ASCO GU 2022: Phase 1 Results of the ODM-208 First-in-Human Phase 1–2 Trial in Patients With Metastatic Castration-Resistant Prostate Cancer (CYPIDES)

( In the Rapid Abstract Session on the first day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, Dr. Fizazi presented a rapid abstract of the initial results of the phase I CYPIDES trial, describing the first-in-human results using ODM-208 in men with castration-resistant prostate cancer (mCRPC).

ODM-208 is a novel, oral, non-steroidal, and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. Through inhibition of CYP11A1, ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signaling pathway.

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This mechanism of action is particularly relevant for patients with activating somatic point mutations in the AR ligand-binding domain (LBD). Such mutations are a known mechanism of resistance to hormone-based therapies in mCRPC.

The CYPIDES trial utilized a phase I dose-finding 3+3 design among men with progressive mCRPC who have previously received ≥1 line of AR signaling inhibitor and ≥1 line of taxane-based chemotherapy. Patients received ODM-208 up to 150 mg/day with glucocorticoid and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT).

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In this phase 1 design, the endpoints of interest were dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling.

As of the data cut-off, 44 patients were treated with ODM-208. The median age of included patients was 70 years. Among the 44 patients, 24 (55%) patients had previously received both abiraterone and enzalutamide, and all had received at least one taxane-based chemotherapy regime.

With the accrual of 41 patients, dose-finding was completed with doses ranging from 10 to 150 mg/day. ODM-208 plasma exposure was dose-proportional.

In terms of biochemical correlates of treatment, serum testosterone was undetectable after 4 weeks of start of ODM-208 in nearly all patients, as were other metabolites including serum DHEA sulfate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone, and pregnenolone.

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The authors hypothesized, as alluded to above, that ODM-20 may be more effective in men with AR mutations as it blocks the production of all AR ligands. This was validated as ODM-20 produced robust PSA responses, particularly among men with mutations in the AR ligand-binding domain.

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In terms of preliminary oncologic efficacy, 32% of evaluable patients achieved a PSA decline of ≥50%. This rate was higher (68%) in patients with activating somatic point mutations in the AR ligand-binding domain than in those men without (8%).

Although tolerated by most patients, the main safety finding was adrenal insufficiency with grade 3 adrenal insufficiency noted in 14/44 (32%) patients. These patients required short-term high-dose glucocorticoid treatment and required hospitalization. A single dose-limiting toxicity occurred at the 50mg BID dosage. Three patients died during the study, all attributable to prostate cancer.

Dr. Fizazi concluded that treatment with ODM-208 among men with heavily pre-treated mCRPC was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. Based on this phase I results, the phase 2 dose-expansion portion of the CYPIDES is ongoing (NCT03436485).

Presented By: Karim Fizazi, PhD, MD, Gustave Roussy, and University of Paris-Saclay