Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES)
Authors
Fizazi, K.Cook, Natalie
Barthelemy, P.
Bernard-Tessier, A.
Baldini, C.
Peters, Niamh
Nykanen, P.
Ikonen, T.
Pohjanjousi, P.
Mattila, L.
Jouhi, L.
Vuorela, A.
Garratt, C.
Utriainen, T.
Affiliation
Gustave Roussy and University of Paris-Saclay, Villejuif, FranceIssue Date
2022
Metadata
Show full item recordAbstract
Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing.Citation
Fizazi K, Cook N, Barthélémy P, Bernard-Tessier A, Baldini C, Peters N, et al. Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).. Vol. 40, Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2022. p. 18–18.Journal
Journal of Clinical OncologyDOI
10.1200/JCO.2022.40.6_suppl.018Additional Links
https://dx.doi.org/10.1200/JCO.2022.40.6_suppl.018Type
Meetings and ProceedingsLanguage
enae974a485f413a2113503eed53cd6c53
10.1200/JCO.2022.40.6_suppl.018