• Robert Dreicer, David MacLean, Ajit Suri, Walter M Stadler, Daniel Shevrin, Lowell Hart, Gary R MacVicar, Omid Hamid, John Hainsworth, Mitchell E Gross, Yuanjun Shi, Iain J Webb, and David B Agus.
• Authors' Affiliations: Cleveland Clinic, Cleveland, Ohio; Takeda Pharmaceuticals International Company; Millennium: The Takeda Oncology Company, Cambridge, Massachusetts; University of Chicago, Chicago; NorthShore University Health System, Evanston; Northwestern University Feinberg School of Medicine, Chicago, Illinois; Florida Cancer Specialists, Fort Myers, Florida; The Angeles Clinic & Research Institute, Los Angeles; University of Southern California Westside Cancer Center, Beverly Hills, California; and Sarah Cannon Cancer Research Institute, Nashville, Tennessee.
• Clin Cancer Res. 2014 Mar 1;20(5):1335-44.

PurposeThe 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 DesignWe 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.ResultsIn 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.Conclusions17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses.©2014 AACR

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