Steroidogenesis inhibitor ODM-209 for metastatic castration-resistant prostate cancer and advanced breast cancer: Results from the first-in-human STESIDES study.

PURPOSE: Patients with metastatic castration-resistant prostate cancer (mCRPC) and advanced breast cancer (aBC) have poor outcomes with standard treatments. We report phase 1 results from the STESIDES (NCT03878823) study of ODM-209, an oral selective CYP11A1 inhibitor that blocks all synthesis of steroid hormones. METHODS: STESIDES was a dose-finding study (3 +3 design) in adults with progressive mCRPC, with or without activating androgen receptor ligand-binding domain (AR-LBD) mutations, who received ≥ 1 prior AR pathway inhibitor and ≥ 1 taxane-based regimen. Participants with aBC were also enrolled. ODM-209 was administered with glucocorticoid and mineralocorticoid replacement therapy. Primary endpoints included dose-limiting toxicities (DLTs) and adverse events (AEs); secondary endpoints included pharmacodynamics and clinical response. RESULTS: Thirty-eight participants received ODM-209 (mCRPC: 34; aBC: 4); dose range: 10-20 mg/day. All experienced AEs; fatigue (53%) and peripheral edema (34%) were most common. Nine (24%) experienced grade ≥ 3 AEs related to ODM-209. Three (8%) had serious adrenal insufficiency events (including terms adrenal insufficiency, glucocorticoid deficiency and adrenocortical insufficiency acute); one was a DLT (participant with aBC). Steroid hormone concentrations were mostly undetectable upon treatment. Ten (29%) participants with mCRPC had prostate-specific antigen decline ≥ 50% (PSA50), including patients with AR-LBD mutations (PSA50 response rate: 9/19 [47%]; 5.6-month median treatment duration for this group). Three of 16 (19%) evaluable participants with mCRPC had partial clinical response. No responses were seen in participants with aBC. CONCLUSIONS: ODM-209 showed activity in heavily pretreated participants with mCRPC, particularly those with activating AR-LBD mutations, with an expected AE profile.