Androgen Receptor Targeted Therapies in Castration-Resistant Prostate Cancer: Bench to Clinic

Int J Urol. 2016 Aug;23(8):654-65. doi: 10.1111/iju.13137. Epub 2016 Jun 14.


The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer.

Keywords: EPI-506; androgen receptor; castration-resistant prostate cancer; novel agents; prostate cancer; splice variants.

Publication types

  • Review

MeSH terms

  • Androgen Antagonists / therapeutic use*
  • Androgens
  • Drug Delivery Systems
  • Drug Resistance, Neoplasm
  • Humans
  • Male
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Radium
  • Receptors, Androgen / drug effects*


  • Androgen Antagonists
  • Androgens
  • Receptors, Androgen
  • Radium-223
  • Radium