1605P - Opevesostat (MK-5684/ODM-208), an oral CYP11A1 inhibitor, in metastatic castration-resistant prostate cancer (mCRPC): Updated CYPIDES phase II results

Background

Opevesostat is an oral, selective inhibitor of CYP11A1 that suppresses production of all steroid hormones and precursors. Initial phase 2 results in mCRPC patients with AR-LBD mutations were previously presented (ESMO 2022). Here we report phase 2 results for both AR-LBD mutation-positive and negative patients.

Methods

Opevesostat 5mg BID (with dexamethasone and fludrocortisone) was evaluated in open-label expansion in patients with progressive mCRPC following ≥1 line of 2^nd generation AR-pathway inhibitor and ≥1 line of taxane-based chemotherapy. An initial cohort enrolled 45 patients with AR-LBD mutations in cell-free DNA (Guardant360), a subsequent extension included 89 mCRPC patients (21 and 68 pts with/without AR-LBD mutations respectively). Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. Opevesostat was continued until disease progression or toxicity.

Results

Overall, 66 AR-LBD mutation-positive and 68 AR-LBD mutation-negative patients (median age 68.5 years) were enrolled. 53.0% and 36.8% had previously received both abiraterone and enzalutamide, and 69.7% and 64.7% had received cabazitaxel in patients with and without AR-LBD mutation respectively. Opevesostat treatment led to PSA₅₀ responses in 53.0% and 14.7% of patients, and PSA₃₀ responses in 68.2% and 29.4% of patients, with and without AR-LBD mutations respectively. At data cut-off (23 Jan 2024), objective responses by RECIST had occurred in 10 patients, 8 with AR-LBD mutations (ORR 18.6% for AR-LBD positive). Opevesostat was well-tolerated: hospitalisation for adrenal insufficiency-like syndrome was much lower than in phase 1 when typically higher opevesostat doses were administered (6.7% vs. 31.9% respectively). Duration of response and safety with a minimum follow up of approximately 6.5 months will be presented.

Conclusions

Administration of Opevesostat to heavily pre-treated mCRPC patients shows promising antitumor activity. PSA₅₀ responses were most frequent among patients harbouring activating AR-LBD mutations.

Clinical trial identification

NCT03436485, First posted: 19 February 2018.

Editorial acknowledgement

Legal entity responsible for the study

Orion Corporation and Merck Sharp and Dohme.

Funding

Orion Corporation and Merck Sharp and Dohme.

Disclosure

K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; 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; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis. G. Roubaud: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer; Financial Interests, Institutional, Advisory Board: Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Coordinating PI: Bayer. A. Bernard-Tessier: Financial Interests, Personal, Invited Speaker: Astellas, Bayer, AstraZeneca; Financial Interests, Personal, Other, travel fees: ORION; Financial Interests, Institutional, Advisory Board: Novartis, Roche, Janssen, MSD, AAA-Novartis; Financial Interests, Personal, Writing Engagement: Bouchara-Recordati; Non-Financial Interests, Principal Investigator: Amgen, Macrogenics, Janssen. G. Gravis: Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Ipsen, AstraZeneca, alliance Merck Pfizer, Bayer, Eisai; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer, BMS, Janssen, Pfizer, Ipsen, Bayer, EISAI; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS; Non-Financial Interests, Principal Investigator: IPSEN, BMS, Merck. A. Flechon: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Janssen, AAA, Bayer, MSD, Pfizer, Merck, BMS; Financial Interests, Personal, Invited Speaker: Novartis. R. Ratta: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Personal, Advisory Board: Pfizer, Merck, Bristol Meyer Squibb, AstraZeneca, Janssen. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen, Gilead; Financial Interests, Personal, Invited Speaker: AstraZeneca. R.J. Jones: Financial Interests, Personal, Advisory Board, advisory board attendance: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker, Honoraria for speaking: Astellas; Financial Interests, Personal, Advisory Board: Bayer, Clovis, Exelixis, Ipsen, Bristol Myers Squibb, Merck Serono, Merck Sharpe Dome, Roche, Janssen, Novartis / AAA, MSD, ASTELLAS, Gilead, AstraZeneca, Pfizer; Financial Interests, Personal, Invited Speaker: Bayer, Ipsen, Bristol Myers Squibb, Merck Serono, Merck Sharpe Dome, Pfizer, Roche, Janssen, Pfizer; Financial Interests, Institutional, Other, IDMC membership: Roche; Financial Interests, Institutional, Other, IDMC member: Stab; Financial Interests, Personal, Other, promotional video: Astellas, Astellas, Astellas, Bayer; Financial Interests, Institutional, Local PI: Janssen, Pfizer, Tail, AstraZeneca, BioXcel, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: Novartis / AAA, Roche, MSK. A. Hussain: Financial Interests, Institutional, Local PI: AstraZeneca, Regeneron, Poseida, FutureChem, Pfizer, Bayer, Bristol Myers Squibb, Exelexis, PSI, Arravive, Nimbus, Infinity, Orion; Financial Interests, Institutional, Funding: Merck. N. Cook: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Local PI: Taiho, Roche, AstraZeneca, Avacta, Bayer, Eisai, UCB, Boeringher, Stemline; Financial Interests, Institutional, Coordinating PI: RedX, Orion, Starpharma, LOXO-Oncology; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Other, Committee chair: Cancer Research UK. M.M.E. Tanner: Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Novartis, Roche, Eli Lilly, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Seagen; Financial Interests, Institutional, Research Funding: Novartis, Roche, Eli Lilly, Seagen, Orion Corporation. R.H. Jones: Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Leadership Role: Roche. C. Garratt: Financial Interests, Personal, Full or part-time Employment: Orion Corporation; Financial Interests, Personal, Stocks/Shares: Orion Corporation. T. Ikonen: Financial Interests, Personal, Full or part-time Employment: Orion. P. Pohjanjousi: Financial Interests, Personal, Full or part-time Employment: Orion; Financial Interests, Personal, Stocks/Shares: Orion. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment, Employee and recipient of Stock: Merck & Co; Financial Interests, Personal, Stocks/Shares: Merck & Co; Non-Financial Interests, Member: ASCO, SITC, EAU. E.S. Antonarakis: Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis, MacroGenics, Merck, Novartis, Seagen; Financial Interests, Institutional, Principal Investigator: Orion; Financial Interests, Personal, Advisory Role: Aadi Bioscience, Blue Earth Diagnostics, Curium, EcoR1, Hookipa Pharma, Lilly, Menarini Silicon Biosystems, Sanofi, Tango Therapeutics, Tempus, z-Alpha; Financial Interests, Institutional, Advisory Role: Amgen, AstraZeneca, Bayer, Janssen, Merck, Pfizer; Financial Interests, Institutional, Advisory Board: Orion. All other authors have declared no conflicts of interest.