The first and rate-limiting enzyme in steroid production, CYP11A1, is specifically inhibited by the oral, non-steroidal drug ODM-208. All steroid hormones and their precursors that may stimulate the androgen receptor (AR) signaling pathway are prevented from being produced by ODM-208. This is especially important for individuals with somatic point mutations in the AR ligand binding domain (LBD), a resistance mechanism to hormone-based treatments for mCRPC. For a study, researchers sought to present the initial findings from the CYPIDES trial’s phase 2 extension.
In an open-label expansion cohort of patients with advancing mCRPC who had previously undergone ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy, ODM-208 5mg BID (with dexamethasone and fludrocortisone) was assessed. Pre-screening of cell-free DNA identified an activating AR LBD mutation in each patient (Guardant 360). The study’s goals included basic safety assessments and safety and preliminary effectiveness evaluations using PSA and RECIST responses. Treatment with ODM-208 was continued until the illness eventually progressed. Eighteen locations across France, Finland, the UK, and the USA participated in the study.
A pre-specified AR LBD mutation was present in 81 of 390 (20.8%) pre-screened individuals; 45 of these patients (median age 68 years) were recruited and received therapy with ODM-208 (43 at data cut-off 17 March 2022). About 51% of patients and 65% of patients had previously taken abiraterone, enzalutamide, docetaxel, and cabazitaxel. According to newly available data, ODM-208 dramatically inhibited androgen production, resulting in at least four partial RECIST responses in 17 evaluable patients and more than 50% best PSA decrease in more than 50% of patients (data immature). Despite being given at normally larger dosages in phase 1, ODM-208 has been well tolerated, with a rate of hospitalization for adrenal insufficiency that is substantially lower (2.3% vs. 33% to date). Data on efficacy and safety will be reported for the entire cohort with at least 5 months of patient follow-up.
ODM-208 was extremely effective in preventing the synthesis of steroid hormones and showed promise of anticancer efficacy when administered to individuals with AR LBD mutations who had received a lot of prior treatment for their mCRPC.
Reference: annalsofoncology.org/article/S0923-7534(22)03347-6/fulltext
