Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

Karim Fizazi, Alice Bernard-Tessier, Guilhem Roubaud, Tapio Utriainen, Philippe Barthélémy, Aude Fléchon, Johannes van der Voet, Gwenaëlle Gravis, Raffaele Ratta, Robert Jones, Omi Parikh, Minna Tanner, Emmanuel S Antonarakis, Capucine Baldini, Niamh Peters, Chris Garratt, Tarja Ikonen, Pasi Pohjanjousi, Heikki Joensuu, Natalie Cook

Research output: Contribution to journalArticleScientificpeer-review

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.)

Original languageEnglish
Number of pages12
JournalNEJM evidence
Volume3
Issue number1
DOIs
Publication statusPublished - 26 Dec 2023
Publication typeA1 Journal article-refereed

Keywords

  • Male
  • Humans
  • Receptors, Androgen/therapeutic use
  • Prostatic Neoplasms, Castration-Resistant/drug therapy
  • Cholesterol Side-Chain Cleavage Enzyme
  • Prostate-Specific Antigen/therapeutic use
  • Treatment Outcome
  • Androgen Receptor Antagonists/pharmacology

Publication forum classification

  • Publication forum level 1

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