World Journal of Urology

, Volume 30, Issue 4, pp 495–503

Novel options for the treatment of castration-resistant prostate cancer

  • Carsten-H. Ohlmann
  • Axel S. Merseburger
  • Henrik Suttmann
  • David Schilling
  • Lutz Trojan
  • Carsten Kempkensteffen
  • Stefan Corvin
  • Michael J. Mathers
  • Patrick J. Bastian
Invited Review


Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials.


Castration-resistant prostate cancer Abiraterone MDV3100 Zibotentan Denosumab Alpharadin 


  1. 1.
    Huggins C (1942) Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 115:1192–1200PubMedCrossRefGoogle Scholar
  2. 2.
    Antonarakis ES, Eisenberger MA (2011) Expanding treatment options for metastatic prostate cancer. N Engl J Med 364:2055–2058PubMedCrossRefGoogle Scholar
  3. 3.
    Heidenreich A, Bellmunt J, Bolla M et al (2010) EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol 59:61–71PubMedCrossRefGoogle Scholar
  4. 4.
    Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1:34–45PubMedCrossRefGoogle Scholar
  5. 5.
    Berthold DR, Pond GR, Soban F et al (2008) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26:242–245PubMedCrossRefGoogle Scholar
  6. 6.
    Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520PubMedCrossRefGoogle Scholar
  7. 7.
    Locke JA, Guns ES, Lubik AA et al (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68:6407–6415PubMedCrossRefGoogle Scholar
  8. 8.
    de Bono JS, Oudard S, Ozguroglu M et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376:1147–1154PubMedCrossRefGoogle Scholar
  9. 9.
    Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822PubMedCrossRefGoogle Scholar
  10. 10.
    Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRefGoogle Scholar
  11. 11.
    Edwards J, Krishna NS, Grigor KM, Bartlett JM (2003) Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89:552–556PubMedCrossRefGoogle Scholar
  12. 12.
    Culig Z, Hoffmann J, Erdel M et al (1999) Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 81:242–251PubMedCrossRefGoogle Scholar
  13. 13.
    Pienta KJ, Bradley D (2006) Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 12:1665–1671PubMedCrossRefGoogle Scholar
  14. 14.
    Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L (2002) Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 168:2439–2443PubMedCrossRefGoogle Scholar
  15. 15.
    Tannock IF, Osoba D, Stockler MR et al (1996) Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14:1756–1764PubMedGoogle Scholar
  16. 16.
    Kantoff PW, Halabi S, Conaway M et al (1999) Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 17:2506–2513PubMedGoogle Scholar
  17. 17.
    Tannock IF, de Wit R, Berry WR et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512PubMedCrossRefGoogle Scholar
  18. 18.
    Galsky MD, Vogelzang NJ (2010) Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol 21:2135–2144PubMedCrossRefGoogle Scholar
  19. 19.
    Higano CS, Schellhammer PF, Small EJ et al (2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115:3670–3679PubMedCrossRefGoogle Scholar
  20. 20.
    Small EJ, Schellhammer PF, Higano CS et al (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094PubMedCrossRefGoogle Scholar
  21. 21.
    Auchus RJ (2001) The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 30:101–119 (vii)PubMedCrossRefGoogle Scholar
  22. 22.
    Rowlands MG, Barrie SE, Chan F et al (1995) Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17, 20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem 38:4191–4197PubMedCrossRefGoogle Scholar
  23. 23.
    Yap TA, Carden CP, Attard G, de Bono JS (2008) Targeting CYP17: established and novel approaches in prostate cancer. Curr Opin Pharmacol 8:449–457PubMedCrossRefGoogle Scholar
  24. 24.
    Attard G, Reid AH, Olmos D, de Bono JS (2009) Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res 69:4937–4940PubMedCrossRefGoogle Scholar
  25. 25.
    Attard G, Reid AH, Yap TA 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 26:4563–4571PubMedCrossRefGoogle Scholar
  26. 26.
    Ryan CJ, Smith MR, Fong L et al (2010) Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 28:1481–1488PubMedCrossRefGoogle Scholar
  27. 27.
    Ryan CJ, Shah S, Efstathiou E et al (2011) Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin Cancer Res 17:4854–4861PubMedCrossRefGoogle Scholar
  28. 28.
    Attard G, Reid AH, A’Hern R et al (2009) Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 27:3742–3748PubMedCrossRefGoogle Scholar
  29. 29.
    Reid AH, Attard G, Danila DC et al (2010) Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 28:1489–1495PubMedCrossRefGoogle Scholar
  30. 30.
    Danila DC, Morris MJ, de Bono JS et al (2010) Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 28:1496–1501PubMedCrossRefGoogle Scholar
  31. 31.
    Scher HI, Heller G, Molina A et al (2011) Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. ASCO Meet Abstr 29:LBA4517Google Scholar
  32. 32.
    Matsunaga N, Kaku T, Ojida A et al (2004) C(17, 20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17, 20)-lyase inhibitors. Bioorg Med Chem 12:4313–4336PubMedCrossRefGoogle Scholar
  33. 33.
    Dreicer R, Agus DB, MacVicar GR, MacLean D, ZhangT, Stadier WM (2010) Safety, pharmacokinetics, and efficacy of TAK-700 in castration-resistant metastatic prostate cancer: a phase I/II open label study. Genitourin Cancer Symp Proc, abstract 103Google Scholar
  34. 34.
    Tran C, Ouk S, Clegg NJ et al (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324:787–790PubMedCrossRefGoogle Scholar
  35. 35.
    Scher HI, Beer TM, Higano CS et al (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375:1437–1446PubMedCrossRefGoogle Scholar
  36. 36.
    Inoue A, Yanagisawa M, Kimura S et al (1989) The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 86:2863–2867PubMedCrossRefGoogle Scholar
  37. 37.
    Smollich M, Wulfing P (2007) The endothelin axis: a novel target for pharmacotherapy of female malignancies. Curr Vasc Pharmacol 5:239–248PubMedCrossRefGoogle Scholar
  38. 38.
    Nelson JB, Udan MS, Guruli G, Pflug BR (2005) Endothelin-1 inhibits apoptosis in prostate cancer. Neoplasia 7:631–637PubMedCrossRefGoogle Scholar
  39. 39.
    Gohji K, Kitazawa S, Tamada H, Katsuoka Y, Nakajima M (2001) Expression of endothelin receptor a associated with prostate cancer progression. J Urol 165:1033–1036PubMedCrossRefGoogle Scholar
  40. 40.
    Yin JJ, Mohammad KS, Kakonen SM et al (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci USA 100:10954–10959PubMedCrossRefGoogle Scholar
  41. 41.
    Opgenorth TJ, Adler AL, Calzadilla SV et al (1996) Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther 276:473–481PubMedGoogle Scholar
  42. 42.
    Carducci MA, Nelson JB, Bowling MK et al (2002) Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 20:2171–2180PubMedCrossRefGoogle Scholar
  43. 43.
    Samara E, Dutta S, Cao G et al (2001) Single-dose pharmacokinetics of atrasentan, an endothelin-A receptor antagonist. J Clin Pharmacol 41:397–403PubMedCrossRefGoogle Scholar
  44. 44.
    Carducci MA, Padley RJ, Breul J et al (2003) Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 21:679–689PubMedCrossRefGoogle Scholar
  45. 45.
    Nelson JB, Love W, Chin JL et al (2008) Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 113:2478–2487PubMedCrossRefGoogle Scholar
  46. 46.
    Carducci MA, Saad F, Abrahamsson PA et al (2007) A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 110:1959–1966PubMedCrossRefGoogle Scholar
  47. 47.
    Michaelson MD, Kaufman DS, Kantoff P, Oh WK, Smith MR (2006) Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer 107:530–535PubMedCrossRefGoogle Scholar
  48. 48.
    Armstrong AJ, Creel P, Turnbull J et al (2008) A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 14:6270–6276PubMedCrossRefGoogle Scholar
  49. 49.
    Morris CD, Rose A, Curwen J et al (2005) Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer 92:2148–2152PubMedCrossRefGoogle Scholar
  50. 50.
    James ND, Caty A, Borre M et al (2009) Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol 55:1112–1123PubMedCrossRefGoogle Scholar
  51. 51.
    Nelson JB, Fizazi K, Miller K (2011) Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29(suppl 7): abstr 117Google Scholar
  52. 52.
    Nilsson S, Franzen L, Parker C et al (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594PubMedCrossRefGoogle Scholar
  53. 53.
    Parker C (2011) Overall survival benefit of radium-223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a Phase III randomized trial (ALSYMPCA). The 2011 European multidisciplinary cancer congress. Stockholm: Eur J Cancer 47(Suppl 2):3Google Scholar
  54. 54.
    Chi KN, Eisenhauer E, Fazli L et al (2005) A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2′-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 97:1287–1296PubMedCrossRefGoogle Scholar
  55. 55.
    Chi KN, Hotte SJ, Yu EY et al (2010) Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 28:4247–4254PubMedCrossRefGoogle Scholar
  56. 56.
    Chi KN, Siu LL, Hirte H et al (2008) A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res 14:833–839PubMedCrossRefGoogle Scholar
  57. 57.
    Mita AC, Denis LJ, Rowinsky EK et al (2009) Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 15:723–730PubMedCrossRefGoogle Scholar
  58. 58.
    Pivot X, Koralewski P, Hidalgo JL et al (2008) A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol 19:1547–1552PubMedCrossRefGoogle Scholar
  59. 59.
    Shigeta K, Miura Y, Naito Y, Takano T (2011) Cabazitaxel for castration-resistant prostate cancer. Lancet 377:121 (author reply 122–123)PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Carsten-H. Ohlmann
    • 1
  • Axel S. Merseburger
    • 2
  • Henrik Suttmann
    • 3
  • David Schilling
    • 4
  • Lutz Trojan
    • 5
  • Carsten Kempkensteffen
    • 6
  • Stefan Corvin
    • 7
  • Michael J. Mathers
    • 8
  • Patrick J. Bastian
    • 9
  1. 1.Department of UrologySaarland UniversityHomburg/SaarGermany
  2. 2.Department of UrologyHannover Medical SchoolHannoverGermany
  3. 3.Urologikum HamburgHamburgGermany
  4. 4.Department of UrologyEberhard-Karls-UniversityTuebingenGermany
  5. 5.Department of Urology, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  6. 6.Department of UrologyCharité, University Medicine BerlinBerlinGermany
  7. 7.Fachzentrum für Urologie EggenfeldenEggenfeldenGermany
  8. 8.PandaMED RemscheidRemscheidGermany
  9. 9.Urologische Klinik und PoliklinikKlinikum der Universität-Campus Großhadern, Ludwig-Maximilians-Universität MünchenMünchenGermany

Personalised recommendations