title: Efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. A systematic review and meta-analysis.
abstract: OBJECTIVE
  We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel).
  
  
  METHODS
  We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).
  
  
  RESULTS
  Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).
  
  
  CONCLUSIONS
  In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).
authors.affiliation: Biomedical Research Division, Dept. of Theoretical and Applied Sciences, Università degli Studi dell'Insubria, Busto Arsizio, Italy; Department of Basic Medical Sciences, Ghent University, Ghent. gianpaolo.perletti@uninsubria.it.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Perletti
authors.forename: Elena
authors.initials: E
authors.lastname: Monti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marras
authors.forename: Anne
authors.initials: A
authors.lastname: Cleves
authors.forename: Vittorio
authors.initials: V
authors.lastname: Magri
authors.forename: Alberto
authors.initials: A
authors.lastname: Trinchieri
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
mesh_terms: D000069501:Abiraterone Acetate; D000736:Androstenes / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D019317:Evidence-Based Medicine; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D000074324:Ipilimumab; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000736:Androstenes; D000911:Antibodies, Monoclonal; D001549:Benzamides; D007093:Imidazoles; D000074324:Ipilimumab; D009281:Naphthalenes; D009570:Nitriles; D043823:Taxoids; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide; D000069501:Abiraterone Acetate; C571806:orteronel