title: Phase II Trial of Carboplatin, Everolimus, and Prednisone in Metastatic Castration-resistant Prostate Cancer Pretreated With Docetaxel Chemotherapy: A Prostate Cancer Clinical Trial Consortium Study.
abstract: OBJECTIVE
  To conduct a phase II trial of the combination of carboplatin, prednisone, and everolimus in metastatic castrate-resistant prostate cancer (mCRPC) as mTOR inhibition can overcome resistance to chemotherapy in prostate cancer.
  
  
  METHODS
  Patients with progressive mCRPC pretreated with docetaxel-based regimen were eligible. Performance status of 0-1 and adequate bone marrow, renal, and liver function were required. Primary end point was time to progression. Treatment consisted of carboplatin (starting dose equal to area under the curve (AUC of 5) intravenously every 21 days along with oral everolimus 5 mg once daily and prednisone 5 mg twice daily.
  
  
  RESULTS
  Twenty-six patients were enrolled with median age of 69 years with 8 patients of African American origin. Grade 3 or 4 thrombocytopenia or neutropenia in 4 of 6 initial patients required dose adjustment of carboplatin to AUC of 4 for subsequent patients. There were no pharmacokinetic interactions between carboplatin and everolimus. The median time to progression was 2.5 months (90% confidence interval [CI], 1.8-4.3 months), and median overall survival was 12.5 months (90% CI, 7.7-18.7 months). Of 10 patients, 8 that demonstrated positive nuclear phosphorylated AKT (pAKT) staining on immunohistochemistry progressed within 9 weeks, whereas 2 patients with negative staining continued without progression for prolonged durations of 30 and 48 weeks. TSC1 gene mutations did not correlate with clinical outcome.
  
  
  CONCLUSIONS
  The addition of the mTOR inhibitor everolimus to carboplatin demonstrated minimal clinical efficacy in metastatic prostate cancer. pAKT testing warrants further evaluation as a predictive marker of response to everolimus therapy.
authors.affiliation: Department of Oncology, Department of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI. Electronic address: vaishamu@karmanos.org.
authors.forename: Ulka
authors.initials: U
authors.lastname: Vaishampayan
authors.affiliation: Department of Oncology, Northshore University Health System, Evanston, IL.
authors.forename: Daniel
authors.initials: D
authors.lastname: Shevrin
authors.affiliation: Department of Oncology, Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Mark
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Oncology, Biostatistics Core, Barbara Ann Karmanos Cancer Institute, Detroit, MI.
authors.forename: Lance
authors.initials: L
authors.lastname: Heilbrun
authors.affiliation: Department of Oncology, John D. Dingell Veterans Medical Center, Detroit, MI.
authors.forename: Susan
authors.initials: S
authors.lastname: Land
authors.affiliation: Department of Oncology, Department of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI.
authors.forename: Karri
authors.initials: K
authors.lastname: Stark
authors.affiliation: Department of Oncology, Department of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Department of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI.
authors.forename: Brenda
authors.initials: B
authors.lastname: Dickow
authors.affiliation: Department of Oncology, Department of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heath
authors.affiliation: Department of Oncology, Biostatistics Core, Barbara Ann Karmanos Cancer Institute, Detroit, MI.
authors.forename: Daryn
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Oncology, John D. Dingell Veterans Medical Center, Detroit, MI.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fontana
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D018450:Disease Progression; D000077143:Docetaxel; D000068338:Everolimus / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D009360:Neoplastic Cells, Circulating; D010766:Phosphorylation; D011241:Prednisone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000032:analysis; D043823:Taxoids / Q000008:administration & dosage; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C000624650:TSC1 protein, human; D043823:Taxoids; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000077143:Docetaxel; D000068338:Everolimus; D016190:Carboplatin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen; D011241:Prednisone