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-na€ ve, metastatic castration-resistant prostate cancer, and serum testosterone <50

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... 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 ¼ 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 ¼ 97), 45 of 84 evaluable patients (54%) achieved a !50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (À7.5 ng/dL) and dehydroepiandrosterone-sulfate (À45.3 mg/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. Clin Cancer Res; 20(5); 1335-44. Ó2014 AACR.