Abstract 1250: ODM-208, a novel, small-molecule CYP11A1 inhibitor, demonstrates strong inhibition of steroid biosynthesis and antitumor activity in castration-resistant prostate cancer (CRPC) model

Abstract

Several new treatments have been developed to target the androgen signaling axis in CRPC over the last decade. Despite the new treatment options, the challenge for managing CRPC is the limited duration of clinical benefit from treatments due to primary and acquired resistance. Altered steroid biosynthesis and adaptive signaling by endogenous steroids especially in AR mutated tumors have been suggested to be one of the resistance mechanisms. Inhibition of CYP11A1 enzyme (cytochrome P450scc) that catalyzes the first step in the steroidogenic pathway and leads to suppression of the synthesis of all steroid hormones and their precursors is expected to be a target with therapeutic potential in CRPC patients. Here we show, using multiple in vitro and in vivo models, selectivity and anti-tumor activity of a potent, orally bioavailable, inhibitor of CYP11A1 enzyme, ODM-208. The potency and specificity of ODM-208 was tested by using targeted screening assay and human recombinant CYP11A1 enzyme. The inhibition potential of ODM-208 in vitro was studied in H295R cells. The selectivity of ODM-208 to wide panel of different target classes including GPCRs, nuclear receptors, ion channels and enzymes was evaluated. Inhibition of steroidogenesis in vivo was studied in intact male dogs after repeated 4-week dosing of ODM-208, with and without corticosteroid replacement therapy. Steroid hormone concentrations in plasma and cell culture media were analyzed by LC-MS/MS. In vivo antitumor effects of ODM-208 were assessed in murine subcutaneous CRPC VCaP xenograft model. Strong reduction of androgen and other steroid hormones in H295R cells was shown with ODM-208, whereas with abiraterone clear increases in concentrations of pregnenolone, progesterone and corticosterone were observed. ODM-208 showed high selectivity to CYP11A1 and no significant off-target binding was detected in the broad panel. ODM-208 exposure-dependent decreases in plasma testosterone and cortisol concentrations were detected. ODM-208 inhibited substantially tumor growth in murine CRPC VCaP xenograft model. A phase 1/2 study of ODM-208 administered concomitantly with corticosteroid replacement and androgen deprivation therapy in metastatic CRPC subjects is ongoing (NCT03436485). In subjects with ODM-208 treatment all studied serum steroid hormones were decreased to under lower limit of quantification in the LC-MS/MS assays. These preclinical and clinical data suggest that ODM-208 has potential to provide clinical benefit to patients with treatment-resistant CRPC bearing altered steroid synthesis and/or mutated AR. Citation Format: Mari Karimaa, Henna Kettunen, Meri Ramela, Suvi Mansikka-Savolainen, Marcin Chrusciel, Outi Simola, Päivi Taavitsainen, Gerd Wohlfahrt, Petteri Rummakko, Annamari Vuorela, Karim Fizazi, Riikka Oksala. ODM-208, a novel, small-molecule CYP11A1 inhibitor, demonstrates strong inhibition of steroid biosynthesis and antitumor activity in castration-resistant prostate cancer (CRPC) model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1250.