New approaches to targeting the androgen receptor pathway in prostate cancer

Pedro Isaacsson Velho, Diogo Assed Bastos, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review


The androgen signaling axis has been the main therapeutic target in the management of advanced prostate cancer for several decades. Over the past years, significant advances have been made in terms of a better understanding the androgen receptor (AR) pathway and mechanisms of castration resistance, along with the development of more potent AR-targeted therapies. New drugs, such as abiraterone, enzalutamide, apalutamide, and darolutamide, have been approved for castration-resistant prostate cancer and also have demonstrated an overall survival benefit in the castration-sensitive state. Despite these major advances, the majority of patients eventually present with disease progression and a rise in prostate-specific antigen, reflecting a continuous dependence of disease on the AR pathway. In this setting, a number of AR-related mechanisms of resistance have been described, and novel strategies to overcome them are an important unmet need. In this manuscript, we review the most promising strategies to target the AR pathway in prostate cancer, including bromodomain and extraterminal (BET)/bromodomain inhibitors, CREB-binding protein/p300 inhibitors, N-terminal domain inhibitors, proteolysis- targeting chimeras, and AR-targeting vaccines. Another interesting and disruptive approach to targeting the AR and potentially reversing resistance to second-generation AR antagonists is the cyclic administration of high-dose testosterone, known as bipolar androgen therapy, which is currently being explored in multiple ongoing trials.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalClinical Advances in Hematology and Oncology
Issue number4
StatePublished - 2021


  • Androgen receptor
  • Prostate cancer

ASJC Scopus subject areas

  • Hematology
  • Oncology


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