title: Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure.
abstract: OBJECTIVE
  To determine the efficacy and toxicity of danusertib (formerly PHA-739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.
  
  
  METHODS
  In this open-label, multicentre phase II trial 88 patients were randomly assigned (1:1 ratio) to receive either danusertib 330 mg/m(2) over 6 h i.v. on days 1, 8 and 15 (arm A, n = 43) or 500 mg/m(2) over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks. The primary endpoint chosen for this exploratory study was PSA response rate at 3 months.
  
  
  RESULTS
  Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint. Median progression-free survival was 12 weeks in both arms. PSA response occurred in one patient in each arm; best overall response was stable disease in eight (18.6%) and 13 (34.2%) patients in arms A and B, respectively. Eleven out of 81 (13.6%) treated patients had stable disease for ≥6 months. Danusertib was generally well tolerated; the most common grade 3 and 4 drug-related adverse event was neutropenia which occurred in 37.2% (arm A) and 15.8% (arm B) of the patients.
  
  
  CONCLUSIONS
  Danusertib monotherapy shows minimal efficacy in patients with castration-resistant prostate cancer. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. h.meulenbeld@erasmusmc.nl
authors.forename: Hielke J
authors.initials: HJ
authors.lastname: Meulenbeld
authors.forename: Jean P
authors.initials: JP
authors.lastname: Bleuse
authors.forename: Elio M
authors.initials: EM
authors.lastname: Vinci
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Giordano
authors.initials: G
authors.lastname: Vitali
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Rossana
authors.initials: R
authors.lastname: Berardi
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.forename: Maria G
authors.initials: MG
authors.lastname: Jannuzzo
authors.forename: Mariangela
authors.initials: M
authors.lastname: Mariani
authors.forename: Anna
authors.initials: A
authors.lastname: Petroccione
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D064127:Aurora Kinases; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000556:secondary; D002369:Castration; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D043823:Taxoids / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D011720:Pyrazoles; D043823:Taxoids; D000077143:Docetaxel; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib