Androgen receptor (AR) plays a central role in prostate cancer and continues to be a driver in castration-resistant prostate cancer (CRPC), with increased AR expression in most cases. Approximately half of the men with CRPC respond initially to abiraterone or enzalutamide, but most relapse within 1 to 2 years. Majority of the abiraterone and enzalutamide-resistant tumors have still high AR expression and persistent AR activity. Several precursor steroids, like testosterone (T) and dihydrotestosterone activate AR, are synthesized in adrenal glands and de novo in tumours. CYP11A1 (cytochrome p450scc) is a mitochondrial enzyme catalysing the conversion of cholesterol to pregnenolone (Preg), which is the first rate-liming step in steroid hormone biosynthesis. ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1 enzyme and suppresses the synthesis of all steroid hormones and precursors.
The inhibition of CYP11A1 was measured in vitro by detecting the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing Preg and T formation by ELISA. Inhibition of the adrenal and testicular hormone production in vivo was tested in the intact male rat assay by analysing plasma concentrations of progesterone (P), corticosterone (C) and T (with LS-MS/MS) after single oral dose of ODM-208. The tumor growth inhibition was studied by using androgen dependent VCaP cells, which were subcutaneously grafted to intact male nude mice. When tumor volumes reached on average 200 mm3, mice were castrated, and after regrowth of the tumors, the oral treatment of ODM-208 was started.
ODM-208 potently inhibits CYP11A1 enzyme and formation of Preg and testosterone with low nM concentrations in vitro. In male rats, clear decreases of P, C and T concentrations can be detected already after single oral administration of ODM-208. In the murine VCaP CRPC xenograft model ODM-208 significantly inhibited tumor growth.
ODM-208 shows promising antitumor activity in preclinical CRPC models and suggests that ODM-208 may have the potential to be an effective treatment in CRPC. Clinical trial in patients with metastatic CRPC is planned to be started in the 2018.
Clinical trial identification
Legal entity responsible for the study
Orion Corporation Orion Pharma Orion Corporation Orion Pharma
Orion Corporation Orion Pharma
R. Oksala, M. Karimaa, M. Ramela, R. Riikonen, P. Rummakko, G. Wohlfahrt, A. Vuorela, M.V. Mustonen, P. Kallio: Employee: Orion Corporation Orion Pharma. All other authors have declared no conflicts of interest.