MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results.
Authors: Karim Fizazi, Guilhem Roubaud, Alice Bernard-Tessier, Gwenaelle Gravis, Aude Flechon, Raffaele Ratta, Philippe Barthelemy, Robert J. Jones, Omi Parikh, Arif Hussain, Hans van der Voet, Natalie Cook, Niamh Peters, Minna Tanner, Robert Hugh Jones, Chris Garratt, Pasi Pohjanjousi, Tarja Ikonen, Christian Heinrich Poehlein, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2024)

159 Background: MK-5684 (previously ODM-208) is a first-in-class, oral, non-steroidal, selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. MK-5684 suppresses the production of all steroid hormones and precursors that may activate the androgen receptor (AR) signaling pathway. Initial phase 1 (ASCO-GU 2022) and phase 2 results in AR-LBD mutation-positive (ESMO 2022) mCRPC patients were previously presented. Now we report phase 2 results for both AR-LBD mutation-positive and negative patients. Methods: MK-5684 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. An initial expansion cohort enrolled 45 patients with an activating AR-LBD mutation identified in cell-free DNA (Guardant360 assay, 74-gene panel), a subsequent extension cohort included mainly AR-LBD mutation-negative patients to attain comparable groups of about 60 patients each, with and without AR-LBD mutations. Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. MK-5684 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA. Data are based on a 17 July 2023 data cut-off. Results: A total of 66 AR-LBD mutation-positive and 68 AR-LBD mutation-negative patients (median age 68.3 years) were enrolled and received MK-5684 treatment. 53% and 33.8% of patients had previously received both abiraterone and enzalutamide, and 63.6% and 55.9% patients had received cabazitaxel in AR-LBD mutation positive and negative groups respectively. MK-5684 profoundly suppressed androgen synthesis resulting in PSA 50 responses in 55.6% and 16.7% of patients and PSA 30 responses in 69.8% and 30.0% of patients, with and without AR-LBD mutations respectively. At the time of abstract data cut-off, objective responses by RECIST had occurred in 8 patients, all with AR-LBD mutations (ORR 20.5% for AR-LBD positive). MK-5684 was well-tolerated: the most common treatment-related adverse events were related to adrenal suppression with the rate of hospitalization for adrenal insufficiency being much lower than in phase 1 when typically higher MK-5684 doses were administered (3.0% vs. 33% respectively). Data with a minimum follow up of approximately 4 months after last patient enrolment will be presented. Conclusions: Administration of MK-5684 to heavily pre-treated mCRPC patients showed promising antitumor activity. PSA 50 responses were most frequent among patients harboring activating AR-LBD mutations. Clinical trial information: NCT03436485 .