Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).

Abstract

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

“…Similarly, CA34, CA79 and CA43 clusters had at least two different patientunique AR genomic architectures achieving similar levels of AR copy number gain, and in CA34, we identified different frequencies of distinct break-points suggesting multiple sub-clones that had independently acquired structural change associated with similar levels of AR amplification. This could justify classification of patients by AR gene class for therapeutic intervention, as for example is being attempted for patients harboring AR mutations (7, 8). Overall, whilst we identified greater intra-patient diversity than described previously, the uniformity across clusters of metastases dominated by a single clone contextualizes these previous results that might have primarily obtained samples from the same cluster (34).…”

“…Selection of clones harboring AR amplification or mutations (2,3), structural rearrangements, splice variants and a plethora of events consistent with treatmentmediated selection to maintain AR activity despite medical efforts to inhibit it result in an often rapidly lethal state that remains poorly understood (1). AR alterations in liquid or tissue biopsies associate with shorter responses to second-line next-generation hormonal treatments (4,5) and new drugs are in development to target aberrant AR (6)(7)(8). However, heterogeneity of AR alterations across metastases could create a challenge that complicates their utility as a biomarker or therapeutic target.…”

Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?

“…Recently, the phase I/II CYPIDES trial explored ODM-208, a CYP11A1 inhibitor able to suppress the synthesis of all steroid hormones and precursors in heavily pretreated patients with an activating AR LBD mutation. ODM-208 showed meaningful PSA reductions and up to four partial responses in 17 evaluable patients [ 138 ].…”

Highlights in Prostate Cancer from ASCO GU 2022

“…16 Novel treatment options on the horizon: ODM-208 and ARV-110 for mCRPC In contrast to abiraterone, which interferes with testosterone biosynthesis by inhibiting CYP17A1, 17 the novel agent ODM-208 acts at the first and rate-limiting stage of steroid hormone synthesis, by blocking CYP11A1 and thus suppressing production not only of androgens and their precursors but also glucocorticoids and mineralocorticoids. 18 This mode of action might benefit especially patients with activating mutations in the AR ligand-binding domain (LBD), as these allow for ligand promiscuity (activation by progesterone and cortisol) and might confer resistance to hormone-based therapies in mCRPC. 19,20 The safety and tolerability of ODM-208 were investigated in heavily pre-treated mCRPC patients in the phase I/II CYPIDES study (n=44).…”

“…19,20 The safety and tolerability of ODM-208 were investigated in heavily pre-treated mCRPC patients in the phase I/II CYPIDES study (n=44). 18 Enrolled patients had previously received at least one line of taxane-based chemotherapy and at least one AR signaling inhibitor. CYPIDES was designed as a classical 3+3 dose-escalation trial with an expansion cohort.…”