title: Treating Patients with Metastatic Castration Resistant Prostate Cancer: A Comprehensive Review of Available Therapies.
abstract: OBJECTIVE
  The availability of newly approved treatment options for metastatic castration resistant prostate cancer is not matched with conclusive data on optimal sequencing strategies and resistance patterns. A comprehensive review of efficacy and safety data for new agents and current knowledge regarding treatment sequencing would enable treating physicians to make rational drug selections in patients with metastatic castration resistant prostate cancer.
  
  
  METHODS
  We searched MEDLINE® and relevant congresses for data on cabazitaxel, docetaxel, 223radium dichloride, abiraterone, enzalutamide and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and biomarkers of response.
  
  
  RESULTS
  Abiraterone and enzalutamide target the androgen axis with different mechanisms of action. Abiraterone blocks cytochrome P450 17, inhibiting androgen synthesis, whereas enzalutamide inhibits androgen receptor, reducing nuclear translocation of the androgen receptor complex and subsequent DNA binding. Both agents provide improved overall survival in patients with metastatic castration resistant prostate cancer who received prior docetaxel treatment and in those who are chemotherapy naïve. Cabazitaxel provides improved overall survival in patients with metastatic castration resistant prostate cancer with prior docetaxel therapy. Sipuleucel-T provides improved overall survival in asymptomatic patients and (223)radium provides improved overall survival in chemotherapy naïve and chemotherapy treated patients with symptomatic bone metastases. Selecting the correct treatment with metastatic castration resistant prostate cancer is complex as no head-to-head trials have been done and comparison between existing trials is difficult due to differences in study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom burden, metastasis type, performance status, comorbidities, adverse event profiles and patient preference. Another consideration is treatment sequence since some agents affect responses to subsequent choices. For example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen targeted agents. Identifying factors predictive of resistance is an area of ongoing research with androgen receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and are currently being studied.
  
  
  CONCLUSIONS
  New therapies for metastatic castration resistant prostate cancer have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.
authors.affiliation: Department of Urologic Oncology, School of Medicine, University of Colorado Denver, Aurora, Colorado. Electronic address: edc@edavidcrawford.com.
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
authors.affiliation: Division of Medical Oncology, Department of Medicine and Department of Urology, School of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Carolina Urologic Research Center, Myrtle Beach, South Carolina.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Shore
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Smilow Cancer Center, Yale University, New Haven, Connecticut.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
mesh_terms: D000726:Androgen Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000736:Androstenes / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D000077143:Docetaxel; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D011868:Radioisotopes / Q000009:adverse effects / Q000627:therapeutic use; D011883:Radium / Q000009:adverse effects / Q000627:therapeutic use; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014020:Tissue Extracts / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000726:Androgen Antagonists; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011868:Radioisotopes; D043823:Taxoids; D014020:Tissue Extracts; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C511774:sipuleucel-T; C540278:enzalutamide; C089740:abiraterone; C581106:radium Ra 223 dichloride; D011883:Radium
keywords: androgen antagonists; castration; drug therapy; neoplasm metastasis; prostatic neoplasms