Androgen Deprivation Therapy

Table 1.

Notable Randomized Trials of Combined Androgen Deprivation and External Beam Radiation Therapy in Locally Advanced Prostate Cancer

Jemal A et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71-96
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
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
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
Labrie FMD (2004) Adrenal androgens and intracrinology. Semin Reprod Med 22: 299-309
Takashi I et al. (2008) The role of testosterone in the pathogenesis of prostate cancer. Int J Urol 15: 472-480
Askew EB et al. (2007) Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem 282: 25801-25816
Feldman BJ and Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34-45
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
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
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
Ohlson N et al. (2005) Cell proliferation and apoptosis in prostate tumors and adjacent nonmalignant prostate tissue in patients at different time-points after castration treatment. Prostate 62: 307-315
Mercader M et al. (2007) Early effects of pharmacological androgen deprivation in human prostate cancer. BJU Int 99: 60-67
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
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
[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
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
Boccon-Gibod L et al. (2007) The role of intermittent androgen deprivation in prostate cancer. BJU Int 100: 738-743
Pienta KJ and Bradley D (2006) Mechanisms underlying the development of androgenindependent prostate cancer. Clin Cancer Res 12: 1665-1671
Tangen CM et al. (2003) Ten-year survival in patients with metastatic prostate cancer. Clin Prostate Cancer 2: 41-45
[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
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
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
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
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
Pollack A et al. (2001) Lack of prostate cancer radiosensitization by androgen deprivation. Int J Radiat Oncol Biol Phys 51: 1002-1007
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
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
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
Messing EM et al. (2006) Immediate versus deferred androgen deprivation treatment in patients with nodepositive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7: 472-479
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
Stephenson AJ et al. (2004) Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 291: 1325-1332
Freedland SJ and Moul JW (2007) Prostate specific antigen recurrence after definitive therapy. J Urol 177: 1985-1991
Lu-Yao GL et al. (2008) Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 300: 173-181
Harle LK et al. (2006) Endocrine complications of androgen-deprivation therapy in men with prostate cancer. Clin Adv Hematol Oncol 4: 687-696
Michaelson MD et al. (2008) Management of complications of prostate cancer treatment. CA Cancer J Clin 58: 196-213
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
Chen CD et al. (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33-39
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
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
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
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
Mohler JL et al. (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10: 440-448
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
Stanbrough M et al. (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66: 2815-2825
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
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
Sato N et al. (1996) Intermittent androgen suppression delays progression to androgenindependent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol 58: 139-146
Wright JL et al. (2006) Intermittent androgen deprivation: clinical experience and practical applications. Urol Clin North Am 33: 167-179
Higano CS et al. (1996) Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 48: 800-804
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
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
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
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
Calais da Silva FM et al. (2006) Phase III intermittent MAB vs continuous MAB [abstract #4513]. J Clin Oncol 24 (Suppl 18): 4513
Malkowicz SB (2001) The role of diethylstilbestrol in the treatment of prostate cancer. Urology 58: 108-113
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
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
Landstrom M et al. (1994) Estrogen treatment postpones the castration-induced dedifferentiation of Dunning R3327-PAP prostatic adenocarcinoma. Prostate 25: 10.18
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
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
Ockrim JL et al. (2004) Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol 172: 2203.2207
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
Bland LB et al. (2005) Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer 103: 717.723
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
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
Sawyers CL et al. (2007) Characterization of a new antiandrogen 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
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
Reid AHM et al. (2008) CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 5: 610.620
Danila DC et al. (2008) Preliminary phase II results of abiraterone acetate in patients with castrationresistant 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
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
Vasaitis T et al. (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17ƒ¿.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
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
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)

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Author(s)

William P. Harris, MD

Medical Oncology Fellow, Fred Hutchinson Cancer Research Center; University of Washington School of Medicine, Seattle, Washington

Disclosures

Disclosure: William P. Harris, MD, has disclosed no relevant financial relationships.

Elahe A. Mostaghel, MD, PhD

Assistant Member; Assistant Professor, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, Washington

Disclosures

Disclosure: Elahe A. Mostaghel, MD, PhD, has disclosed no relevant financial relationships.

Peter S. Nelson, MD

Member; Professor, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, Washington

Disclosures

Disclosure: Peter S. Nelson, MD, has disclosed that he has acted as a consultant for and has received grant/research support from GlaxoSmithKline.

Bruce Montgomery, MD

Associate Professor, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, Washington

Disclosures

Disclosure: Bruce Montgomery, MD, has disclosed that he has received grant/research support from Cougar Biotechnology and GlaxoSmithKline.

Editor(s)

Suzanne Farley

Deputy Editor, Nature Clinical Practice Urology

Disclosures

Disclosure: Suzanne Farley has disclosed no relevant financial relationships.

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Summary and Introduction

Summary

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.

Introduction

Prostate cancer is the most common solid tumor and the second most common cause of cancer death among men in the United States,^[1] and its worldwide incidence is the second highest of all male non-skin malignancies.^[2] At present, approximately 85% of newly diagnosed prostate cancers are localized to the prostate, with the remainder representing invasive or metastatic disease.^[3] Recognized treatment options for early-stage disease include surgery, radiation therapy and active surveillance. For many men with metastatic or high-risk localized disease, androgen deprivation is a critical component of therapy, either alone or in combination with other modalities. This Review will provide an overview of historical and contemporary approaches to androgen deprivation in patients with advanced prostate cancer, and address its current clinical indications: either as monotherapy or in combination with local therapy. Mechanisms of resistance to classical androgen deprivation, which might be exploited to therapeutic effect in early and late-stage cancer, will be discussed, as will several promising new therapies that are undergoing early assessment.

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Historical Approaches to Androgen Deprivation Therapy

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Table 1.

Androgen Deprivation Therapy: Progress in Understanding Mechanisms of Resistance and Optimizing Androgen Depletion

Summary and Introduction

Summary

Introduction

Table of Contents

Table 1.

References

Faculty and Disclosures

Author(s)

William P. Harris, MD

Elahe A. Mostaghel, MD, PhD

Peter S. Nelson, MD

Bruce Montgomery, MD

Editor(s)

Suzanne Farley

Androgen Deprivation Therapy: Progress in Understanding Mechanisms of Resistance and Optimizing Androgen Depletion

Summary and Introduction

Summary

Introduction

Table of Contents