Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

Abstract

BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)

Figure 1.. Plasma Levels of Androgenic and Nonandrogenic Steroid Hormones during Treatment with ODM-208 5 mg Twice a Day in Patients in Phase 2.

In all five panels, the y axis is a log scale. Most values above the lower limit of quantification (LLoQ) after day 1 were detected in patients in whom ODM-208 administration had been interrupted. Samples below the LLoQ were superimposed as half the LLoQ. Testosterone (Panel A). Androstenedione (Panel B). Dehydroepiandrosterone sulfate (Panel C). Aldosterone (Panel D). Cortisol (Panel E). D denotes day; and W, week.

Figure 2.. Change in Prostate-Specific Antigen (PSA) after Treatment with ODM-208.

Best change (percentage) in PSA from baseline in the total phase 1 population (Panel A) and in the androgen receptor gene mutation (AR^mut) subpopulation (inset) and in phase 2 (Panel B). Change in PSA from baseline over time in individual patients in phase 1 (Panel C) and phase 2 (Panel D) by androgen receptor gene mutation status. AR^wt denotes androgen receptor gene wild type; and mo, months.

Figure 3.. Swimmer Plots Showing Time on Treatment.

Panel A shows phase 1 and Panel B shows phase 2 by androgen receptor gene mutation status. AR^mut denotes androgen receptor gene mutation; AR^wt, androgen receptor gene wild type; mo, months; PSA, prostate-specific antigen; and RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.