545P Preclinical profile of EPI-7386, a second-generation N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer

Abstract

Disease progression in metastatic castration-resistant prostate cancer (mCRPC) patients largely remains androgen receptor (AR) dependent. Resistance inevitably arises to current anti-androgens through numerous ligand binding domain (LBD)-associated mechanisms. EPI-7386 is a second-generation aniten which inhibits AR transcriptional activity by binding to the AR N-terminal domain (NTD), thus bypassing these resistance mechanisms. A phase I trial in patients with anti-androgen resistant mCRPC is currently being initiated. The preclinical anti-tumor and safety profile of EPI-7386 will be presented. EPI-7386 potency and selectivity was assessed using reporter and viability assays in cellular models. Pharmacodynamic markers were measured by qPCR, NanoString and RNAseq. The pre-clinical safety profile was assessed both in in vitro assays and in rat and dog toxicology studies. EPI-7386 has an IC50 of 421 nM in LNCaP reporter assays, it inhibited both AR full-length and AR-V7 dependent gene expression and maintained antitumor activity in AR-V7-expressing tumor models, including in in vivo models resistant to enzalutamide (ENZ). Transcriptomic analysis of EPI-7386 revealed on-target anti-AR activity, with a profile overlapping but distinct from ENZ, while the combination of the two agents demonstrated broader and deeper AR pathway inhibition. IND-enabling studies in rats and dogs showed on-target activity with good tolerability at drug exposures several fold higher than those active in tumor xenograft models. PK simulations suggest predicted tolerated and active doses can be achieved during the phase I dose escalation. EPI-7386, a second-generation aniten, is a potent AR NTD inhibitor, with a favorable safety and ADME profile, good pharmaceutical characteristics, and a long predicted human half-life supporting once-daily oral dosing with tablets. In vivo, EPI-7386 demonstrated anti-tumor activity as a single agent in the setting of anti-androgen clinical resistance and enhanced efficacy in combination therapy. A phase I study is scheduled to begin Q2 2020.