title: Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen.
abstract: OBJECTIVE
  Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0).
  
  
  METHODS
  Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.
  
  
  RESULTS
  Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.
  
  
  CONCLUSIONS
  Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.
authors: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; mahahuss@umich.edu.
authors: Maha
authors: M
authors: Hussain
authors: MD Anderson Cancer Center, Houston, Texas;
authors: Paul G
authors: PG
authors: Corn
authors: Massachusetts General Hospital Cancer Center, Boston;
authors: M Dror
authors: MD
authors: Michaelson
authors: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland;
authors: Hans J
authors: HJ
authors: Hammers
authors: Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon;
authors: Joshi J
authors: JJ
authors: Alumkal
authors: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California;
authors: Charles J
authors: CJ
authors: Ryan
authors: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin; and.
authors: Justine Y
authors: JY
authors: Bruce
authors: Takeda Pharmaceuticals International Co.;
authors: Susan
authors: S
authors: Moran
authors: Takeda Pharmaceuticals International Co.;
authors: Shih-Yuan
authors: SY
authors: Lee
authors: Millennium: The Takeda Oncology Company, Cambridge, Massachusetts;
authors: H Mark
authors: HM
authors: Lin
authors: Duke University Medical Center, Durham, North Carolina.
authors: Daniel J
authors: DJ
authors: George
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D015519:Bone Density / Q000187:drug effects; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000627:therapeutic use*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D007093:Imidazoles; D009281:Naphthalenes; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; C571806:orteronel