Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer: A review of their discovery, development, and place in therapy

Abstract

Background: Early identification of the biological activity of luteinizing hormone-releasing hormone (LHRH) paved the way for the synthesis of analogues with enhanced potency and biological properties. Early testing in animal models and humans provided insight into the potential clinical uses of these substances, and, within 10 years, LHRH-agonist therapy had become available for use in patients with advanced prostate cancer (PC). Over time, the role of LHRH-agonist therapy has expanded to include use as part of multimodal treatment regimens throughout the course of the disease. Objectives: This article reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PC. Methods: Relevant clinical studies were identified through searches of the English-language literature indexed on MEDLINE through May 2006. The main search terms were prostate cancer and LHRH agonist. Results: Results of the initial therapeutic trials of sustained-release depot formulations of LHRH agonists in patients with PC were reported in the mid-1980s, indicating that these agents were effective and well tolerated in improving clinical symptoms and producing medical castration. Longer-term studies and subsequent meta-analyses of randomized controlled trials in patients with advanced PC found no significant differences in overall survival when single-therapy androgen suppression was achieved through the use of LHRH-agonist therapy or orchiectomy. Randomized trials have reported significant improvements in diseasefree and overall survival in patients with locally advanced or high-grade PC treated with LHRH agonists in addition to radiotherapy. Several prospective randomized trials have reported decreases in rates of positive surgical margins with short-term (6 weeks to 4 months) neoadjuvant LHRH-agonist therapy in patients with stage T1 to T3a PC undergoing prostatectomy. Definitive comparisons of immediate and delayed treatment in patients with biochemical relapse have not been reported. However, the results of several studies suggest that immediate LHRH-agonist therapy (or orchiectomy) may improve the course of disease progression and survival. The risks of long-term treatment (eg, osteoporosis; fracture; anabolic loss of muscle mass, with a tendency toward weight gain) must be considered carefully in patients who are likely to receive chronic LHRH-agonist therapy. Intermittent schedules have been developed to reduce the adverse effects associated with LHRH-agonist therapy; some reports support sparing effects on bone and muscle mass and relative improvements in toxicities during off-therapy periods, whereas others have documented continuing decreases in bone mineral density (BMD), with the rate of bone loss highest during the early cycles of therapy. Bisphosphonate therapy has been shown to increase BMD in patients with PC and may therefore be beneficial when overt symptoms of osteopenia or osteoporosis are present. Conclusions: LHRH-agonist therapy has been the mainstay of treatment for advanced PC for >20 years. Clinical evidence supports expanding use of these agents at an earlier stage of disease and as part of multimodal regimens that include radiotherapy. There is a need for further study of the efficacy of adjuvant LHRH-agonist therapy along with prostatectomy, in patients with biochemical failure, in intermittent regimens, and in conjunction with cytotoxic therapies in late-stage disease.