Mechanisms, Challenges, and Opportunities in Combined Radiation and Hormonal Therapies

Androgen receptor signaling blockade is perhaps the first example of targeted therapy in the treatment of cancer. Since the initial observations that prostate cancers depend on hormone signaling, hormonal therapies remain a cornerstone in the treatment of metastatic prostate cancer. Androgen deprivation therapy has been shown to improve outcomes involving treatment of prostate cancers with radiotherapy, though a mechanistic understanding into the optimal sequencing of androgen deprivation therapy and radiotherapy remains incomplete. In this review we highlight key clinical trials designed to study combinations of hormonal and radiotherapies and introduce recent discoveries into the complex biology of androgen receptor signaling and DNA damage and repair. These emerging mechanistic and translational studies may have profound implications on both our understanding of hormonal therapy and radiotherapy combinations and the development of novel treatment strategies for locally-advanced and metastatic castrate resistant prostate cancer. (C) 2021 Elsevier Inc. All rights reserved.