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

Shore, N. D. ; Abrahamsson, Per-Anders LU ; Anderson, J. ; Crawford, E. D. and Lange, P. (2013) In Prostate Cancer and Prostatic Diseases 16(1). p.7-15
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... (More)
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. Prostate Cancer and Prostatic Diseases (2013) 16, 7-15; doi:10.1038/pcan.2012.25; published online 3 July 2012 (Less)
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type
Contribution to journal
publication status
published
subject
keywords
androgen deprivation therapy, gonadotrophin-releasing hormone, agonists, antagonists
in
Prostate Cancer and Prostatic Diseases
volume
16
issue
1
pages
7 - 15
publisher
Nature Publishing Group
external identifiers
  • wos:000314866700002
  • scopus:84873704195
ISSN
1476-5608
DOI
10.1038/pcan.2012.25
language
English
LU publication?
yes
id
b01d473d-fc8d-4a0a-a041-9e6927053f48 (old id 3577051)
date added to LUP
2016-04-01 10:13:21
date last changed
2020-09-16 01:11:27
@article{b01d473d-fc8d-4a0a-a041-9e6927053f48,
  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. Prostate Cancer and Prostatic Diseases (2013) 16, 7-15; doi:10.1038/pcan.2012.25; published online 3 July 2012},
  author       = {Shore, N. D. and Abrahamsson, Per-Anders and Anderson, J. and Crawford, E. D. and Lange, P.},
  issn         = {1476-5608},
  language     = {eng},
  number       = {1},
  pages        = {7--15},
  publisher    = {Nature Publishing Group},
  series       = {Prostate Cancer and Prostatic Diseases},
  title        = {New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists},
  url          = {http://dx.doi.org/10.1038/pcan.2012.25},
  doi          = {10.1038/pcan.2012.25},
  volume       = {16},
  year         = {2013},
}