Targeted inhibition of CYP11A1 in castration-resistant prostate cancer

Fizazi, Karim, Bernard-Tessier, Alice, Roubaud, Guilhem, Utriainen, Tapio, Barthélémy, Philippe, Fléchon, Aude, van der Voet, Johannes, Gravis, Gwenaëlle, Ratta, Raffaele, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Parikh, Omi, Tanner, Minna, Antonarakis, Emmanuel S., Baldini, Capucine, Peters, Niamh, Garratt, Chris, Ikonen, Tarja, Pohjanjousi, Pasi, Joensuu, Heikki and Cook, Natalie 2024. Targeted inhibition of CYP11A1 in castration-resistant prostate cancer. NEJM Evidence 3 (1) 10.1056/EVIDoa2300171

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
ISSN:	2766-5526
Funders:	commercial
Date of First Compliant Deposit:	22 February 2024
Date of Acceptance:	13 November 2023
Last Modified:	26 Jun 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/166424

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