ODM-209, a CYP 11A1 inhibitor in patients with mCRPC: Results from the STESIDES phase 1 study.

5060 Background: ODM-209 is a novel, oral selective inhibitor of CYP11A1, that blocks production of all steroid hormones and precursors that may activate hormone receptor (e.g. androgen or estrogen) signaling pathways. It’s mode of action is similar to ODM-208/MK-5684 currently in phase 3 clinical development in patients with metastatic castration resistant prostate cancer (mCRPC). We report the results of the first-in-man phase I STESIDES study (NCT03878823). Methods: STESIDES was a dose finding Phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. Four patients with ER-positive/HER2 negative (ER+/HER2-) breast cancer (BC) were also enrolled. ODM-209 was administered once or twice daily with glucocorticoid and mineralocorticoid replacement therapy and androgen deprivation therapy (in men with mCRPC). Endpoints included dose-limiting toxicities (DLTs), adverse events (AE’s), pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory molecular profiling. Patients with and without androgen receptor ligand-binding domain ( AR-LBD) activating mutations were included. Results: 38 patients (median age 67 yrs.) received ODM-209 in doses ranging from 10 to 20 mg/day. Of 34 patients with mCRPC, 18 (53%) had previously received both abiraterone and enzalutamide, and 18 (53%) patients both docetaxel and cabazitaxel; 19 patients (56%) had activating AR-LBD mutations detected at baseline. All 4 BC patients had ESR1 mutations. Steroid hormone concentrations were mostly undetectable on treatment as expected. Patients generally tolerated the treatment well. The most commonly reported AE’s were fatigue (53%) and peripheral oedema (34%). Adrenal insufficiency was recorded in 4 patients (11%), of which 2 were considered serious, 1 case being a DLT in a patient with BC at 15 mg/day. Hyponatremia (21%) and hyperkalemia (16%) were also common and used as an indication to increase corticosteroid replacement dose. In patients with mCRPC serum testosterone was undetectable (limit of detection 0.2 ng/dL) in almost all patients in all dose groups at Day 8 and remained so at 16 weeks. 10 (29%) patients with mCRPC achieved a PSA decline of ≥50%, being 9/19 (47%) and 1/15 (7%) in patients with and without AR-LBD mutations respectively. 3/11 (27%) evaluable patients with mCRPC achieved a partial response by RECIST (1 in an AR-LBD wild-type patient). No responses were seen in patients with BC. The median duration of treatment was 4.8 and 3.7 months in mCRPC patients with and without activating AR-LBD mutations. Conclusions: Phase 1 results of ODM-209 suggest activity in heavily pre-treated patients with mCRPC particularly in those with activating AR-LBD mutations, with expected on-target AE’s. Similar findings were recently reported with ODM-208/MK-5684 (NEJM Evidence 2023). Clinical trial information: NCT03878823 .