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New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists

Prostate Cancer and Prostatic Diseases volume 16, pages 7–15 (2013)Cite this article

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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.

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Acknowledgements

The authors thank Marc B Garnick (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for his contribution to the abarelix component of the manuscript. Medical writing assistance (funded by Ferring Pharmaceuticals) was provided by Thomas Lavelle of Bioscript Stirling Ltd.

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Authors and Affiliations

  1. Carolina Urologic Research Center, Myrtle Beach, SC, USA

    N D Shore

  2. Department of Urology, Malmö-Lund University Hospital, Malmö, Sweden

    P-A Abrahamsson

  3. Department of Urology, Royal Hallamshire Hospital, Sheffield, UK

    J Anderson

  4. Department of Urology, University of Colorado at Denver, Denver, CO, USA

    E D Crawford

  5. Institute for Prostate Cancer Research, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    P Lange

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Correspondence to N D Shore.

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Neal D Shore: Consultant: Ferring, Sanofi, Watson, Astellas, Dendreon, Janssen, Amgen. Per-Anders Abrahamsson: no financial interest or conflicts with regard to the compounds included in this manuscript. John Anderson: previously received honoraria from Ferring Pharmaceuticals. E David Crawford: is an advisor to Ferring Pharmaceuticals, GlaxoSmithKline, Centocor and Sanofi-Aventis, and has been a meeting participant for Aureon. Paul Lange: no conflicts of interest.

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Shore, N., Abrahamsson, PA., Anderson, J. et al. New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists. Prostate Cancer Prostatic Dis 16, 7–15 (2013). https://doi.org/10.1038/pcan.2012.25

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  • DOI: https://doi.org/10.1038/pcan.2012.25

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