A subcutaneous delivery system for the extended release of leuprolide acetate for the treatment of prostate cancer

Abstract

Following Huggins’ original observation of the dependence of the prostate on androgens, testosterone suppression by either orchiectomy or oestrogen compounds (e.g., diethylstilbesterol [DES]) became the standard palliative treatment for advanced prostate cancer. Early studies showed testosterone suppression improved symptoms and patient survival by several months but was not curative. In addition, DES treatment resulted in significant cardiovascular morbidity and mortality from increased thrombotic events. Thus, both orchiectomy and DES were indicated for palliation in late stage disease, but were considered too extreme for earlier stage disease. The discovery of the hypothalamic peptide, luteinising hormone releasing hormone (LHRH), and its stimulatory release of luteinising hormone (LH) from the pituitary gland led to the synthesis of LHRH analogues (i.e., hormone therapy). LHRH analogues (e.g., leuprolide acetate) desensitise and downregulate pituitary LHRH receptors, thus reducing LH synthesis and release. The reduced release, in turn, decreases testosterone levels to those observed in DES-treated and orchiectomised patients. In contrast, LHRH analogues do not increase cardiovascular events. Therefore, leuprolide acetate therapy has been adopted as a safer alternative to DES and is considered to be generally reversible. This increased safety has allowed LHRH therapy to be applied in earlier stage prostate cancer. Recent studies have shown decreased rates of biochemical failure and a potential for increased patient survival with hormone therapy in conjunction with radical prostatectomy or radiation therapy. This article will focus on the literature supporting early, adjuvant LHRH therapy and Eligard® 7.5 mg, a new depot formulation of leuprolide acetate that uses the Atrigel® drug delivery system, causing an increase in bioavailability and optimising testosterone suppression – two key features of depot hormone suppression.