermore, prior to the development of ER-targeted therapy, androgens were used to treat breast cancers with favorable clinical responses. RAD140 is an oral, nonsteroidal, nonaromatizable selective androgen receptor modulator (SARM) with a distinct tissue selectivity profile and mechanism of action. Here we examined the molecular activity of RAD140 in breast cancer cells and evaluated its efficacy using AR/ER+ breast cancer xenograft models. The tissue-specific activity of RAD140 was examined using androgen response element (ARE)-driven reporter assay in AR/ER+ ZR75 breast cancer cells and AR+ LNCaP prostate cancer cells. RAD140 was shown to be a potent AR agonist, comparable to dihydrotestosterone (DHT), in breast cancer cells, but did not induce AR activity in prostate cancer cells, while DHT demonstrated full AR agonist activity. In vivo anti-tumor efficacy of RAD140 as monotherapy, compared with fulvestrant, or in combination with a CDK4/6 inhibitor (palbociclib) or mTOR inhibitor (everolimus) was evaluated in AR/ER+ patient derived xenograft (PDX) models and cell line-derived xenograft (CDX) models. Tumor-bearing mice were randomized into treatment groups and received vehicle, RAD140, fulvestrant, palbociclib, everolimus or combinations of RAD140 with palbociclib or everolimus. Tumor volume and growth was measured to evaluate efficacy. At the end of the study, plasma and tumor samples were collected for pharmacokinetic and pharmacodynamic analysis. In AR/ER+ breast cancer PDX models, RAD140 treatment led to substantial tumor growth inhibition that was greater than that seen with fulvestrant. Furthermore, combination of RAD140 with palbociclib or everolimus produced further enhanced anti-tumor efficacy in these models. In summary, RAD140 demonstrated tissue-selective AR agonism with marked anti-tumor activity in AR/ER+ breast cancer CDX and PDX models, together with enhanced anti-tumor activity in combination with a CDK4/6 inhibitor or mTOR inhibitor. Citation Format: Ziyang Yu, Suqin He, Jeffrey Brown, Chris Miller, Jamal Saeh, Gary Hattersley. RAD140, an orally available selective androgen receptor modulator, inhibits the growth of AR/ER positive breast cancer cell line- and patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3608. doi:10.1158/1538-7445.AM2017-3608