ODM-208 for Metastatic Castration-resistant Prostate Cancer: Safety and Pharmacokinetics Study

ODM-208 is a novel, orally administered, non-steroidal small molecule that specifically and fully suppresses the mitochondrial cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. This enzyme is responsible for the initial and rate-limiting stage in steroidogenesis, resulting in a shortage of naturally occurring steroid hormones. In the Cypides phase 1 trial, the pharmacokinetics (PK) and pharmacodynamics (PD) of ODM-208 were evaluated in males with progressive metastatic castration-resistant prostate cancer (mCRPC) who had previously undergone treatment with at least one round of both second-generation AR pathway inhibitor (ARPI) and taxane chemotherapy. The study measured serum testosterone levels to assess the PD of ODM-208.

ODM-208 was administered at seven different dosage levels ranging from 3 mg to 75 mg b.i.d. in conjunction with corticosteroid replacement therapy and ADT. Plasma concentrations of ODM-208 were assessed for pharmacokinetic evaluation on the first day following a solitary administration and on the eighth day following multiple administrations. The impact of ODM-208 administration on serum testosterone levels was assessed by gauging testosterone concentrations on days 1 and 8 before and at various intervals after dosing. The application of population pharmacokinetic modeling allowed for estimating the pharmacokinetic-pharmacodynamic relationship. Following oral administration, swift uptake of ODM-208 was noted. The median duration for the attainment of peak plasma concentration (t_max) was observed to be 2 hours following the administration of a solitary dose of ODM-208. The pharmacokinetic parameters, specifically the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax), remained consistent after 7 days of repeated dosing compared to a single dose.

The mean elimination t_½of ODM-208 was 3 h, and the steady state was reached within one week. The area under the concentration-time curve from 0 to 24 hours (AUC_0-24) of ODM-208 exhibited an almost dose-proportional increase. Following a singular administration of ODM-208 in varying doses of 3, 5, 15, 25, 50, and 75 mg on day 1, serum testosterone concentrations showed a swift decline. Following a week of repeated dosing, the concentrations were observed to have decreased to levels that were either close to or below the lower limit of quantification (LLoQ), which is 0.2 ng/dL or <0.0069 nmol/L. The exposure to ODM-208 exhibited a nearly dose-proportional increase and decrease, while the concentrations of ODM-208 remained comparable on days 1 and 8. Studies have demonstrated that ODM-208 can achieve systemic plasma concentrations that can significantly decrease serum testosterone levels across a broad range of doses.

Source: https://oncologypro.esmo.org/meeting-resources/esmo-congress/the-pharmacokinetics-and-the-pharmacodynamic-effect-of-odm-208-an-inhibitor-of-cholesterol-side-chain-cleavage-enzyme-cyp11a1

Clinical Trail: https://clinicaltrials.gov/ct2/show/NCT03436485

A. Bernard-Tessier, P. Nykanen, T. Utriainen, N. Cook, P. Barthelemy, C. Baldini, N. Peters, T. Ikonen, P. Pohjanjousi, M. Karimaa, J. Malkki, P.T. Toivanen, C. Garratt, K. Fizazi/The pharmacokinetics and the pharmacodynamic effect of ODM-208, an inhibitor of cholesterol side-chain cleavage enzyme (CYP11A1)/Annals of Oncology (2022) 33 (suppl_7): S616-S652. 10.1016/annonc/annonc1070