Preclinical Characterization Of Zen-3694, A Novel Bet Bromodomain Inhibitor Entering Phase I Studies For Metastatic Castration-Resistant Prostate Cancer (Mcrpc)

Metastatic castration resistant prostate cancer (mCRPC) is a major unmet medical need due to its widespread occurrence and incurable status. Current standard of care for advanced prostate cancer is androgen-deprivation therapy (ADT), and upon failure, patients are administered secondary ADT with androgen receptor (AR) antagonists such as enzalutamide and abiraterone. While most patients display an initial response to these agents, eventually all become resistant via various mechanisms that often result in constitutive AR signaling including mutations of the AR, and the generation of AR splice variants that bypass the ligand binding domain. Other mechanisms of resistance to AR antagonists include up-regulation of the glucocorticoid receptor (GR), and partial to complete loss of AR signaling through neuroendocrine differentiation. Recent evidence suggests that BET bromodomain inhibitors (BETi) could be efficacious in AR-signaling positive or negative mCRPC that are resistant to current therapies. ZEN-3694 is an orally bioavailable, potent BETi that selectively binds to both bromodomains of the BET proteins. In vitro, ZEN-3694 has demonstrated strong activity against several prostate cancer cell lines with submicromolar potency, including AR positive and AR negative, neuroendocrine, and enzalutamide resistant cell lines. In VCaP AR-positive prostate cancer cells, ZEN-3694 inhibited proliferation synergistically with enzalutamide, resulting in potent up-regulation of the CDKN1C/KIP2 tumor suppressor gene. In 22Rv1 cells displaying constitutive AR signaling through the AR-V7 splice variant, ZEN-3694 inhibited AR signaling, and in an in vitro LNCaP model of acquired resistance to enzalutamide characterized by GR up-regulation, ZEN-3694 decreased levels of GR in a dose-dependent manner. Furthermore, in the PC3 AR-null cell line, the expression of a subset of NF-KB-dependent genes reported to be involved in mCRPC bone metastasis was found to be inhibited by ZEN-3694. In vivo, using multiple prostate cancer cell line xenografts such as 22Rv1, and VCaP, ZEN-3694 showed efficacy in inhibiting tumor progression at well-tolerated doses, and modulating target gene expression. ZEN-3694 also inhibited progression of a patient-derived xenograft (PDX) LuCaP 35CR that is resistant to enzalutamide. In summary, our results indicate that ZEN-3694 demonstrates potent activity in advanced metastatic prostate cancer targeting multiple mechanisms of enzalutamide resistance in CRPC, including AR-V7 signaling and GR up-regulation in different preclinical models. This together supports the clinical development of ZEN-3694 as a single agent, and in combination with enzalutamide in mCRPC patients that have failed first line ADT. We are implementing a robust translational medicine program in the phase 1 study to measure target engagement and explore mechanisms of enzalutamide resistance and sensitivity to ZEN-3694 in patients. Citation Format: Sarah Attwell, Ravi Jahagirdar, Karen Norek, Cyrus Calosing, Laura Tsujikawa, Olesya A. Kharenko, Reena G. Patel, Emily M. Gesner, Eva Corey, Holly M. Nguyen, Sanjay Lakhotia, Henrik C. Hansen, Eric Campeau. Preclinical characterization of ZEN-3694, a novel BET bromodomain inhibitor entering phase I studies for metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-207.