title: Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.
abstract: OBJECTIVE
  Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.
  
  
  METHODS
  Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.
  
  
  RESULTS
  One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).
  
  
  CONCLUSIONS
  Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
authors.affiliation: University of Michigan, Ann Arbor, MI, USA. dcsmith@umich.edu
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.forename: Aymen A
authors.initials: AA
authors.lastname: Elfiky
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.forename: Paul G
authors.initials: PG
authors.lastname: Corn
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Harzstark
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Spira
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.forename: Avishay
authors.initials: A
authors.lastname: Sella
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Christian
authors.initials: C
authors.lastname: Scheffold
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Weitzman
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000813:Anilides / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D016723:Bone Remodeling; D024042:Collagen Type I / Q000097:blood; D018572:Disease-Free Survival; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D010455:Peptides / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D010455:Peptides; D011725:Pyridines; C052929:collagen type I trimeric cross-linked peptide; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases; D000469:Alkaline Phosphatase