PURPOSE: The androgen receptor pathway remains active in men with prostate 
cancer whose disease has progressed following surgical or medical castration. 
Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, 
reversible inhibitor of 17,20-lyase, a key enzyme in the production of 
androgenic hormones.
EXPERIMENTAL DESIGN: We conducted a phase I/II study in men with progressive, 
chemotherapy-naïve, metastatic castration-resistant prostate cancer, and serum 
testosterone <50 ng/dL. In the phase I part, patients received orteronel 100 to 
600 mg twice daily or 400 mg twice a day plus prednisone 5 mg twice a day. In 
phase II, patients received orteronel 300 mg twice a day, 400 mg twice a day 
plus prednisone, 600 mg twice a day plus prednisone, or 600 mg once a day 
without prednisone.
RESULTS: In phase I (n = 26), no dose-limiting toxicities were observed and 13 
of 20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) 
decline from baseline at 12 weeks. In phase II (n = 97), 45 of 84 evaluable 
patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean 
reductions from baseline in testosterone (-7.5 ng/dL) and 
dehydroepiandrosterone-sulfate (-45.3 μg/dL) were observed. Unconfirmed partial 
responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases 
in circulating tumor cells were documented. Fifty-three percent of phase II 
patients experienced grade ≥3 adverse events irrespective of causality; most 
common were fatigue, hypokalemia, hyperglycemia, and diarrhea.
CONCLUSIONS: 17,20-Lyase inhibition by orteronel was tolerable and results in 
declines in PSA and testosterone, with evidence of radiographic responses.