Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action.

Abstract

<b>Purpose:</b> Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER⁺) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in <i>in vivo</i> and <i>in vitro</i> models of AR/ER⁺ breast cancer.<b>Experimental Design:</b> A series of <i>in vitro</i> assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER⁺ breast cancer xenograft models.<b>Results:</b> RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER⁺ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the <i>ESR1</i> gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER⁺ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.<b>Conclusions:</b> RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of <i>ESR1</i> It inhibits the growth of multiple AR/ER⁺ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER⁺ breast cancer patients. <i>Clin Cancer Res; 23(24); 7608-20. ©2017 AACR</i>.