Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion

A Corrigendum to this article was published on 01 March 2009

Abstract

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.

Key Points

  • Androgen deprivation therapy remains a critical component of treatment in men with advanced prostate cancer, and data supports its use in metastatic disease and in conjunction with surgery or radiation therapy in specific settings

  • Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit

  • Current androgen deprivation strategies seem to incompletely suppress androgen levels and AR-mediated effects at the tissue level

  • Multiple mechanisms are implicated in the development of castration resistance, but the majority involve continued activation of the AR, which might be targeted by novel therapeutic agents

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Androgen action.
Figure 2: Mechanisms of castration resistance in prostate cancer.

Similar content being viewed by others

References

  1. Jemal A et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71–96

    Article  Google Scholar 

  2. Kamangar F et al. (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24: 2137–2150

    Article  Google Scholar 

  3. Cooperberg MR et al. (2004) The contemporary management of prostate cancer in the United States: lessons from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE), a national disease registry. J Urol 171: 1393–1401

    Article  Google Scholar 

  4. Huggins C and Hodges CV (1941) Studies on prostate cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293–297

    CAS  Google Scholar 

  5. Labrie FMD (2004) Adrenal androgens and intracrinology. Semin Reprod Med 22: 299–309

    Article  CAS  Google Scholar 

  6. Takashi I et al. (2008) The role of testosterone in the pathogenesis of prostate cancer. Int J Urol 15: 472–480

    Article  Google Scholar 

  7. Askew EB et al. (2007) Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem 282: 25801–25816

    Article  CAS  Google Scholar 

  8. Feldman BJ and Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34–45

    Article  CAS  Google Scholar 

  9. Taplin ME (2007) Drug Insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol 4: 236–244

    Article  CAS  Google Scholar 

  10. Mostaghel EA et al. (2007) Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 67: 5033–5041

    Article  CAS  Google Scholar 

  11. Loblaw DA et al. (2007) Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 25: 1596–1605

    Article  CAS  Google Scholar 

  12. Ohlson N et al. (2005) Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment. Prostate 62: 307–315

    Article  Google Scholar 

  13. Mercader M et al. (2007) Early effects of pharmacological androgen deprivation in human prostate cancer. BJU Int 99: 60–67

    Article  CAS  Google Scholar 

  14. Montironi R et al. (1994) Effects of combination endocrine treatment on normal prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. J Clin Pathol 47: 906–913

    Article  CAS  Google Scholar 

  15. Agus DB et al. (1999) Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst 91: 1869–1876

    Article  CAS  Google Scholar 

  16. [No authors listed] (2000) Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 355: 1491–1498

  17. D'Amico AV et al. (2004) 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 292: 821–827

    Article  CAS  Google Scholar 

  18. Boccon-Gibod L et al. (2007) The role of intermittent androgen deprivation in prostate cancer. BJU Int 100: 738–743

    Article  CAS  Google Scholar 

  19. Pienta KJ and Bradley D (2006) Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 12: 1665–1671

    Article  CAS  Google Scholar 

  20. Tangen CM et al. (2003) Ten-year survival in patients with metastatic prostate cancer. Clin Prostate Cancer 2: 41–45

    Article  Google Scholar 

  21. [No authors listed] (1997) Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 79: 235–246

  22. Bolla M et al. (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360: 103–108

    Article  CAS  Google Scholar 

  23. Lawton CA et al. (2001) Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49: 937–946

    Article  CAS  Google Scholar 

  24. Pilepich MV et al. (2001) Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50: 1243–1252

    Article  CAS  Google Scholar 

  25. Denham JW et al. (2005) Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 6: 841–850

    Article  CAS  Google Scholar 

  26. Pollack A et al. (2001) Lack of prostate cancer radiosensitization by androgen deprivation. Int J Radiat Oncol Biol Phys 51: 1002–1007

    Article  CAS  Google Scholar 

  27. D'Amico AV et al. (2008) Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy. J Clin Oncol 26: 2979–2983

    Article  CAS  Google Scholar 

  28. Bolla M et al. (2007) Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT—results of the randomized EORTC Phase III trial 22961. JCO 2007 Annual Meeting Proceedings Part 1 25, 5014 [abstract #5014]. J Clin Oncol 25 (Suppl 18): 5014

    Google Scholar 

  29. Messing EM et al. (1999) Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781–1788

    Article  CAS  Google Scholar 

  30. Messing EM et al. (2006) Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7: 472–479

    Article  CAS  Google Scholar 

  31. Schröder FH et al. (2004) Early versus delayed endocrine treatment of pN1–3 M0 prostate cancer without local treatment of the primary tumor: results of the European Organization for the Research and Treatment of Cancer 30846—a phase III study. J Urol 172: 923–927

    Article  Google Scholar 

  32. Stephenson AJ et al. (2004) Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 291: 1325–1332

    Article  CAS  Google Scholar 

  33. Freedland SJ and Moul JW (2007) Prostate specific antigen recurrence after definitive therapy. J Urol 177: 1985–1991

    Article  Google Scholar 

  34. Lu-Yao GL et al. (2008) Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 300: 173–181

    Article  CAS  Google Scholar 

  35. Harle LK et al. (2006) Endocrine complications of androgen-deprivation therapy in men with prostate cancer. Clin Adv Hematol Oncol 4: 687–696

    PubMed  Google Scholar 

  36. Michaelson MD et al. (2008) Management of complications of prostate cancer treatment. CA Cancer J Clin 58: 196–213

    Article  Google Scholar 

  37. Seruga B and Tannock IF (2004) Intermittent androgen blockade should be regarded as standard therapy in prostate cancer. Nat Clin Pract Oncol 5: 574–576

    Article  Google Scholar 

  38. Chen CD et al. (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33–39

    Article  Google Scholar 

  39. Kraus S et al. (2006) Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer Res 66: 11047–11054

    Article  CAS  Google Scholar 

  40. Setlur SR and Rubin MA (2005) Current thoughts on the role of the androgen receptor and prostate cancer progression. Adv Anat Pathol 12: 265–270

    Article  CAS  Google Scholar 

  41. Liu J et al. (1985) Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue. J Clin Endocrinol Metab 61: 129–133

    Article  CAS  Google Scholar 

  42. Mostaghel EA et al. (2007) Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 67: 5033–5041

    Article  CAS  Google Scholar 

  43. Mohler JL et al. (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10: 440–448

    Article  CAS  Google Scholar 

  44. Montgomery RB et al. (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68: 4447–4454

    Article  CAS  Google Scholar 

  45. Stanbrough M et al. (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66: 2815–2825

    Article  CAS  Google Scholar 

  46. Dillard PR et al. (2008) Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol 295: 115–120

    Article  CAS  Google Scholar 

  47. Locke JA et al. (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68: 6407–6415

    Article  CAS  Google Scholar 

  48. Sato N et al. (1996) Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol 58: 139–146

    Article  CAS  Google Scholar 

  49. Wright JL et al. (2006) Intermittent androgen deprivation: clinical experience and practical applications. Urol Clin North Am 33: 167–179

    Article  Google Scholar 

  50. Higano CS et al. (1996) Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 48: 800–804

    Article  CAS  Google Scholar 

  51. Higano C et al. (2004) Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 64: 1182–1186

    Article  Google Scholar 

  52. Miller K et al. (2007) Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer [abstract #5015]. J Clin Oncol 25 (Suppl 18): 5015

    Google Scholar 

  53. Calais da Silva FM et al. (2008) Five years survival and risk of death in a phase III study of intermittent monotherapy versus continuous combined androgen deprivation [abstract #16034]. J Clin Oncology 26 (Suppl 15): 16034

    Article  Google Scholar 

  54. Tunn U et al. (2004) Intermittent is as effective as continuous androgen deprivation in patients with PSA relapse after radical prostatectomy [abstract #1458]. J Urol 171 (Suppl 4): 384

    Article  Google Scholar 

  55. Calais da Silva FM et al. (2006) Phase III intermittent MAB vs continuous MAB [abstract #4513]. J Clin Oncol 24 (Suppl 18): 4513

    Google Scholar 

  56. Malkowicz SB (2001) The role of diethylstilbestrol in the treatment of prostate cancer. Urology 58: 108–113

    Article  CAS  Google Scholar 

  57. Ricke WA et al. (2008) Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. FASEB J 22: 1512–1520

    Article  CAS  Google Scholar 

  58. Pravettoni A et al. (2007) Estrogen receptor beta (ERbeta) and inhibition of prostate cancer cell proliferation: studies on the possible mechanism of action in DU145 cells. Mol Cell Endocrinol 263: 46–54

    Article  CAS  Google Scholar 

  59. Landström M et al. (1994) Estrogen treatment postpones the castration-induced dedifferentiation of Dunning R3327-PAP prostatic adenocarcinoma. Prostate 25: 10–18

    Article  Google Scholar 

  60. Kitahara S et al. (1999) Effects of intravenous administration of high-dose diethylstilbestrol diphosphate on serum hormonal levels in patients with hormone-refractory prostate cancer. Endocrin J 46: 659–664

    Article  CAS  Google Scholar 

  61. Byar D and Corle DK (1988) Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 7: 165–170

    Google Scholar 

  62. Ockrim JL et al. (2004) Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol 172: 2203–2207

    Article  CAS  Google Scholar 

  63. Purnell JQ et al. (2006) Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer. J Lipid Res 47: 349–355

    Article  CAS  Google Scholar 

  64. Bland LB et al. (2005) Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer 103: 717–723

    Article  CAS  Google Scholar 

  65. Kandola S et al. (2007) Transdermal oestrogen therapy as a second-line hormonal intervention in prostate cancer: a bad experience. BJU Int 99: 53–55

    Article  CAS  Google Scholar 

  66. Klotz L et al. (2008) The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 102: 1531–1538

    Article  CAS  Google Scholar 

  67. Sawyers CL . et al. (2007) Characterization of a new anti-androgen MDV-3100 effective in preclinical models of hormone refractory prostate cancer [abstract #48]. Presented at the ASCO 2007 Prostate Cancer Symposium: February 22–24, Orlando, FL, USA

  68. Scher HI et al. (2008) Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC) [abstract #5006]. J Clin Oncol 26 (Suppl 15): 5006

    Article  Google Scholar 

  69. Reid AHM et al. (2008) CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 5: 610–620

    Article  CAS  Google Scholar 

  70. Danila DC . et al. (2008) Preliminary phase II results of abiraterone acetate in patients with castration-resistant metastatic prostate cancer after failure of docetaxel-based chemotherapy [abstract #3]. Presented at the ASCO 2008 Genitourinary Cancers Symposium: February 14–16, San Francisco, CA, USA

  71. Attard G et al. (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26: 4563–4571

    Article  CAS  Google Scholar 

  72. Vasaitis T et al. (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther 7: 2348–2357

    Article  CAS  Google Scholar 

  73. Mostaghel EA and Nelson PS (2008) Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab 22: 243–258

    Article  CAS  Google Scholar 

  74. GlaxoSmithKline (online 10 December 2008) NCT00470834: Prostate Cancer Study In Men Who Have Failed First-Line Androgen Deprivation Therapy [http://clinicaltrials.gov/ct2/show/NCT00470834] (accessed 12 December 2008)

Download references

Acknowledgements

This work was made possible by funding through the NIH/NCI Pacific Northwest Prostate Cancer SPORE grant P50CA97186 (to PS Nelson and B Montgomery) and the Kirschstein-NRSA T32 training grant (to WP Harris).Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bruce Montgomery.

Ethics declarations

Competing interests

PS Nelson has declared that he has acted as a consultant and received grant/research support from GlaxoSmithKline.

B Montgomery had declared that he has received grant/research support from Cougar Biotechnology.

WP Harris and EA Mostaghel declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harris, W., Mostaghel, E., Nelson, P. et al. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Rev Urol 6, 76–85 (2009). https://doi.org/10.1038/ncpuro1296

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro1296

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing