Intermittent Androgen Deprivation Therapy in Advanced Prostate Cancer

Abstract

Prostate cancer is an androgen driven cancer. Androgen deprivation therapy (ADT) has been the standard first line therapy for metastatic prostate cancer. Medical castration with Luteinizing hormone releasing hormone (LHRH) agonists and more recently LHRH antagonists has largely supplanted surgical castration. Key issues in optimizing ADT have been timing of ADT initiation in metastatic prostate cancer (early vs deferred), monotherapy with LHRH agonist alone vs combination therapy with an anti-androgen, and the schedule of medical castration (intermittent vs continuous). After numerous trials attempting to clarify the role of anti-androgens in initial therapy of metastatic prostate cancer with conflicting results on survival benefit with combination therapy, meta-analyses suggest a small but measurable prolongation in overall survival. The lower incidence of severe adverse events including cord compression in advanced prostate cancer with early ADT has established immediate initiation of ADT upon diagnosis of metastatic prostate cancer as standard clinical practice. The schedule of ADT has been the subject of extensive investigation spurred by early preclinical work suggesting continuous pressure of castration promoted development of castration resistance. Trials testing intermittent ADT in several clinical contexts including in patients with biochemical recurrence, suggested intermittent ADT is comparable to continuous ADT. However, except for the JPR7, trials had mixed patient populations and/or were not powered for overall survival (OS). The only OS powered large phase 3 trial in metastatic disease (INT-0162/SWOG-9346) demonstrated that survival with intermittent ADT is not comparable to that with continuous therapy. Continuous ADT therefore continues to be the standard; however, therapy should be tailored to a patient's individual needs with adequate counseling. Novel inhibitors of androgen synthesis including abiraterone and androgen receptor antagonists such as enzalutamide, and cytotoxic chemotherapy already proven to be effective in castration resistant prostate cancer are under investigation in hormone sensitive prostate cancer. If validated, they would represent a long overdue paradigm shift in advanced hormone sensitive prostate cancer management.