EAU 2017: Targeting enzalutamide-resistant prostate cancer using the novel androgen receptor inhibitor ODM-201

London, England (UroToday.com) The androgen receptor (AR) plays a key role in the treatment of prostate cancer and its lethal castration-resistant form. Treatment with first line treatment approved AR inhibitors eventually results in the inevitable treatment resistance. Therefore, new drugs need to be evaluated for second-line therapy. Investigators in this study tested the novel AR inhibitor ODM-201 in a preclinical second-line scenario of Enzalutamide-resistant prostate cancer.

For this study LNCaP derived Enzalutamide-resistant MR49F cell line was used to evaluate the potential use of ODM-201 in second-line therapy after development of Enzalutamide resistance. MTS (Cell Proliferation Colorimetric) assay was performed to evaluate the effect of ODM-201 on cell growth. Additionally, Luciferase assay was used to evaluate the drug effect on AR transcriptional activity. Fluorescence microscopy was used to investigate the mode of action of ODM-201, and real-time PCR used to evaluate its effect on AR-targeted genes.

Furthermore, the investigators implanted Enzalutamide-resistant MR49F tumors in castrated mice and compared the effect of ODM-201 treatment with vehicle and Enzalutamide (served as positive control) on tumor volume and serum PSA. Post in vivo, cell proliferation was analyzed by immunohistochemical staining of Ki67 in xenografts.

Results demonstrated that Enzalutamide-resistant MR49F cells, after being treated with ODM-201 led to both a dose-dependent cell growth inhibition in MTS assay and a dose-dependent inhibition of AR transcriptional activity in Luciferase assay.ODM-201, which is a new AR inhibitor, impeded the nuclear translocation of the AR. Treatment with ODM-201 also led to a down-regulation of AR-targeted genes. In the Enzalutamide-resistant MR49F xenograft model, ODM-201 significantly reduced both tumor volume and serum PSA compared to vehicle and Enzalutamide. Immunohistochemical staining showed that expression of the cell proliferation marker Ki67 was significantly lower in ODM-201 treated xenografts of mice.

In conclusion, the novel AR inhibitor ODM-201 exhibited a promising efficacy in a second-line therapy scenario of Enzalutamide-resistant prostate cancer both in vitro and in vivo. This study paves the path for the next step of clinical trials evaluating ODM-201 in patients with Enzalutamide-resistant prostate cancer.

Speaker: Borgmann H., Ozistanbullu D., Beraldi E., Dalal K., Fazli L., Gleave M.

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto

at the #EAU17 - March 24-28, 2017- London, England
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