1364MO - Preliminary phase II results of the CYPIDES study of ODM-208 in metastatic castration-resistant prostate (mCRPC) cancer patients

Background

ODM-208 is a first in class, 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 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 mCRPC. We report the first results of the phase 2 expansion of the CYPIDES trial.

Methods

ODM-208 5mg BID (with dexamethasone and fludrocortisone) was evaluated in an open-label expansion cohort in patients with progressing mCRPC who had previously received ≥1 line of 2^nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy. All patients had a pre-specified activating AR LBD mutation by pre-screening of cell-free DNA (Guardant 360). Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. ODM-208 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA.

Results

81 of 390 (20.8%) pre-screened patients had a pre-specified AR LBD mutation, of which 45 patients (median age 68 yrs) were enrolled and initiated ODM-208 treatment (43 at data cut-off 17 March 2022). 51% patients had previously received both abiraterone and enzalutamide, and 65% patients both docetaxel and cabazitaxel. Based on the emerging data ODM-208 profoundly suppressed androgen synthesis resulting in >50% best PSA reduction in more than 50% patients and at least 4 RECIST partial responses in 17 evaluable patients (data immature). ODM-208 has been well-tolerated with a much lower rate of hospitalisation for adrenal insufficiency than in phase 1 with typically higher doses (2.3% vs. 33% to date). Efficacy and safety data will be presented for the complete cohort with at least 5 months follow-up for all patients.

Conclusions

Administration of ODM-208 to heavily pre-treated mCRPC patients with AR LBD mutation was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. NCT03436485.

Clinical trial identification

NCT03436485.

Editorial acknowledgement

Legal entity responsible for the study

Orion Corporation.

Funding

Orion Corporation.

Disclosure

K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion. A. Bernard-Tessier: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Other, travel fees: Orion, Bayer; Financial Interests, Institutional, Advisory Board: Novartis; Non-Financial Interests, Principal Investigator: Amgen. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen. T. Utriainen: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Orion. A. Flechon: Financial Interests, Personal, Expert Testimony: Sanofi, AstraZeneca, Astellas, Janssen, AAA, Bayer; Financial Interests, Personal, Invited Speaker: Novartis. G. Gravis Mescam: Financial Interests, Institutional, Advisory Board: AAA, Alliance Merck-Pfizer, Astellas, BMS, Janssen, Pfizer, Ipsen, alliance Merck Pfizer; Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Sanofi, Ipsen, AstraZeneca, BMS; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. R. Ratta: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Personal, Advisory Board: Pfizer, Merck, Bristol Meyer Squibb, AstraZeneca. M.M.E. Tanner: Financial Interests, Personal, Advisory Board: Roche Finland, Pfizer, Novartis, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis, Roche Finland, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Novartis, Roche, AbbVie, Boehringer Ingelheim, Orion. C. Garratt: Financial Interests, Personal, Full or part-time Employment: Orion Pharma UK Ltd.; Financial Interests, Personal, Stocks/Shares: Orion Corporation. P. Pohjanjousi: Financial Interests, Personal, Full or part-time Employment: Orion. T. Ikonen: Financial Interests, Personal, Full or part-time Employment: Orion. E.S. Antonarakis: Financial Interests, Institutional, Advisory Role: Janssen, Astellas, Sanofi, Dendreon, Bayer, BMS, Amgen, ESSA, Constellation, Blue Earth, Exact sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis, Eli Lilly; Financial Interests, Institutional, Research Grant: Janssen, J&J, Sanofi, BMS, Pfizer, AstraZeneca, Novartis, Curium, Constellation, ESSA, Celgene, Merck, Bayer, Clovis. N. Cook: Financial Interests, Institutional, Invited Speaker: Roche, Taiho, Roche, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boehringher, Stemline, Ergomed; Non-Financial Interests, Advisory Role: Roche. All other authors have declared no conflicts of interest.