ODM-208, a novel CYP11A1-inhibitor as a therapeutic approach for the treatment of castration-resistant prostate cancer (original) (raw)
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European urology focus, 2017
Patients with castration-resistant prostate cancer (CRPC) had extended responses to the androgen receptor antagonist ODM-201, in phase 1/2 studies. To evaluate the safety and antitumour activity of prolonged ODM-201 treatment in patients with CRPC. The ARADES trial was a multicentre phase 1 (dose escalation) and phase 2 (dose expansion) trial; 134 patients with CRPC were stratified by previous chemotherapy to receive ODM-201. This paper reports extended follow-up in CYP17 inhibitor (CYP17i)-naïve patients. Patients (n=77) received oral ODM-201 twice daily at daily doses of 200-1800mg. Safety, measured as the occurrence of adverse events (AEs), prostate-specific antigen (PSA), and radiographic progression. The safety profile of extended ODM-201 treatment (median treatment duration 8.2 mo, 95% confidence interval [CI] 5.6-11.0) was consistent with that reported at the time of the original data cutoff in the main ARADES trial, with no unexpected safety concerns over time. The majority ...
2018
a Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Comprehensive Cancer Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Kuopio University Hospital, Kuopio, Finland; Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; e Tampere University Hospital, Tampere, Finland; Orion Corporation, Orion Pharma, Espoo, Finland E U R O P E A N U R O L O G Y F O C U S 3 ( 2 0 17 ) 6 0 6 – 6 1 4
The Journal of Steroid Biochemistry and Molecular Biology, 2018
We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropintreated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.