Abstract
Abstract Background: The vast majority of metastatic castration-resistant prostate cancers (mCRPC) progress with rising prostate-specific antigen, underlying a persistent dependence on the androgen receptor (AR) pathway. Despite standard of care treatment targeting the AR axis, anti-androgen resistance inevitably arise and involve mechanisms including AR gene amplification, ligand-binding domain (LBD) mutations and expression of constitutively active AR splice variants lacking the LBD (e.g. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its transcriptional activity even in the presence of LBD-driven resistance. EPI-7386 is a potent and stable second generation NTD inhibitor (Aniten) currently in preclinical development. The efficacy, safety profile and distinct mechanism of action of this molecule in LBD inhibitor resistant CRPC models will be presented. Methods: EPI-7386 potency was assessed using reporter cellular models, or viability assays in a variety of cell lines, expressing or not the AR. Pharmacodynamic markers of activity in AR full length or AR-V7 driven models was determined by qPCR or RNAseq. The stability and selectivity of the molecule were characterized with screening and functional assays, while safety was assessed in specific IND enabling studies. Results: EPI-7386 has an IC50 of 421 nM in LNCaP reporter assays, a similar range to the most active LBD inhibitors, but contrary to these drugs, antitumor activity was maintained in models of CRPC expressing AR-V7. As expected, no activity was observed in non-AR driven models. EPI-7386 can inhibit effectively the expression of AR full length driven genes (PSA, FKBP5 or STEAP4), but can also modulate the expression of genes driven by AR V7, including UBE2C or B4GALT1. Additionally, EPI-7386 also demonstrated remarkable activity in several models in vivo, including a CRPC patient derived xenograft (PDX) resistant to enzalutamide (ENZ). Interestingly, RNAseq analysis showed on target activity, but with a different transcriptomic profile than ENZ, which suggests that the combination of both LBD and NTD AR inhibition could provide more robust and thorough inhibition of the AR-pathway. The enhanced activity of such combination was confirmed in vivo in the CRPC model VCaP. IND-enabling studies demonstrated on target activity, and well-tolerated profile for EPI-7386, supporting an IND filing in 1Q 2020. Early clinical development plans including efficacy endpoints will be presented. Conclusions: The second generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It has a favorable safety and ADME profile, with predicted long half-life in human, supporting once daily dose. In vivo, EPI-7386 demonstrated potential as a single agent in overcoming anti-androgen clinical resistance as well as in combination therapy. The clinical strategy supporting the development of this new generation of aniten will be discussed. Citation Format: Nan Hyung Hong, Ronan Le Moigne, C. Adriana Banuelos, Nasrin R. Mawji, Teresa Tam, Jun Wang, Raymond J. Andersen, Alessandra Cesano, Marianne D. Sadar, Han-Jie Zhou, Peter Virsik. Pre-clinical development of the second-generation N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1953.
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