A Novel Inhibitor of Steroid-Hormone Biosynthesis in Advanced Prostate Cancer

Multiple randomized trials have provided compelling evidence of an improvement in overall survival for patients with hormone-sensitive metastatic prostate cancer managed with androgen deprivation therapy (ADT) plus intensification with agents including abiraterone, enzalutamide, apalutamide, darolutamide, and docetaxel. Despite this, most patients progress to a castration-resistant disease state, which is currently incurable. The development of novel hormonal agents that can overcome the myriad resistance pathways remains an important area of investigation.

In an industry-sponsored phase 1/2 trial, investigators evaluated ODM-208, a novel inhibitor of cytochrome P450 11A, in patients with progressive metastatic castration-resistant prostate cancer that had been treated with one or more androgen receptor pathway inhibitors and taxane-based chemotherapies. Phase 1 included 47 patients, regardless of androgen receptor (AR) gene mutation status, and phase 2 included 45 patients, all with AR mutations in plasma circulating tumor DNA.

In phase 2, the median age was 69 years, 84% of patients had received ≥3 lines of prior therapy, and 78% had ECOG performance status 1. The most common mutation was L702H (41%). Patients were treated with ODM-208 (5 mg twice daily) plus dexamethasone (1 mg/day) and fludrocortisone (0.1 mg/day).

Prostate-specific antigen levels decreased by 50% or more in 73.7% of patients with AR mutations and 8.7% of patients with AR wild type in phase 1 and in 53.3% of patients (all with AR mutations) in phase 2.

The most-frequent treatment-emergent adverse event in phase 1 was adrenal insufficiency (36.2%). In phase 2, 80% of patients experienced grade ≥3 toxicity.