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.
Eur Urol Focus
; 6(1): 63-70, 2020 01 15.
Article
en En
| MEDLINE
| ID: mdl-30194031
ABSTRACT
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, ANDPARTICIPANTS:
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 STATISTICALANALYSIS:
ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed. RESULTS ANDLIMITATIONS:
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 (AUC0-12) values increased dose dependently until the 300mg dose. The AUC was lower on day 8 after repeated dosing compared with day 1 from the 200mg dose upwards. Decreases in testosterone levels were seen with ODM-204 treatment confirming androgen deprivation. Of the patients, 13% also demonstrated a >50% decrease in PSA at week 12 and continued ODM-204 treatment for over a year.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. PATIENTSUMMARY:
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.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Esteroide 17-alfa-Hidroxilasa
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Antagonistas de Receptores Androgénicos
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Neoplasias de la Próstata Resistentes a la Castración
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Imidazoles
Tipo de estudio:
Clinical_trials
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Prognostic_studies
Límite:
Aged
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Aged80
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Eur Urol Focus
Año:
2020
Tipo del documento:
Article
País de afiliación:
Finlandia