(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a prostate cancer poster session. Dr. Karim Fizazi presented the results of CYPIDES, a phase 2 trial evaluating MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without androgen receptor (AR) ligand binding domain (LBD) mutations.
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 AR signaling pathway.
The initial phase 1 and phase 2 results in AR-LBR mutation positive mCRPC patients have been previously presented at ASCO GU 2022 and ESMO 2022, respectively. In this report, Dr. Fizazi presented the phase 2 results for both AR-LBD mutation-positive and negative patients.
MK-5684, administered at a 5 mg dose twice daily along with dexamethasone and fludrocortisone, was evaluated in an open-label expansion cohort in mCRPC patients, who had previously received ≥1 androgen receptor pathway inhibitor (ARPI) and ≥1 taxane-based chemotherapy. The initial expansion cohort enrolled 45 patients with an activating AR-LBD mutation, identified in cell-free DNA (Guardant360 assay, 74-gene panel). The subsequent extension cohort included mainly AR-LBD mutation-negative patients, to allow for attainment of comparable groups of about 60 patients each, with and without AR-LBD mutations.
The primary study objectives were to evaluate safety and preliminary efficacy outcomes, assessed by PSA and RECIST response, along with standard safety measures. Treatment with MK-5684 was continued until evidence of subsequent disease progression. The study was conducted at 18 sites across France, Finland, the United Kingdom, and USA. The study data cut-off date was July 17, 2023.
The study cohort included a total 134 patients, of whom 66 and 68 were AR-LBD mutation-positive and negative, respectively. The median patient age was 68.3 years. Among patients in the AR-LBD mutation positive and negative groups, 53% and 34% of patients had previously received both abiraterone and enzalutamide, respectively, whereas 64% and 56% had received cabazitaxel, respectively.
Among patients with and without AR-LBD mutations, treatment with MK-5684 resulted in PSA50 responses in 56% and 17% of patients and PSA30 responses in 70% and 30% of patients, respectively.
At the time of data cut-off, objective responses, per RECIST, had occurred in 8 patients, all of whom were AR-LBD mutation positive (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 the phase 1 report, when typically, higher MK-5684 doses were administered (3% versus 33%, respectively).
Dr. Fizazi concluded that administration of MK-5684 to heavily pre-treated mCRPC patients showed promising antitumor activity. PSA50 responses were most frequent among patients harboring activating AR-LBD mutations.
Presented by: Karim Fizazi, MD, PhD, Professor, Department of Medicine, Institut Gustave Roussy, Paris, France
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024