Resistance to second-generation androgen receptor antagonists in prostate cancer

Nat Rev Urol. 2021 Apr;18(4):209-226. doi: 10.1038/s41585-021-00438-4. Epub 2021 Mar 19.


The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Androgen Receptor Antagonists / therapeutic use*
  • Benzamides / therapeutic use*
  • Drug Resistance, Neoplasm*
  • Humans
  • Male
  • Nitriles / therapeutic use*
  • Phenylthiohydantoin / therapeutic use*
  • Prostatic Neoplasms / drug therapy*
  • Pyrazoles / therapeutic use*
  • Thiohydantoins / therapeutic use*


  • Androgen Receptor Antagonists
  • Benzamides
  • Nitriles
  • Pyrazoles
  • Thiohydantoins
  • apalutamide
  • darolutamide
  • Phenylthiohydantoin
  • enzalutamide