KEY TAKEAWAYS
- The CYPIDES phase I/II trial aimed to present phase 2 outcomes for AR-LBD mutation-positive and negative mCRPC patients following MK-5684 administration.
- MK-5684 yielded notable antitumor effects in heavily treated mCRPC patients, with PSA50 responses particularly prevalent in activating AR-LBD mutation carriers.
MK-5684, formerly known as ODM-208, is a pioneering oral, non-steroidal, selective inhibitor targeting CYP11A1, the primary enzyme in steroid biosynthesis. This effectively suppresses the production of steroid hormones and precursors capable of activating the androgen receptor (AR) signaling pathway. Earlier presentations included phase 1 data (ASCO-GU 2022) and phase 2 results in AR-LBD mutation-positive metastatic castration-resistant prostate cancer (mCRPC) patients (ESMO 2022).
Karim Fizazi and his team spearheaded the study that aimed to present phase 2 outcomes for both AR-LBD mutation-positive and negative patients.
The study evaluated the outcome of MK-5684 5mg BID (administered with dexamethasone and fludrocortisone) in patients with progressive mCRPC who had previously undergone ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy.
The study was conducted across 18 sites in France, Finland, the UK, and the USA, with data based on a cutoff date of July 17, 2023. Initially, 45 patients with activating AR-LBD mutations identified via cell-free DNA (Guardant360 assay, 74-gene panel) were enrolled, followed by the inclusion of mainly AR-LBD mutation-negative patients in a subsequent extension cohort to achieve comparable groups of approximately 60 patients each, with and without AR-LBD mutations.
Safety and preliminary efficacy were the primary objectives, evaluated through PSA and RECIST responses and standard safety measures. Treatment with MK-5684 continued until disease progression.
About 66 patients with AR-LBD mutations and 68 without were enrolled, with a median age of 68.3 years, all receiving MK-5684 treatment. Among them, 53% and 33.8% had previously undergone both abiraterone and enzalutamide, and 63.6% and 55.9% had received cabazitaxel in the AR-LBD mutation-positive and negative groups, respectively. MK-5684 significantly suppressed androgen synthesis, resulting in PSA50 responses in 55.6% and 16.7% of patients, and PSA30 responses in 69.8% and 30.0%, respectively, with and without AR-LBD mutations.
By the abstract data cutoff, objective responses by RECIST were observed in 8 patients, all with AR-LBD mutations (ORR 20.5% for AR-LBD positive). MK-5684 demonstrated tolerability, with adrenal suppression-related adverse events (AEs) being the most common.
Hospitalization rates for adrenal insufficiency were markedly lower than in phase 1, where higher MK-5684 doses were typically administered (3.0% vs. 33% respectively). Detailed data with a minimum follow-up of approximately 4 months after the last patient enrollment will be presented.
The study demonstrated promising antitumor activity with MK-5684 in heavily treated mCRPC patients. PSA50 responses were notably higher in those with activating AR-LBD mutations. Research was funded by Orion Corporation, Orion Pharma.
Source: https://meetings.asco.org/abstracts-presentations/230141
Clinical Trial: https://clinicaltrials.gov/study/NCT03436485
Fizazi K, Roubaud G, Bernard-Tessier A, et al. (2024). “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.” J Clin Oncol 42, 2024 (suppl 4; abstr 159) DOI: 10.1200/JCO.2024.42.4_suppl.159
