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Prostate Cancer
Volume 2012 (2012), Article ID 327253, 11 pages
http://dx.doi.org/10.1155/2012/327253
Review Article

Castration-Resistant Prostate Cancer: Mechanisms, Targets, and Treatment

Oncology Division, Hospital de Santa Maria, Instituto de Medicina Molecular, 1649-039 Lisbon, Portugal

Received 26 September 2011; Revised 1 December 2011; Accepted 20 December 2011

Academic Editor: William L. Dahut

Copyright © 2012 Teresa Maria Santos Amaral et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. N. Howlader, A. M. Noone, M. Krapcho, et al., SEER Cancer Statistics Review, 1975–2008, National Cancer Institute, Bethesda, Md, USA, 2011, based on November 2010 SEER data submission, posted to the SEER web site, http://seer.cancer.gov/csr/1975_2008/.
  2. R. B. Marques, N. F. Dits, S. Erkens-Schulze, W. M. Weerden, and G. Jenster, “Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models,” PLoS ONE, vol. 5, no. 10, Article ID e13500, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. G. Attard, D. Sarker, A. Reid, R. Molife, C. Parker, and J. S. De Bono, “Improving the outcome of patients with castration-resistant prostate cancer through rational drug development,” British Journal of Cancer, vol. 95, no. 7, pp. 767–774, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. W. P. Harris, E. A. Mostaghel, P. S. Nelson, and B. Montgomery, “Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion,” Nature Clinical Practice Urology, vol. 6, no. 2, pp. 76–85, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. R. M. Attar, C. H. Takimoto, and M. M. Gottardis, “Castration-resistant prostate cancer: locking up the molecular escape routes,” Clinical Cancer Research, vol. 15, no. 10, pp. 3251–3255, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. S. Sun, C. C. T. Sprenger, R. L. Vessella et al., “Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant,” Journal of Clinical Investigation, vol. 120, no. 8, pp. 2715–2730, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. P. A. Watson, Y. F. Chen, M. D. Balbas et al., “Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 39, pp. 16759–16765, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. C. J. Paller and E. S. Antonarakis, “Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer,” Drug Design, Development and Therapy, no. 5, pp. 117–124, 2011. View at Publisher · View at Google Scholar · View at PubMed
  9. J. E. Ang, D. Olmos, and J. S. De Bono, “CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer,” British Journal of Cancer, vol. 100, no. 5, pp. 671–675, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. S. S. Dutt and A. C. Gao, “Molecular mechanisms of castration-resistant prostate cancer progression,” Future Oncology, vol. 5, no. 9, pp. 1403–1413, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. E. D. Crawford, M. A. Eisenberger, D. G. McLeod et al., “A controlled trial of leuprolide with and without flutamide in prostatic carcinoma,” New England Journal of Medicine, vol. 321, no. 7, pp. 419–424, 1989. View at Scopus
  12. M. A. Eisenberger, B. A. Blumenstein, E. D. Crawford et al., “Bilateral orchiectomy with or without flutamide for metastatic prostate cancer,” New England Journal of Medicine, vol. 339, no. 15, pp. 1036–1042, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. I. F. Tannock, R. De Wit, W. R. Berry et al., “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1502–1512, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. S. K. Pal, P. Twardowski, and O. Sartor, “Critical appraisal of cabazitaxel in the management of advanced prostate cancer,” Clinical Interventions in Aging, vol. 5, pp. 395–402, 2010.
  15. P. W. Kantoff, C. S. Higano, N. D. Shore et al., “Sipuleucel-T immunotherapy for castration-resistant prostate cancer,” New England Journal of Medicine, vol. 363, no. 5, pp. 411–422, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. E. J. Small, S. Halabi, N. A. Dawson et al., “Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583),” Journal of Clinical Oncology, vol. 22, no. 6, pp. 1025–1033, 2004. View at Publisher · View at Google Scholar · View at PubMed
  17. D. R. Berthold, C. N. Sternberg, and I. F. Tannock, “Management of advanced prostate cancer after first-line chemotherapy,” Journal of Clinical Oncology, vol. 23, no. 32, pp. 8247–8252, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. S. J. Kim and S. I. Kim, “Current treatment strategies for castration-resistant prostate cancer,” Korean Journal of Urology, vol. 52, no. 3, pp. 157–165, 2011. View at Publisher · View at Google Scholar · View at PubMed
  19. H. Suzuki, K. Okihara, H. Miyake et al., “Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade,” Journal of Urology, vol. 180, no. 3, pp. 921–927, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. W. Kassouf, S. Tanguay, and A. G. Aprikian, “Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails,” Journal of Urology, vol. 169, no. 5, pp. 1742–1744, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. R. Joyce, M. A. Fenton, P. Rode et al., “High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy,” Journal of Urology, vol. 159, no. 1, pp. 149–153, 1998. View at Scopus
  22. O. Kucuk, E. Fisher, C. M. Moinpour et al., “Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235),” Urology, vol. 58, no. 1, pp. 53–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Lodde, L. Lacombe, and Y. Fradet, “Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer,” Urology, vol. 76, no. 5, pp. 1189–1193, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. G. Sonpavde, T. E. Hutson, and W. R. Berry, “Hormone refractory prostate cancer: management and advances,” Cancer Treatment Reviews, vol. 32, no. 2, pp. 90–100, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. D. C. Smith, B. G. Redman, L. E. Flaherty, L. LI, M. Strawderman, and K. J. Pienta, “A Phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer,” Urology, vol. 52, no. 2, pp. 257–260, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. J. S. De Bono, C. J. Logothetis, A. Molina et al., “Abiraterone and increased survival in metastatic prostate cancer,” New England Journal of Medicine, vol. 364, no. 21, pp. 1995–2005, 2011. View at Publisher · View at Google Scholar · View at PubMed
  27. G. A. Potter, S. Elaine Barrie, M. Jarman, and M. G. Rowlands, “Novel steroidal inhibitors of human cytochrome P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer,” Journal of Medicinal Chemistry, vol. 38, no. 13, pp. 2463–2471, 1995.
  28. G. Attard, A. S. Belldegrun, and J. S. De Bono, “Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer,” British Journal of Urology International, vol. 96, no. 9, pp. 1241–1246, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. S. E. Barrie, B. P. Haynes, G. A. Potter et al., “Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P45017α inhibitors,” Journal of Steroid Biochemistry and Molecular Biology, vol. 60, no. 5-6, pp. 347–351, 1997. View at Publisher · View at Google Scholar
  30. M. Jarman, S. Elaine Barrie, and J. M. Liera, “The 16,17-double bond is needed for irreversible inhibition of human cytochrome P45017α by abiraterone (17-(3-Pyridyl)androsta-5,16-dien-3β-ol) and related steroidal inhibitors,” Journal of Medicinal Chemistry, vol. 41, no. 27, pp. 5375–5381, 1998.
  31. P. Vishnu and W. W. Tan, “Update on options for treatment of metastatic castration-resistant prostate cancer,” OncoTargets and Therapy, vol. 3, pp. 39–51, 2010. View at Scopus
  32. A. O. Sartor, “Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space,” Journal of Hematology and Oncology, vol. 4, article 18, 2011. View at Publisher · View at Google Scholar · View at PubMed
  33. D. Bianchini, A. Zivi, S. Sandhu, and J. S. de Bono, “Horizon scanning for novel therapeutics for the treatment of prostate cancer,” Annals of Oncology, vol. 21, supplement 7, pp. vii43–vii55, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. H. I. Scher, A. Anand, D. Rathkopf et al., “Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study,” The Lancet, vol. 375, no. 9724, pp. 1437–1446, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. L. Zarour and J. Alumkal, “Emerging therapies in castrate-resistant prostate cancer,” Current Urology Reports, vol. 11, no. 3, pp. 152–158, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. F. Saad, D. M. Gleason, R. Murray et al., “A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma,” Journal of the National Cancer Institute, vol. 94, no. 19, pp. 1458–1468, 2002. View at Scopus
  37. K. P. Weinfurt, K. J. Anstrom, L. D. Castel, K. A. Schulman, and F. Saad, “Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer,” Annals of Oncology, vol. 17, no. 6, pp. 986–989, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. F. Saad, D. M. Gleason, R. Murray et al., “Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer,” Journal of the National Cancer Institute, vol. 96, no. 11, pp. 879–882, 2004. View at Scopus
  39. T. H. Diamond, J. Winters, A. Smith et al., “The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study,” Cancer, vol. 92, no. 6, pp. 1444–1450, 2001. View at Publisher · View at Google Scholar · View at Scopus
  40. R. S. Israeli, S. J. Rosenberg, D. R. Saltzstein et al., “The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy,” Clinical Genitourinary Cancer, vol. 5, no. 4, pp. 271–277, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. M. R. Smith, J. Eastham, D. M. Gleason, D. Shasha, S. Tchekmedyian, and N. Zinner, “Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer,” Journal of Urology, vol. 169, no. 6, pp. 2008–2012, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. K. Fizazi, M. Carducci, M. Smith et al., “Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study,” The Lancet, vol. 377, no. 9768, pp. 813–822, 2011. View at Publisher · View at Google Scholar
  43. E. Steenland, J. Leer, H. Van Houwelingen et al., “The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis study,” Radiotherapy and Oncology, vol. 52, no. 2, pp. 101–109, 1999. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. M. Van Der Linden, J. J. Lok, E. Steenland et al., “Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment,” International Journal of Radiation Oncology Biology Physics, vol. 59, no. 2, pp. 528–537, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. W. F. Harstell, C. B. Scott, D. W. Bruner et al., “Randomized trial of short-versus long-course radiotherapy for palliation of painful bone metastases,” Journal of the National Cancer Institute, vol. 97, no. 11, pp. 798–804, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. E. Chow, K. Harris, G. Fan, M. Tsao, and W. M. Sze, “Palliative radiotherapy trials for bone metastases: a systematic review,” Journal of Clinical Oncology, vol. 25, no. 11, pp. 1423–1436, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. O. M. Salazar, T. Sandhu, N. W. Da Motta et al., “Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA),” International Journal of Radiation Oncology Biology Physics, vol. 50, no. 3, pp. 765–775, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. D. P. Dearnaley, R. J. Bayly, R. P. A'Hern, J. Gadd, M. M. Zivanovic, and V. J. Lewington, “Palliation of bone metastases in prostate cancer. Hemibody irradiation or strontium-89?” Clinical Oncology, vol. 4, no. 2, pp. 101–107, 1992. View at Scopus
  49. V. J. Lewington, A. J. McEwan, D. M. Ackery et al., “A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone,” European Journal of Cancer, vol. 27, no. 8, pp. 954–958, 1991. View at Publisher · View at Google Scholar · View at Scopus
  50. K. Buchali, H. J. Correns, M. Schuerer, D. Schnorr, H. Lips, and K. Sydow, “Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma,” European Journal of Nuclear Medicine, vol. 14, no. 7-8, pp. 349–351, 1988. View at Scopus
  51. A. T. Porter, A. J. B. McEwan, J. E. Powe et al., “Results of a randomized Phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 25, no. 5, pp. 805–813, 1993. View at Scopus
  52. P. M. Quilty, D. Kirk, J. J. Bolger, et al., “A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer,” Radiotherapy and Oncology, vol. 31, no. 1, pp. 33–40, 1994. View at Publisher · View at Google Scholar
  53. G. O. N. Oosterhof, J. T. Roberts, T. M. De Reijke et al., “Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group,” European Urology, vol. 44, no. 5, pp. 519–526, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. A. N. Serafini, S. J. Houston, I. Resche et al., “Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial,” Journal of Clinical Oncology, vol. 16, no. 4, pp. 1574–1581, 1998. View at Scopus
  55. O. Sartor, R. H. Reid, P. J. Hoskin et al., “Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer,” Urology, vol. 63, no. 5, pp. 940–945, 2004. View at Publisher · View at Google Scholar · View at PubMed
  56. C. Parker, D. Heinrich, J. M. O'Sullivan, et al., “Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer: a phase III randomized trial (ALSYMPCA),” European Journal of Cancer, vol. 47, supplement 2, abstract 1LBA, p. 3, 2011.
  57. D. P. Petrylak, C. M. Tangen, M. H. A. Hussain et al., “Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1513–1520, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. M. D. Galsky and N. J. Vogelzang, “Docetaxel-based combination therapy for castration-resistant prostate cancer,” Annals of Oncology, vol. 21, no. 11, pp. 2135–2144, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. M. D. Galsky, E. J. Small, W. K. Oh et al., “Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer,” Journal of Clinical Oncology, vol. 23, no. 7, pp. 1439–1446, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. M. Hussain, C. M. Tangen, P. N. Lara et al., “Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group Trial S0111,” Journal of Clinical Oncology, vol. 23, no. 34, pp. 8724–8729, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. J. E. Rosenberg, W. K. Kelly, M. D. Michaelson, et al., “A randomized phase II study of ixabepilone (Ix) or mitoxantrone and prednisone (MP) in patients with taxane (T)-resistant hormone refractory prostate cancer (HRPC),” Journal of Clinical Oncology, vol. 23, no. 16S, abstract #5166, p. 4566, 2005.
  62. K. N. Chi, E. K. Beardsley, P. M. Venner, et al., “A phase II study of patupilone in patients with metastatic hormone refractory prostate cancer (HRPC) who have progressed after docetaxel,” Journal of Clinical Oncology, vol. 26, no. 15s, Abstract #5166, 2008.
  63. E. K. Beardsley, F. Saad, and B. Eigl, “A phase II study of patupilone in patients (patients) with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel,” Journal of Clinical Oncology, vol. 27, no. 15s, abstract #5139, 2009.
  64. J. E. Rosenberg, V. K. Weinberg, W. K. Kelly et al., “Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone,” Cancer, vol. 110, no. 3, pp. 556–563, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. J. S. Bono, P. Maroto, E. Calvo, et al., “Phase II study of eribulin mesylate (E7389) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC) stratified by prior taxane therapy,” Annals of Oncology, pp. mdr380v1–mdr380, 2011.
  66. J. S. De Bono, S. Oudard, M. Ozguroglu et al., “Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial,” The Lancet, vol. 376, no. 9747, pp. 1147–1154, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. E. J. Small, P. F. Schellhammer, C. S. Higano et al., “Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3089–3094, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. C. S. Higano, P. F. Schellhammer, E. J. Small et al., “Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer,” Cancer, vol. 115, no. 16, pp. 3670–3679, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. E. J. Small, N. Sacks, J. Nemunaitis et al., “Granulocyte macrophage colony-stimulating factor-secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer,” Clinical Cancer Research, vol. 13, no. 13, pp. 3883–3891, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. M. Hussain, M. R. Smith, C. Sweeney, et al., “Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial,” Journal of Clinical Oncology, vol. 29, supplement, abstract 4516, 2011.
  71. E. Cha and L. Fong, “Therapeutic vaccines for prostate cancer,” Current Opinion in Molecular Therapeutics, vol. 12, no. 1, pp. 77–85, 2010. View at Scopus
  72. P. W. Kantoff, T. J. Schuetz, B. A. Blumenstein et al., “Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1099–1105, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. G. Sonpave, K. M. Slawin, D. M. Spencer, and J. M. Levitt, “Emerging vaccine therapy approaches for prostate cancer,” Reviews in Urology, vol. 12, pp. 25–34, 2010.
  74. M. A. Carducci and A. Jimeno, “Targeting bone metastasis in prostate cancer with endothelin receptor antagonists,” Clinical Cancer Research, vol. 12, no. 20, pp. 6296s–6300s, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. M. A. Carducci, F. Saad, P.-A. Abrahamsson et al., “A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer,” Cancer, vol. 110, no. 9, pp. 1959–1966, 2007. View at Publisher · View at Google Scholar · View at PubMed
  76. W. K. Kelly, S. Halabi, M. A. Carducci, et al., “A randomized, double-bind, placebo-controlled phase III trial comparing docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): survival results of CALGB 90401,” Journal of Clinical Oncology, vol. 28, no. 18s, abstract LBA4511, 2010.
  77. NCT01057810 Randomized, Double-Blind, Phase 3 Trial to Compare the Efficacy of Ipilumumab vs Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naïve Castration Resistant Prostate Cancer.
  78. G. Sonpavde, P. O. Periman, D. Bernold et al., “Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy,” Annals of Oncology, vol. 21, no. 2, pp. 319–324, 2010. View at Publisher · View at Google Scholar · View at PubMed
  79. M. A. Carducci, R. J. Padley, J. Breul et al., “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,” Journal of Clinical Oncology, vol. 21, no. 4, pp. 679–689, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. Phase III Study of Docetaxel and Atrasentan Versus Docetaxel and Placebo for Patients With Advanced Hormone Refractory Prostate Cancer National Institutes of Health. Clinical Trials 2011, http://clinicaltrials.gov/.
  81. N. D. James, A. Caty, H. Payne et al., “Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial,” British Journal of Urology International, vol. 106, no. 7, pp. 966–973, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Non-metastatic Hormone Resistant Prostate Cancer (ENTHUSE M0) NCT00626548.
  83. A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer (ENTHUSE M1C) NCT00617669.
  84. W. L. Dahut, J. L. Gulley, P. M. Arlen et al., “Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer,” Journal of Clinical Oncology, vol. 22, no. 13, pp. 2532–2539, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. G. Di Lorenzo, W. D. Figg, S. D. Fossa et al., “Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study,” European Urology, vol. 54, no. 5, pp. 1089–1096, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. J. Picus, S. Halabi, W. K. Kelly et al., “A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer,” Cancer, vol. 117, no. 3, pp. 526–533, 2011. View at Publisher · View at Google Scholar · View at PubMed
  87. Y. M. Ning, J. L. Gulley, P. M. Arlen et al., “Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer,” Journal of Clinical Oncology, vol. 28, no. 12, pp. 2070–2076, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. National Institutes of Health Clinical Trials database, http://clinicaltrials.gov/.
  89. E. J. Small, N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison, “A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer,” Clinical Cancer Research, vol. 13, no. 6, pp. 1810–1815, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. L. Fong, S. S. Kwek, S. O'Brien et al., “Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF,” Cancer Research, vol. 69, no. 2, pp. 609–615, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. NCT00861614 A Randomized, Double-Blind, Phase 3 Trial Comparing Ipilumumab vs. Placebo Following Radiotherapy in Subjects With Castration Resistant Prostate Cancer That Have Received Prior Treatment With Docetaxel.
  92. W. L. Dahut, C. Scripture, E. Posadas et al., “A phase II clinical trial of sorafenib in androgen-independent prostate cancer,” Clinical Cancer Research, vol. 14, no. 1, pp. 209–214, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. J. B. Aragon-Ching, L. Jain, J. L. Gulley et al., “Final analysis of a phase II trial using sorafenib for metastaticcastration-resistant prostate cancer,” British Journal of Urology International, vol. 103, no. 12, pp. 1636–1640, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. S. Steinbild, K. Mross, A. Frost et al., “A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV,” British Journal of Cancer, vol. 97, no. 11, pp. 1480–1485, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. K. N. Chi, S. L. Ellard, S. J. Hotte et al., “A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer,” Annals of Oncology, vol. 19, no. 4, pp. 746–751, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. A. J. Zurita, G. Liu, T. Hutson, et al., “Sunitinib in combination with docetaxel and prdnisone in patients (pts) with metastatic hormone-refrectory prostate cancer (mHRPC),” Journal of Clinical Oncology, vol. 27, no. 15s, abstract 5166, 2009.
  97. T. A. Yap, D. Olmos, A. T. Brunetto et al., “Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies,” Journal of Clinical Oncology, vol. 29, no. 10, pp. 1271–1279, 2011. View at Publisher · View at Google Scholar · View at PubMed