Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Initial systemic therapy for castration sensitive prostate cancer

Richard J Lee, MD, PhD
Matthew R Smith, MD, PhD
Section Editors
Nicholas Vogelzang, MD
W Robert Lee, MD, MS, MEd
Jerome P Richie, MD, FACS
Deputy Editor
Michael E Ross, MD


The critical role of androgens in stimulating prostate cancer growth was established in 1941 by Charles Huggins [1,2]. These findings led to the development of androgen deprivation therapy (ADT) as the treatment for patients with advanced prostate cancer.

Although ADT is palliative, it can normalize serum levels of prostate-specific antigen (PSA) in over 90 percent of patients and can produce objective tumor responses in 80 to 90 percent. This antitumor activity can improve quality of life by reducing bone pain as well as the rates of complications (eg, pathologic fracture, spinal cord compression, ureteral obstruction).

The duration of response to ADT for patients with metastatic disease is highly variable, and most prostate cancer patients eventually experience disease progression despite treatment. Patients who have progressed while on ADT are said to have castration resistant disease, although such tumors may remain responsive to additional therapies directed against androgenic stimulation of the prostate cancer.

Docetaxel was subsequently shown to prolong survival in men with castration resistant prostate cancer. Randomized controlled trials have demonstrated that chemohormonal therapy combining docetaxel with ADT offers a clinically meaningful survival advantage for patients with castration sensitive metastatic disease. (See "Chemotherapy in castration-resistant prostate cancer", section on 'Chemotherapy-naive patients' and 'Chemohormonal therapy' below.)

The initial therapy for men with castration sensitive metastatic prostate cancer will be reviewed here. An overview of the treatment of disseminated prostate cancer is presented separately, as are special considerations for patients whose only manifestation of disseminated disease is a rising serum PSA. (See "Overview of the treatment of disseminated prostate cancer" and "Rising serum PSA after treatment for localized prostate cancer: Systemic therapy".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: May 2017. | This topic last updated: Feb 16, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effects of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293.
  2. Huggins C, Stevens J, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941; 43:209.
  3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007; 25:1596.
  4. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on July 06, 2012).
  5. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014; 65:467.
  6. Byar DP. Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 1973; 32:1126.
  7. Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 1988; :165.
  8. Loblaw DA, Mendelson DS, Talcott JA, et al. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 2004; 22:2927.
  9. Oefelein MG, Feng A, Scolieri MJ, et al. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology 2000; 56:1021.
  10. Cassileth BR, Soloway MS, Vogelzang NJ, et al. Patients' choice of treatment in stage D prostate cancer. Urology 1989; 33:57.
  11. Chapman JP. Comparison of testosterone and LH values in subcapsular vs total orchiectomy patients. Urology 1987; 30:27.
  12. Zhang XZ, Donovan MP, Williams BT, Mohler JL. Comparison of subcapsular and total orchiectomy for treatment of metastatic prostate cancer. Urology 1996; 47:402.
  13. James ND, Spears MR, Clarke NW, et al. Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol 2015; 67:1028.
  14. Tolis G, Ackman D, Stellos A, et al. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci U S A 1982; 79:1658.
  15. Schally AV, Coy DH, Arimura A. LH-RH agonists and antagonists. Int J Gynaecol Obstet 1980; 18:318.
  16. Waxman J, Man A, Hendry WF, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J (Clin Res Ed) 1985; 291:1387.
  17. Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991; 324:93.
  18. Limonta P, Montagnani Marelli M, Moretti RM. LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action. Expert Opin Investig Drugs 2001; 10:709.
  19. Shahidi M, Norman AR, Gadd J, et al. Recovery of serum testosterone, LH and FSH levels following neoadjuvant hormone cytoreduction and radical radiotherapy in localized prostate cancer. Clin Oncol (R Coll Radiol) 2001; 13:291.
  20. Hall MC, Fritzsch RJ, Sagalowsky AI, et al. Prospective determination of the hormonal response after cessation of luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. Urology 1999; 53:898.
  21. Djavan B, Eastham J, Gomella L, et al. Testosterone in prostate cancer: the Bethesda consensus. BJU Int 2012; 110:344.
  22. Crook JM, O'Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012; 367:895.
  23. Klotz L, O'Callaghan C, Ding K, et al. Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 2015; 33:1151.
  24. Suzman DL, Antonarakis ES. Does degree of androgen suppression matter in hormone-sensitive prostate cancer? J Clin Oncol 2015; 33:1098.
  25. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on July 18, 2012).
  26. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.
  27. Klotz L, Boccon-Gibod L, Shore ND, et al. 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 2008; 102:1531.
  28. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010; 57:836.
  29. Schröder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106:182.
  30. Smith MR, Klotz L, Persson BE, et al. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol 2010; 184:2313.
  31. Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology 2014; 83:1122.
  32. Klotz L, Miller K, Crawford ED, et al. Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Eur Urol 2014; 66:1101.
  33. Kuhn JM, Billebaud T, Navratil H, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989; 321:413.
  34. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321:419.
  35. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998; 339:1036.
  36. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 2000; 355:1491.
  37. Schmitt B, Bennett C, Seidenfeld J, et al. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 2000; :CD001526.
  38. Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002; 95:361.
  39. Klotz L, Schellhammer P, Carroll K. A re-assessment of the role of combined androgen blockade for advanced prostate cancer. BJU Int 2004; 93:1177.
  40. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013; 368:1314.
  41. Calais da Silva F, Calais da Silva FM, Gonçalves F, et al. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol 2014; 66:232.
  42. Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol 2014; 15:592.
  43. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387:1163.
  44. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737.
  45. Sweeney C, Chen YH, Liu G, et al. Long term efficacy and QOL data of chemohormonal therapy in low and high volume hormone naïve metastatic prostate cancer: E3805 CHAARTED trial. Abstract 72 OPD, 2016 European Society of Medical Oncology meeting.
  46. Patrick-Miller LJ, Chen YH, Carducci MA, et al. Quality of life (QOL) analysis from CHAARTED: Chemohormonal androgen ablation randomized trial in prostate cancer (E3805). Abstract 5004, 2016 American Society of Clinical Oncology meeting.
  47. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14:149.
  48. Gravis G, Boher JM, Joly F, et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol 2015.
  49. Smith MR, Lee WC, Brandman J, et al. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005; 23:7897.
  50. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352:154.
  51. Smith MR, Boyce SP, Moyneur E, et al. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006; 175:136.
  52. Segal RJ, Reid RD, Courneya KS, et al. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 2003; 21:1653.
  53. Ross RW, Small EJ. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 2002; 167:1952.
  54. Bae DC, Stein BS. The diagnosis and treatment of osteoporosis in men on androgen deprivation therapy for advanced carcinoma of the prostate. J Urol 2004; 172:2137.
  55. Saad F, Olsson C, Schulman CC. Skeletal morbidity in men with prostate cancer: quality-of-life considerations throughout the continuum of care. Eur Urol 2004; 46:731.