ODM-204 a novel dual inhibitor of CYP17A1 and androgen receptor: Early results from phase I dose escalation in men with castration-resistant prostate cancer.

246 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression, various AR mutations and persistent activation of AR signaling axis by residual tissue androgens and other steroids. Inhibiting both the AR and androgen biosynthesis may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and the AR that has shown activity in nonclinical tumor models. Methods: We report early data of the DUALIDES phase I dose escalation part (NCT02344017), in which patients with metastatic CRPC (mCRPC) were enrolled into ODM-204 dose levels of 50, 100, 200, 300, 500 mg twice daily. Data cut-off was Oct 14th2016. Results: In the trial 23 patients with progressive mCRPC received increasing doses of ODM-204. At baseline, the median age of patients was 70 yrs (57-84 yrs), and median PSA was 46.5 ng/mL (0.7-249.6 ng/mL). Median time on treatment was 11.6 weeks (0.3-60.4 wks). Nine (39%) patients continued treatment for more than 12 weeks, and 4 (17.4%) patients were still receiving treatment at the time of data cutoff. ODM-204 was generally well tolerated, and the most commonly reported adverse events (AEs) were fatigue (n = 6, 26%), nausea (n = 6, 26%), decreased appetite (n = 5, 22%,) diarrhea (n = 5, 22%), and vomiting (n = 5, 22%). Two patients discontinued treatment due to an AE. The AUCt and Cmax values of ODM-204 in plasma increased with dose up to 300 mg after a single dose. Steady state values on day 8 were unexpectedly decreased in most patients, especially at higher doses, contrary to what was observed in the nonclinical monkey studies. Further, decreased predose concentrations were observed on day 29. PSA decreases were seen in 7 (30%) patients, and the median decrease was 47% (2-99%). At 12 weeks, 3 (13%) patients had a PSA response ( ≥ 50% reduction from baseline). Conclusions: Although evidence of anticancer activity was provided with ODM-204 in mCRPC, decreasing steady state concentration was observed. Clinical trial information: NCT02344017.