Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor

Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease and resistance to ligand binding domain (LBD)-linked therapies inevitably emerges. Mechanisms of resistance to anti-androgens include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (e.g. AR-V7). Inhibition of the N-terminal domain (NTD) of the AR can inhibit transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in anti-androgen refractory mCRPC patients, revealing the need for more potent and metabolically stable NTD inhibitors. EPI-7386 represents a second generation of NTD inhibitors (Anitens) that are more active and more metabolically stable than EPI-506. Methods: Chemical structure activity relationships were explored to increase molecule potency while maintaining target specificity using a wide variety of CRPC models in vivo and in vitro. The stability and selectivity of the molecules were characterized with a panel of selective screening and functional assays. The mechanism of action and pathway engagement markers were followed by qPCR and RNAseq. Results: EPI-7386 was chosen as the IND candidate. The molecule demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity demonstrated in AR-V7-driven cellular models. The antiproliferative effect correlated with the inhibitory effect on AR driven genes, including specifically AR-V7 driven genes such as UBE2C. EPI-7386 controlled tumor growth and induced tumor regressions in several CRPC xenografts, including AR-V7-driven 22Rv1 and enzalutamide resistant LNCaP95 models, as well as the VCaP model. Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model. EPI-7386 was well tolerated in animal models, and therapeutic levels could be achieved without displaying signs of toxicity in a 14-day rat study. Pharmacodynamic markers will be presented, in addition to their incorporation in the future clinical plan. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It shows on-target activity in AR full length and AR-V7 driven models, and demonstrates a high therapeutic index in preclinical models. As a single agent, EPI-7386 may overcome anti-androgen clinical resistance in advanced mCRPC as well as potentially in combination therapy with anti-androgens in earlier stages of the disease. The clinical strategy supporting the development of this Aniten N-terminal domain inhibitor of AR will be discussed. Citation Format: Ronan Le Moigne, C. Adriana Banuelos, Nasrin R Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J Andersen, Alessandra Cesano, Marianne D Sadar, Han-Jie Zhou, Peter Virsik. Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B117. doi:10.1158/1535-7163.TARG-19-B117