Authors: Nan Hyung Hong, Paul Pearson, Veronique Lauriault, Peter Virsik, Alessandra Cesano, Han-Jie Zhou, Ronan Le Moigne Affiliations: ESSA Pharmaceuticals, Houston, TX, USA Abstract Body: "Androgen receptor (AR) signaling remains an important driver even in late stage prostate cancer. While current anti-androgen therapies targeting the ligand binding domain (LBD) are effective, resistance to these therapies ultimately develops, and new methods of inhibiting the AR pathway are needed. Selectively targeting the N-terminal domain (NTD) of AR represents a novel method of blocking AR signaling by inhibiting AR essential transactivation domain. EPI-7386 is a potent NTD inhibitor (Aniten) which has demonstrated in vitro activity in cells expressing full-length AR (AR-FL), with an IC50 ~ 400 nM on inhibiting AR driven genes. Importantly, EPI-7386 targets the AR-FL and AR splice variants which are resistant to currently approved antiandrogens such as 2nd generation antiandrogens (enzalutamide, apalutamide and darolutamide) and has a selective anti-proliferative activity against both AR-FL and AR-V7 driven cell lines. A Phase 1 clinical trial of EPI-7386 in mCRPC patients failing standard of care therapies is underway and its non-clinical efficacy, selectivity, and safety profile are presented. We confirmed AR-FL target engagement by EPI-7386 in LNCaP cells, which occurs independently of AR activation status by Cellular Thermal Shift Assay (CETSA). In AR-V7 expressing LNCaP95 cells, EPI-7386 showed superior activity to enzalutamide by inhibiting both AR-FL and AR-V7 regulated genes. Transcriptomic analysis demonstrated that EPI-7386 suppresses AR-associated gene expression in a manner similar to lutamides but with a few notable differences, suggesting the possibility of a more robust and thorough inhibition of the AR pathway with combination treatment. Indeed, the combination of EPI-7386 with lutamides resulted in broader and deeper inhibition of AR-associated transcriptional activity in both LNCaP and VCaP cells. These observations translated in vivo to significant inhibition of tumor growth in AR-driven resistant animal models in which enzalutamide showed no activity, and confirmed the advantage of combining EPI-7386 with a LBD inhibitor. In IND-enabling toxicity studies in rats and dogs EPI-7386 was well tolerated at exposures several folds higher than efficacious doses in animal xenograft models. PK simulations predicted that tolerated and efficacious doses can be achieved during the phase 1 dose escalation. In conclusion, EPI-7386 is a potent inhibitor of AR pathway that has the capacity to overcome resistance to current anti-androgen therapies by uniquely inhibiting AR-mediated signaling. The agent has the potential of providing clinical benefit as a single agent in patients whose tumors are progressing on anti-androgens or in combination with current anti-androgens in earlier line patients. The Phase I dose escalation first in human clinical trial of EPI-7386 single agent (NCT04421222) is currently enrolling." Funding Acknowledgments: All work was supported by ESSA Pharma Corresponding Author Email: firstname.lastname@example.org Conflict of Interest: I am shareholder and employee of ESSA Pharma
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