AUA 2016: Galeterone shows anti-tumor activity in multiple pre-clinical models that express androgen receptor splice variants, supporting correlative patient data seen in ARMOR2 - Session Highlights

San Diego, CA USA ( An interesting podium presentation in today’s Prostate Cancer: Advanced (including Drug Therapy) III session at the AUA 2016 demonstrates that Galeterone shows anti-tumor activity in multiple pre-clinical models that express androgen receptor splice variants. Dr V. Njarreminded said Galeterone is a selective, multi-targeted, small molecule that enhances androgen receptor (AR) degradation, inhibits androgen biosynthesis, and antagonizes androgen binding to the AR thus disrupting androgen signaling at multiple points in the pathway.

Furthermore, AR splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the ligand binding domain, and has been implicated in castration resistant prostate cancer (CRPC) progression and resistance to abiraterone and enzalutamide.

AR-V7 expression is found in approximately 11-26% of metastatic CRPC (mCRPC) patients prior to treatment with second-generation anti-androgens or chemotherapy. In their previous study the authors used multiple experimental approaches to examine the mechanism by which Galeterone inhibits the growth of prostate cancer cells or tumors expressing AR splice variants, such as AR-V7. The effects of Galeterone on prostate tumor cell signaling and growth were evaluated by the reductions in AR protein levels, in vitro measures of AR-dependent gene expression and tumor cell viability. Furthermore, the in vivo efficacy of Galeterone in mouse xenograft models were monitored and the PSA responses in patients whose CTCs express truncated AR were measured. The authors found that Galeterone attenuates tumor cell proliferation, AR signaling and xenograft tumor growth using cells and tumors that express AR splice variants. Interestingly, Galeterone treatment also causes dose-dependent reductions in AR protein including the AR splice variant protein. These results may explain the PSA responses seen clinically with Galeterone treatment in men with mCRPC whose tumors contain truncated AR.

The authors conclude that Galeterone has a unique mechanism of AR protein downregulation that occurs in both splice variant and full-length AR, supporting the hypothesis that Galeterone-induced AR downregulation is independent of the AR ligand binding domain. Finally the authors described the ARMOR3-SV trial where patients were randomized to enzalutamide and galeterone. Results are anticipated in the near future.


Presented By: V. Njarreminded, MD

Written By: Miki Haifler MD. Fox Chase Cancer Center, Philadelphia, PA. at the 2016 AUA Annual Meeting - May 6 - 10, 2016 – San Diego, California, USA