ODM-204, a Novel Dual Inhibitor of CYP17A1 and Androgen Receptor: Early Results from Phase I Dose Escalation in Men with Castration-resistant Prostate Cancer.
Androgen receptor
CYP17A1
Castration-resistant prostate cancer
ODM-204
Phase I clinical trial
Journal
European urology focus
ISSN: 2405-4569
Titre abrégé: Eur Urol Focus
Pays: Netherlands
ID NLM: 101665661
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
24
05
2018
revised:
17
07
2018
accepted:
27
08
2018
pubmed:
9
9
2018
medline:
21
5
2021
entrez:
9
9
2018
Statut:
ppublish
Résumé
Most prostate cancer patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy treatment. CRPC growth is mediated mostly by androgen receptor signalling driven by primary androgens synthesised largely by the CYP17A1 enzyme. To evaluate the safety profile and dose-limiting toxicities of ODM-204. In this open, uncontrolled, nonrandomised, multicentre, tolerability and pharmacokinetic first-in-man phase I dose escalation study, patients with metastatic CRPC were randomised to receive ODM-204 in sequential cohorts of five dose levels (ie, 50, 100, 200, 300, and 500mg twice daily) concomitantly with prednisone. ODM-204, a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed. Of the 23 patients enrolled into the study, 60.9% experienced mild adverse effects considered to be related to the study treatment, which were fatigue, increased/decreased appetite, nausea, asthenia, diarrhoea, and weight decrease. ODM-204 area under the curve (AUC ODM-204 was well tolerated up to the highest evaluated dose. There were decreases in both testosterone and PSA levels, suggesting preliminary antitumour activity in the treatment of CRPC. The pharmacokinetic properties of the molecule, however, prevent further development. This study looked at the safety of ODM-204, a novel dual inhibitor of CYP17A1 and the androgen receptor, in castration-resistant prostate cancer patients. ODM-204 treatment was found to be well tolerated, and it also reduced both serum testosterone and prostate-specific antigen levels, but the properties of the molecule prevent further development.
Sections du résumé
BACKGROUND
Most prostate cancer patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy treatment. CRPC growth is mediated mostly by androgen receptor signalling driven by primary androgens synthesised largely by the CYP17A1 enzyme.
OBJECTIVE
To evaluate the safety profile and dose-limiting toxicities of ODM-204.
DESIGN, SETTING, AND PARTICIPANTS
In this open, uncontrolled, nonrandomised, multicentre, tolerability and pharmacokinetic first-in-man phase I dose escalation study, patients with metastatic CRPC were randomised to receive ODM-204 in sequential cohorts of five dose levels (ie, 50, 100, 200, 300, and 500mg twice daily) concomitantly with prednisone.
INTERVENTION
ODM-204, a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed.
RESULTS AND LIMITATIONS
Of the 23 patients enrolled into the study, 60.9% experienced mild adverse effects considered to be related to the study treatment, which were fatigue, increased/decreased appetite, nausea, asthenia, diarrhoea, and weight decrease. ODM-204 area under the curve (AUC
CONCLUSIONS
ODM-204 was well tolerated up to the highest evaluated dose. There were decreases in both testosterone and PSA levels, suggesting preliminary antitumour activity in the treatment of CRPC. The pharmacokinetic properties of the molecule, however, prevent further development.
PATIENT SUMMARY
This study looked at the safety of ODM-204, a novel dual inhibitor of CYP17A1 and the androgen receptor, in castration-resistant prostate cancer patients. ODM-204 treatment was found to be well tolerated, and it also reduced both serum testosterone and prostate-specific antigen levels, but the properties of the molecule prevent further development.
Identifiants
pubmed: 30194031
pii: S2405-4569(18)30241-4
doi: 10.1016/j.euf.2018.08.022
pii:
doi:
Substances chimiques
Androgen Receptor Antagonists
0
Imidazoles
0
ODM-204
0
CYP17A1 protein, human
EC 1.14.14.19
Steroid 17-alpha-Hydroxylase
EC 1.14.14.19
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
63-70Informations de copyright
Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.