Prostate Cancer Management: What Does the Future Hold?

Abstract

Originally achieved through surgical castration or the administration of oestrogen analogues, androgen-deprivation therapy (ADT) has been the mainstay treatment of advanced prostate cancer (PCa) for >40 yr. In the years following Andrew Schally's characterisation of the structure of luteinising hormone-releasing hormone (LHRH) in the early 1980s, LHRH agonists have provided PCa patients with an alternative to surgery-based ADT without the notable adverse events (AEs) that may be associated with oestrogen analogues. Furthermore, the development of LHRH analogues has had the added benefit of allowing therapeutic reversibility, which is an important aspect of modern-day ADT. Further benefits that have arisen from the development of LHRH analogues have been an increased understanding of optimal serum testosterone suppression, the development of longer-duration depot formulations that are less likely to induce reinjection testosterone “flares”, and the management of the initial treatment flare with LHRH antagonists. Despite these recent advances, the treatment of PCa with LHRH agonists remains suboptimal when compared with surgical castration, and there is still room for therapeutic improvement. Potential mechanisms by which to deliver such therapeutic improvements will require further investigation into intracellular steroidogenesis and androgen pharmacology, pharmacology of LHRH agonists and antagonists, and improving the management of the AEs that are associated with ADT. This article reviews the advances that have been made in improving the recoverability of the hypothalamic–pituitary–testicular axis after cessation of LHRH agonist treatment, the improvements in drug-based intracellular castration in terms of the inhibition of intraprostatic steriodogenesis, the targeting of aberrant testosterone receptor function/levels, and strategies to manage the AEs that are associated with ADT.