Advancements in Prostate Cancer Therapy: The EPI-7386 AR NTD Inhibitor

The androgen receptor (AR) pathway is crucial for the progression of metastatic castration-resistant prostate cancer (mCRPC). Resistance to anti-androgen therapies can occur through various mechanisms, such as AR gene amplification, mutations in the ligand-binding domain, and the presence of constitutively-active AR splice variants like AR-V7. A new approach involves inhibiting the N-terminal domain (NTD) of AR, which can suppress its transcriptional activity despite resistance caused by the ligand-binding domain. The first-generation NTD inhibitor, EPI-506, showed modest effects in a Phase I clinical trial for mCRPC patients.

EPI-7386, a more potent and stable AR NTD inhibitor, is currently in development for clinical trials. It was designed to enhance potency and stability, characterized through in vivo and in vitro CRPC models and assays. EPI-7386 showed a significant increase in potency against AR-driven cells and was effective even in AR-V7-driven models. It was capable of controlling tumor growth and inducing regressions in CRPC xenografts, including those resistant to enzalutamide. The combination of enzalutamide with EPI-7386 resulted in a more pronounced antitumor response.

EPI-7386 has demonstrated its potential as a single agent to overcome clinical resistance to anti-androgens and as part of combination therapy in earlier stages of the disease. The clinical development strategy for this new generation of AR NTD inhibitors will be discussed. The study was conducted by ESSA Pharmaceuticals, with funding and disclosures provided by the company and its employees. Other authors have no conflicts of interest to declare.