title: Sequences and combinations of multifaceted therapy in advanced prostate cancer.
abstract: OBJECTIVE
  Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for use in advanced prostate cancer. The next wave of investigations is focused on the development of combinations and optimal sequences of the currently available agents. The focus of this article is to provide an update on clinical developments in advanced prostate cancer occurring within the past year and to highlight the ongoing investigations of promising novel targets and compounds.
  
  
  RESULTS
  The clinical use of enzalutamide prior to chemotherapy demonstrated improvement in progression-free survival and overall survival as compared with placebo in metastatic castrate resistant prostate cancer. This report of the Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (PREVAIL) trial led to the Food and Drug Administration approval of this agent. Novel agents such as cabozantinib and custirsen that had shown promising results in phase II trials revealed disappointing results in the phase III setting. The breakthrough report, of the ability of the androgen receptor splice variant mutation, detected in circulating tumor cells, to predict lack of response to abiraterone or enzalutamide, and the remarkable responses of poly(ADP-ribose) polymerase inhibitors in prostate cancer with breast cancer genes 1 and 2 (BRCA1/2) mutations, have elevated hopes of a bright future in the biomarker-driven therapeutic arena.
  
  
  CONCLUSIONS
  As the clinical application of the recently approved multifaceted therapies widens, trials addressing optimal sequences and combinations are gaining importance. In addition, exploring the utility of therapies in the hormone naive or nonmetastatic settings is an area of active investigation. Early use of available agents, optimal sequencing and aid of biomarkers to guide therapeutic choices will make the achievement of lifetime remissions in advanced prostate cancer a reachable goal.
authors: aKarmanos Cancer Institute bDepartment of Oncology, Wayne State University, Detroit, Michigan, USA.
authors: Ulka N
authors: UN
authors: Vaishampayan
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D024682:BRCA2 Protein / Q000097:blood; D003131:Combined Modality Therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D009364:Neoplasm Recurrence, Local; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000097:blood
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D047428:Protein Kinase Inhibitors; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D017430:Prostate-Specific Antigen