title: Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08).
abstract: BACKGROUND
  The phosphatase and tensin homolog (PTEN) tumor suppressor gene is deregulated in many advanced prostate cancers, leading to activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway and thus increased cell survival.
  
  
  OBJECTIVE
  To evaluate everolimus, an inhibitor of mTOR, in patients with metastatic castration-resistant prostate cancer (mCRPC), and to explore potentially predictive serum biomarkers by proteomics, the significance of PTEN status in tumor tissue, and the impact of everolimus on immune cell subpopulations and function.
  
  
  METHODS
  A total of 37 chemotherapy-naive patients with mCRPC and progressive disease were recruited to this single-arm phase 2 trial (ClinicalTrials.gov identifier NCT00976755).
  
  
  METHODS
  Everolimus was administered continuously at a dose of 10mg daily.
  
  
  METHODS
  The primary end point was progression-free survival (PFS) at 12 wk defined as the absence of prostate-specific antigen (PSA), radiographic progression, or clinical progression. Groups were compared using Wilcoxon rank-sum tests or Fisher exact tests for continuous and discrete variables, respectively. Time-to-event end points were analyzed using the Kaplan-Meier method and univariate Cox regression.
  
  
  CONCLUSIONS
  A total of 13 patients (35%; 95% confidence interval, 20-53) met the primary end point. Confirmed PSA response ≥50% was seen in two (5%), and four further patients (11%) had a PSA decline ≥30%. Higher serum levels of carboxypeptidase M and apolipoprotein B were predictive for reaching the primary end point. Deletion of PTEN was associated with longer PFS and response. Treatment was associated with a dose-dependent decrease of CD3, CD4, and CD8 T lymphocytes and CD8 proliferation and an increase in regulatory T cells. Small sample size was the major limitation of the study.
  
  
  CONCLUSIONS
  Everolimus activity in unselected patients with mCRPC is moderate, but PTEN deletion could be predictive for response. Several serum glycoproteins were able to predict PFS at 12 wk. Prospective validation of these potential biomarkers is warranted.
  
  
  BACKGROUND
  This study is registered with ClinicalTrials.gov with the identifier NCT00976755. Results of this study were presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology (June 3-7, 2011; Chicago, IL, USA) and the annual meeting of the German, Austrian, and Swiss Societies for Oncology and Hematology (September 30-October 4, 2011; Basel, Switzerland).
authors.affiliation: Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland. arnoud.templeton@kssg.ch
authors.forename: Arnoud J
authors.initials: AJ
authors.lastname: Templeton
authors.forename: Valérie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.forename: Christian
authors.initials: C
authors.lastname: Rothermundt
authors.forename: Daniela
authors.initials: D
authors.lastname: Bärtschi
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dröge
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.forename: Markus
authors.initials: M
authors.lastname: Borner
authors.forename: Eva
authors.initials: E
authors.lastname: Fechter
authors.forename: Frank
authors.initials: F
authors.lastname: Stenner
authors.forename: Ralph
authors.initials: R
authors.lastname: Winterhalder
authors.forename: Beat
authors.initials: B
authors.lastname: Müller
authors.forename: Ralph
authors.initials: R
authors.lastname: Schiess
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Jan H
authors.initials: JH
authors.lastname: Rüschoff
authors.forename: George
authors.initials: G
authors.lastname: Thalmann
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.forename: Silke
authors.initials: S
authors.lastname: Gillessen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005060:Europe; D000068338:Everolimus; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016016:Proportional Hazards Models; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D020123:Sirolimus