Approaches to minimize castration in the treatment of advanced prostate cancer

• Intermittent ADT and peripheral blockade are 2 approaches to minimizing castration.
• To date, their role in biochemical relapse and metastatic disease has not been fully defined.
• Ongoing studies with potent AR antagonists may provide path forward for noncastrating approach.

BackgroundAndrogen deprivation therapy (ADT) remains the cornerstone of primary systemic treatment for men with metastatic disease and is a commonly applied therapy in the biochemically relapsed setting. Despite the high response rate with ADT, resistance is universal. Furthermore, over the past decade, there has been a growing appreciation for the significant short-term and long-term toxicities of continuous ADT (CADT). The rationale to develop alternative androgen receptor (AR) targeting strategies that seek to minimize or eliminate the need for upfront castration therapy is 2-fold—(1) delay the emergence of AR-independent disease, potentially improving long-term disease outcomes and (2) mitigate the short-term and long-term side effects of CADT, improving quality of life and potentially lessening comorbidities related to ADT including osteoporosis, diabetes, and potentially cardiovascular disease. The 2 most rigorously studied alternatives to CADT include intermittent ADT and peripheral androgen blockade with the use of first-generation or second-generation AR antagonists. Both intermittent ADT and peripheral androgen blockade have been evaluated in the biochemically relapsed and metastatic setting in multiple phase 2 and 3 studies.AimIn the current review, we aim to discuss the data from these studies, as well as the emerging noncastrating strategies.