TY - JOUR
T1 - Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer
AU - Fizazi, Karim
AU - Bernard-Tessier, Alice
AU - Roubaud, Guilhem
AU - Utriainen, Tapio
AU - Barthélémy, Philippe
AU - Fléchon, Aude
AU - Van Der Voet, Johannes
AU - Gravis, Gwenaëlle
AU - Ratta, Raffaele
AU - Jones, Robert
AU - Parikh, Omi
AU - Tanner, Minna
AU - Antonarakis, Emmanuel S.
AU - Baldini, Capucine
AU - Peters, Niamh
AU - Garratt, Chris
AU - Ikonen, Tarja
AU - Pohjanjousi, Pasi
AU - Joensuu, Heikki
AU - Cook, Natalie
N1 - Publisher Copyright:
© 2023 Massachusetts Medical Society.
PY - 2024/1
Y1 - 2024/1
N2 - BACKGROUND Prostate cancer is regulated by steroid hormones, even in castrationresistant 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 5mg twice a day with dexamethasone 1mg/fludrocortisone 0.1mg 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 5mg 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 steroidhormone 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; Clinical- Trials.gov number, NCT03436485.)
AB - BACKGROUND Prostate cancer is regulated by steroid hormones, even in castrationresistant 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 5mg twice a day with dexamethasone 1mg/fludrocortisone 0.1mg 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 5mg 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 steroidhormone 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; Clinical- Trials.gov number, NCT03436485.)
UR - https://www.scopus.com/pages/publications/105024590043
UR - https://www.scopus.com/pages/publications/105024590043#tab=citedBy
U2 - 10.1056/EVIDoa2300171
DO - 10.1056/EVIDoa2300171
M3 - Article
C2 - 38320513
AN - SCOPUS:105024590043
SN - 2766-5526
VL - 3
JO - NEJM Evidence
JF - NEJM Evidence
IS - 1
ER -