title: Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial.
abstract: BACKGROUND
  ODM-201 is a novel androgen receptor (AR) inhibitor designed to block the growth of prostate cancer cells through high-affinity binding to the AR and inhibition of AR nuclear translocation. This trial assessed ODM-201's safety, pharmacokinetics, and activity in men with metastatic castration-resistant prostate cancer.
  
  
  METHODS
  The ARADES trial is an open-label phase 1-2 trial undertaken in 23 hospitals across Europe and USA with ongoing long-term follow-up. Men with progressive metastatic castration-resistant prostate cancer, who had castrate concentrations of testosterone and an Eastern Cooperative Oncology Group score of 0-1 were enrolled. In the phase 1 part of the trial, patients were given oral ODM-201 at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. In phase 2, patients were randomly assigned centrally and stratified by previous chemotherapy and treatment with CPY17 inhibitors, to receive one of three daily doses of ODM-201 (200 mg, 400 mg, and 1400 mg). The primary endpoint in phase 1 was safety and tolerability, whereas in phase 2 it was the proportion of patients with a PSA response (50% or greater decrease in serum PSA) at week 12. All analyses included patients who had received at least one dose of ODM-201. This trial is registered with ClinicalTrials.gov, number NCT01317641, and NCT01429064 for the follow-up after 12 weeks.
  
  
  RESULTS
  We enrolled patients between April 5, 2011, and March 12, 2013. In phase 1, 24 patients were enrolled to six sequential cohorts of three to six patients and received a daily dose of ODM-201, 200-1800 mg. No dose-limiting toxic effects were reported and the maximum tolerated dose was not reached. In phase 1, three patients reported eight adverse events of grade 3 (fracture, muscle injury, laceration, paralytic ileus, pain, presyncope, urinary retention, and vomiting) and one patient had a grade 4 adverse event (lymphoedema). None of the grade 3-4 adverse events were deemed to be related to ODM-201. Of the phase 1 patients, the four who received 200 mg, seven who received 400 mg, and three who received 1400 mg entered the phase 2 part of the trial. In addition to these patients, 110 were randomly assigned to three groups: 200 mg (n=38), 400 mg (n=37), and 1400 mg (n=35). For these patients, the most common treatment-emergent adverse events were fatigue or asthenia (15 [12%] of 124 patients), hot flush (six [5%]), and decreased appetite (five [4%]). One patient (<1%) had a grade 3 treatment-emergent adverse event (fatigue); no patients had a treatment-emergent grade 4 adverse event. 38 patients who received 200 mg, 39 who received 400 mg, and 33 who received 1400 mg were assessable for PSA response at 12 weeks. 11 (29%) patients in the 200 mg group, 13 (33%) in the 400 mg group, and 11 (33%) in the 1400 mg group had a PSA response at 12 weeks.
  
  
  CONCLUSIONS
  Our results suggest that ODM-201 monotherapy in men with progressive metastatic castration-resistant prostate cancer provides disease suppression and that ODM-201 has a favourable safety profile. These findings support further investigation of clinical responses with ODM-201 in men with castration-resistant prostate cancer.
  
  
  BACKGROUND
  Orion Corporation Orion Pharma, Endo Pharmaceuticals Inc.
authors: Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: fizazi@igr.fr.
authors: Karim
authors: K
authors: Fizazi
authors: Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors: Christophe
authors: C
authors: Massard
authors: Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
authors: Petri
authors: P
authors: Bono
authors: Velindre Cancer Centre, Cardiff, UK.
authors: Robert
authors: R
authors: Jones
authors: Kuopio University Hospital, Kuopio, Finland.
authors: Vesa
authors: V
authors: Kataja
authors: Queen Elizabeth Hospital, Birmingham, UK.
authors: Nicholas
authors: N
authors: James
authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
authors: Jorge A
authors: JA
authors: Garcia
authors: Churchill Hospital, Oxford, UK.
authors: Andrew
authors: A
authors: Protheroe
authors: Tampere University Hospital, Tampere, Finland.
authors: Teuvo L
authors: TL
authors: Tammela
authors: Christie Hospital NHS, Manchester, UK.
authors: Tony
authors: T
authors: Elliott
authors: Orion Corporation Orion Pharma, Espoo, Finland.
authors: Leena
authors: L
authors: Mattila
authors: Orion Corporation Orion Pharma, Espoo, Finland.
authors: John
authors: J
authors: Aspegren
authors: Orion Corporation Orion Pharma, Espoo, Finland.
authors: Annamari
authors: A
authors: Vuorela
authors: Endo Pharmaceuticals, Malvern, USA.
authors: Peter
authors: P
authors: Langmuir
authors: Orion Corporation Orion Pharma, Espoo, Finland.
authors: Mika
authors: M
authors: Mustonen
mesh_terms: D000284:Administration, Oral; D000368:Aged; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D061214:Patient Safety; D018579:Patient Selection; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D059002:Androgen Receptor Antagonists; D011720:Pyrazoles; C000607739:darolutamide; D017430:Prostate-Specific Antigen