title: Systemic therapy in men with metastatic castration-resistant prostate cancer: a systematic review.
abstract: OBJECTIVE
  Since 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC.
  
  
  METHODS
  Searches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC.
  
  
  RESULTS
  Twenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival.
  
  
  CONCLUSIONS
  Docetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.
authors.affiliation: Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario, Canada. andrew.loblaw@sunnybrook.ca
authors.forename: D A
authors.initials: DA
authors.lastname: Loblaw
authors.forename: C
authors.initials: C
authors.lastname: Walker-Dilks
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.forename: S J
authors.initials: SJ
authors.lastname: Hotte
mesh_terms: D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D043823:Taxoids / Q000008:administration & dosage; D014020:Tissue Extracts / Q000008:administration & dosage
chemical_list: D000736:Androstenes; D000737:Androstenols; D043823:Taxoids; D014020:Tissue Extracts; D000077143:Docetaxel; C552428:cabazitaxel; C511774:sipuleucel-T; C089740:abiraterone