Preliminary phase II results of the CYPIDES study of ODM208 in metastatic castration-resistant prostate (mCRPC) cancer patients

ODM-208 is a first in class, oral, non-steroidal, and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in mCRPC. We report the first results of the phase 2 expansion of the CYPIDES trial. ODM-208 5mg BID (with dexamethasone and fludrocortisone) was evaluated in an open-label expansion cohort in patients with progressing mCRPC who had previously received ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy. All patients had a pre-specified activating AR LBD mutation by pre-screening of cell-free DNA (Guardant 360). Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. ODM-208 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA. 81 of 390 (20.8%) pre-screened patients had a pre-specified AR LBD mutation, of which 45 patients (median age 68 yrs) were enrolled and initiated ODM-208 treatment (43 at data cut-off 17 March 2022). 51% patients had previously received both abiraterone and enzalutamide, and 65% patients both docetaxel and cabazitaxel. Based on the emerging data ODM-208 profoundly suppressed androgen synthesis resulting in >50% best PSA reduction in more than 50% patients and at least 4 RECIST partial responses in 17 evaluable patients (data immature). ODM-208 has been well-tolerated with a much lower rate of hospitalisation for adrenal insufficiency than in phase 1 with typically higher doses (2.3% vs. 33% to date). Efficacy and safety data will be presented for the complete cohort with at least 5 months follow-up for all patients. Administration of ODM-208 to heavily pre-treated mCRPC patients with AR LBD mutation was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. NCT03436485.