New Considerations for ADT in Advanced Prostate Cancer and the Emerging Role of GnRH Antagonists

N D Shore; P-A Abrahamsson; J Anderson; E D Crawford; P Lange

Disclosures

Prostate Cancer Prostatic Dis. 2013;16(1):7-15. 

In This Article

Abstract and Introduction

Abstract

Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.

Introduction

Androgen deprivation therapy (ADT) is first-line treatment for advanced/metastatic prostate cancer (PCa) and recommended before, during or after definitive radiotherapy for intermediate and high-risk localized PCa.[1–3] ADT is also commonly used for short periods to shrink prostate volume in patients contemplating interstitial seed implantation of PCa,[2,4] in glands >50 g, albeit this indication does not have a US Food and Drug Administration (FDA) or European Medicines Agency (EMEA) labelled indication. ADT may be accomplished with bilateral orchiectomy or via gonadotrophin-releasing hormone (GnRH) agonists or antagonists.

GnRH agonists became the leading ADT due to the reduced psychological morbidity and almost equivalent efficacy to surgical castration.[1] However, agonists display several shortcomings including testosterone surge/microsurges.[1,5] GnRH antagonists were developed with a view toward overcoming the physiologic drawbacks of agonists.

Irrespective of how it is achieved, testosterone suppression causes adverse events (AEs), e.g. hot flushes, osteoporosis and cardiometabolic effects.[6] PSA testing has increased the proportion of PCa patients diagnosed at earlier stages. The consequent increase in ADT utilization highlights the importance of strategies to reduce AEs associated with testosterone suppression.

This review compares ADT delivered by GnRH agonists and antagonists and assesses the potential future role of GnRH antagonists in PCa therapy. Novel strategies to minimize the AE risk of testosterone reduction are also explored.

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