title: Phase I/II trial of orteronel (TAK-700)--an investigational 17,20-lyase inhibitor--in patients with metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: David
authors.initials: D
authors.lastname: MacLean
authors.forename: Ajit
authors.initials: A
authors.lastname: Suri
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Daniel
authors.initials: D
authors.lastname: Shevrin
authors.forename: Lowell
authors.initials: L
authors.lastname: Hart
authors.forename: Gary R
authors.initials: GR
authors.lastname: MacVicar
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Gross
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Shi
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Webb
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D009281:Naphthalenes; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; C571806:orteronel