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
  • Published:

Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy

Abstract

For the past decade, docetaxel has remained the global standard of care for frontline treatment of metastatic castration-resistant prostate cancer (mCRPC). Until recently, there were limited options for patients with mCRPC following docetaxel failure or resistance, but now the approved treatment choices for these patients have expanded to include abiraterone acetate, cabazitaxel and enzalutamide. Additionally, the radioactive therapeutic agent radium-223 dichloride has been recently approved in patients with CRPC with bone metastases. Although each of these agents has been shown to convey significant survival benefit as a monotherapy, preclinical findings suggest that combining such innovative strategies with traditional treatments may achieve additive or synergistic effects, further augmenting patient benefit. This review will discuss the transformation of the post-docetaxel space in mCRPC, highlighting the spectrum of newly approved agents in this setting in the USA and the European Union, as well as summarizing treatments with non-chemotherapeutic mechanisms of action that have demonstrated promising results in recent phase 3 trials. Lastly, this review will address the potential of combinatorial regimens in mCRPC, including the pairing of novel immunotherapeutic approaches with chemotherapy, radiotherapy or androgen ablation.

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

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

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

Figure 1

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  PubMed  Google Scholar 

  2. NCCN NCCN Clinical Practice Guidelines in Oncology–Prostate Cancer. V1. 2012. Available at http://www.nccn.org Accessed 25 March 2013.

  3. Horwich A, Parker C, Bangma C, Kataja V, and on behalf of the ESMO Guidelines Working Group. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl 5): v129–v133.

    Article  PubMed  Google Scholar 

  4. Abdollah F, Schmitges J, Sun M, Jeldres C, Tian Z, Briganti A et al. Comparison of mortality outcomes after radical prostatectomy versus radiotherapy in patients with localized prostate cancer: a population-based analysis. Int J Urol 2012; 19: 836–844.

    Article  PubMed  Google Scholar 

  5. Maluf FC, Smaletz O, Herchenhorn D . Castration-resistant prostate cancer: systemic therapy in 2012. Clinics 2012; 67: 389–394.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Risk M, Corman JM . The role of immunotherapy in prostate cancer: an overview of current approaches in development. Rev Urol 2009; 11: 16–27.

    PubMed  PubMed Central  Google Scholar 

  7. Ross RW, Xie W, Regan MM, Pomerantz M, Nakabayashi M, Daskivich TJ et al. Efficacy of androgen deprivation therapy in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect. Cancer 2008; 112: 1247–1253.

    Article  PubMed  Google Scholar 

  8. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et alProstate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26: 1148–1159.

    Article  PubMed  Google Scholar 

  9. Huang X, Chau CH, Figg WD . Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures. J Hematol Oncol 2012; 5: 35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF et al. for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–422.

    Article  CAS  PubMed  Google Scholar 

  11. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN et alfor the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 35: 1502–1512.

    Article  Google Scholar 

  12. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–1520.

    Article  CAS  PubMed  Google Scholar 

  13. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF . Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 26: 242–245.

    Article  CAS  PubMed  Google Scholar 

  14. Marín-Aguilera M, Codony-Servat J, Kalko SG, Fernández PL, Bermudo R, Buxo E et al. Identification of docetaxel resistance genes in castration-resistant prostate cancer. Mol Cancer Ther 2012; 11: 329–339.

    Article  PubMed  Google Scholar 

  15. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I et alfor the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration- resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet 2010; 376: 1147–1154.

    Article  CAS  PubMed  Google Scholar 

  16. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ et alfor the COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983–992.

    Article  CAS  PubMed  Google Scholar 

  17. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et alfor the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et alfor the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    Article  CAS  PubMed  Google Scholar 

  19. Parker C, Nilsson S, Heinrich D, O'Sullivan JM, Fossa SD, Chodacki A et al Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). Presented at the 2012 American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA. 1–5 June 2012, (abstract LBA4512).

  20. Provenge (sipuleucel-T) (package insert) Dendreon Corporation, Seattle, WA, 2011.

  21. Zytiga (abiraterone acetate) (package insert) Centocor Ortho Biotech, Inc, Horsham, PA, USA, 2012.

  22. Zytiga (abiraterone acetate) (summary of product characteristics) Janssen-Cilag International N.V, Beerse, Belgium, 2012.

  23. Jevtana (cabazitaxel) (package insert) Sanofi-Aventis, Bridgewater, NJ, USA, 2013.

  24. Jevtana (cabazitaxel) (summary of product characteristics) Sanofi-Aventis Groupe, Paris, France, 2013.

  25. Xtandi (enzalutamide) (package insert) Astellas Pharma US, Inc, Northbrook, IL, USA, 2012.

  26. Xofigo (radium Ra 223 dichloride) (package insert) Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ, USA, 2013.

  27. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  28. Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G . The anticancer immune response: indispensable for therapeutic success? J Clin Invest 2008; 118: 1991–2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zitvogel L, Tesniere A, Kroemer G . Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 2006; 6: 715–727.

    Article  CAS  PubMed  Google Scholar 

  30. Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010; 37: 533–546.

    Article  CAS  PubMed  Google Scholar 

  31. US Yervoy (ipilimumab) (package insert) Bristol-Myers Squibb Company, Princeton, NJ, 2013.

  32. EU Yervoy (ipilimumab) (package insert) Bristol-Myers Squibb S.r.l, Anagni, Italy, 2012.

  33. Sheikh NA, Petrylak D, Kantoff P, Dela Rosa C, Stewart FP, Kuan LY et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother 2013; 62: 137–147.

    Article  CAS  PubMed  Google Scholar 

  34. Ryan CJ, Smith MR, deBono JS, Molina A, Logothetis CJ, de Souza P et al for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2012; 368: 138–148.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rathkopf DE, Smith MR, De Bono JS, Logothetis C, Shore N, De Souza PL et al. Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302). J Clin Oncol 2013; 31: 310s (abstract 5009).

    Google Scholar 

  36. Scher HI, Fizazi K, Saad F, Chi KN, Taplin M, Sternberg CN et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide, an androgen receptor inhibitor. J Clin Oncol 2013; 31: (abstract 6).

  37. Xgeva (denosumab) (package insert) Amgen Inc, Thousand Oaks, CA, USA, 2013.

  38. Vogelzang NJ, Helle SI, Johannessen DC, O’Sullivan JM, Garcia-Vargas JE, Gillies C et al. Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial. J Clin Oncol 2013; 31: 324s (abstract 5068).

    Google Scholar 

  39. Nilsson S, Sartor AO, Bruland OS, Fang F, Aksnes A-K, Parker C . Pain analyses from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases. J Clin Oncol 2013; 31: 317s (abstract 5038).

    Article  Google Scholar 

  40. Higano D, Saad F, Somer B, Curti B, Petrylak D, Drake CG et al A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration- resistant prostate cancer (CRPC). Presented at the 2009 Genitourinary Cancers Symposium, Orlando, FL, USA. 26–28 February 2009, (abstract LBA150).

  41. Clinical Trials.gov NCT00861614. Study of immunotherapy to treat advanced prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT00861614?term=00861614&rank=1 Accessed 4 June 2013.

  42. Clinical Trials.gov NCT01057810. Phase 3 study of immunotherapy to treat advanced prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01057810?term=NCT01057810&rank=1 Accessed 4 June 2013.

  43. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012; 18: 2039–2047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maio M, Bondarenko I, Robert C, Thomas L, Garbe C, Testib A et al. Four-year survival update for metastatic melanoma (MM) patients (pts) treated with ipilimumab (IPI)+dacarbazine (DTIC) on phase 3 study CA184-024. Ann Oncol 2012; 23 (Suppl 9): ix367 (abstract 1127P).

    Google Scholar 

  45. Lebbe C, Weber JS, Maio M, Neyns B, Harmankaya K, Chin K et al. Five-year survival rates for patients (pts) with metastatic melanoma (MM) treated with ipilimumab (IPI) in phase II trials. Ann Oncol 2012; 23 (Suppl 9): ix363 (abstract 1116PD).

    Google Scholar 

  46. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526.

    Article  CAS  PubMed  Google Scholar 

  48. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol 2013; 24: 1813–1821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 501–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 509–517.

    Article  CAS  PubMed  Google Scholar 

  51. Clinical Trials.gov NCT01145508. Docetaxel and prednisone with or without vaccine therapy in treating patients with metastatic hormone-resistant prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01145508?term=NCT01145508&rank=1 Accessed 4 June 2013.

  52. Clinical Trials.gov NCT01420965. Sipuleucel-T, CT-011, and cyclophosphamide for advanced prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01420965?term=NCT01420965&rank=1 Accessed 4 June 2013.

  53. Clinical Trials.gov NCT00450463. Vaccine therapy with PROSTVAC/TRICOM and flutamide versus flutamide alone to treat prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT00450463?term=NCT00450463&rank=1 Accessed 4 June 2013.

  54. Clinical Trials.gov NCT00583752. Phase II study of adenovirus/PSA vaccine in men with recurrent prostate cancer after local therapy APP21http://clinicaltrials.gov/ct2/show/NCT00583752?term=00583752&rank=1 Accessed 4 June 2013.

  55. Clinical Trials.gov NCT01194271. Neoadjuvant ipilimumab in prostate cancer http://clinicaltrials.gov/ct2/show/NCT01194271?term=NCT01194271&rank=1 Accessed 4 June 2013.

  56. Clinical Trials.gov NCT01377389. Ipilimumab+androgen deprivation therapy in prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01377389?term=NCT01377389&rank=1 Accessed 4 June 2013.

  57. Clinical Trials.gov NCT01431391. Sequencing of sipuleucel-T and ADT in men with non-metastatic prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01431391?term=NCT01431391&rank=1 Accessed 4 June 2013.

  58. Clinical Trials.gov NCT01487863. Concurrent versus sequential treatment with sipuleucel-t and abiraterone in men with metastatic castrate resistant prostate cancer (mCRPC)http://clinicaltrials.gov/ct2/show/NCT01487863?term=NCT01487863&rank=1 Accessed 4 June 2013.

  59. Clinical Trials.gov NCT01498978. Ipilimumab in combination with androgen suppression therapy in treating patients with metastatic hormone-resistant prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01498978?term=NCT01498978&rank=1 Accessed 4 June 2013.

  60. Clinical Trials.gov identifier NCT01688492. Combining ipilimumab with abiraterone acetate plus prednisone in chemotherapy and immunotherapy-naïve patients with progressive metastatic castration-resistant prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01688492?term=NCT01688492&rank=1 Accessed 4 June 2013.

  61. Clinical Trials.gov NCT01436968. Phase 3 study of ProstAtak with standard radiation therapy for localized prostate cancer (PrTK03)http://clinicaltrials.gov/ct2/show/NCT01436968?term=NCT01436968&rank=1 Accessed 4 June 2013.

  62. Clinical Trials.gov NCT01696877. A neoadjuvant study of androgen ablation combined with cyclophosphamide and GVAX vaccine for localized prostate cancerhttp://clinicaltrials.gov/ct2/show/NCT01696877?term=NCT01696877&rank=1 Accessed 4 June 2013.

  63. Drake CG, Scher HI, Bossi A, van den Eertwegh AJM, McHenry B, Fitzmaurice TF et al. CA184-043: A randomized, double-blind, phase III trial comparing ipilimumab versus placebo following a single dose of radiotherapy in patients with castration-resistant prostate cancer who have received prior treatment with docetaxel. J Clin Oncol 2012; 30 (suppl)(abstract TPS4689).

  64. Sharma P, Wagner K, Wolchok JD, Allison JP . Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer 2011; 11: 805–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Corn PG . The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development. Cancer Manag Res 2012; 4: 183–193.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Dayyani F, Gallick GE, Logothetis CJ, Corn PG . Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 2011; 103: 1665–1675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kuroda K, Liu H, Kim S, Guo M, Navarro V, Bander NH . Docetaxel down-regulates the expression of androgen receptor and prostate-specific antigen but not prostate-specific membrane antigen in prostate cancer cell lines: Implications for PSA surrogacy. Prostate 2009; 69: 1579–1585.

    Article  CAS  PubMed  Google Scholar 

  68. Terry S, Ploussard G, Allory Y, Nicolaiew N, Boissière-Michot F, Maillé P et al. Increased expression of class III β-tubulin in castration-resistant human prostate cancer. Br J Cancer 2009; 101: 951–956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF et al. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 2011; 108: 16723–16728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Slovin SR . Toward maximizing immunotherapy in metastatic castration-resistant prostate cancer—rationale for combinatorial approaches using chemotherapy. Front Oncol 2012; 2: 43.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ma Y, Conforti R, Aymeric L, Locher C, Kepp O, Kroemer G et al. How to improve the immunogenicity of chemotherapy and radiotherapy. Cancer Metastasis Rev 2011; 30: 71–82.

    Article  CAS  PubMed  Google Scholar 

  72. McDonnell AM, Nowak AK, Lake RA . Contribution of the immune system to the chemotherapeutic response. Semin Immunopathol 2011; 33: 353–367.

    Article  CAS  PubMed  Google Scholar 

  73. Brown IE, Blank C, Kline J, Kacha AK, Gajewski TF . Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol 2006; 177: 4521–4529.

    Article  CAS  PubMed  Google Scholar 

  74. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY . A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 2010; 16: 4583–4594.

    Article  CAS  PubMed  Google Scholar 

  75. Vicari AP, Luu R, Zhang N, Patel S, Makinen SR, Hanson DC et al. Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 2009; 58: 615–628.

    Article  CAS  PubMed  Google Scholar 

  76. Garnett CT, Schlom J, Hodge JW . Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res 2008; 14: 3536–3544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mokyr MB, Kalinichenko T, Gorelik L, Bluestone JA . Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Res 1998; 58: 5301–5304.

    CAS  PubMed  Google Scholar 

  78. Jure-Kunkel MN, Masters G, Girit E, Dito G, Lee FY . Antitumor activity of anti-CTLA-4 monoclonal antibody (mAb) in combination with ixabepilone in preclinical tumor models. J Clin Oncol 2008; 26 (15 suppl): 144s (abstract 3048).

    Google Scholar 

  79. Lee FL, Jure-Kunkel MN, Salvati ME . Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence. Ther Adv Med Oncol 2011; 3: 11–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nowak A, Robinson B, Lake R . Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 2003; 63: 4490–4496.

    CAS  PubMed  Google Scholar 

  81. Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 2006; 12: 1260–1269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Small E, Higano C, Tchekmedyian N, Sartor O, Stein B, Young R et al. Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer. J Clin Oncol 2006; 24 (suppl 18): 4609.

    Google Scholar 

  83. Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 2005; 11: 3353–3362.

    Article  CAS  PubMed  Google Scholar 

  84. Sanda MG, Smith DC, Charles LG, Hwang C, Pienta KJ, Schlom J et al. Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer. Urology 1999; 53: 260–266.

    Article  CAS  PubMed  Google Scholar 

  85. Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res 2008; 14: 4526–4531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tollefson MK, Karnes RJ, Thompson RH, Granberg CF, Hillman DW, Breau RH et al A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer. Presented at the American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium, San Francisco, CA, USA. 5–7 March 2010, (abstract 168).

  87. Drake CG . Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 2010; 10: 580–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13: 1050–1059.

    Article  CAS  PubMed  Google Scholar 

  89. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM . Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 2005; 174: 7516–7523.

    Article  CAS  PubMed  Google Scholar 

  90. Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN et al. Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol 2003; 170: 6338–6347.

    Article  CAS  PubMed  Google Scholar 

  91. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW . External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 2004; 64: 4328–4337.

    Article  CAS  PubMed  Google Scholar 

  92. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15: 5379–5388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pilones KA, Kawashima N, Yang AM, Babb JS, Formenti SC, Demaria S. . Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res 2009; 15: 597–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11: 728–734.

    CAS  PubMed  Google Scholar 

  95. Harris TJ, Hipkiss EL, Borzillary S, Wada S, Grosso JF, Yen HR et al. Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate 2008; 68: 1319–1329.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Antonarakis ES, Drake CG . Combining immunological and androgen-directed approaches: an emerging concept in prostate cancer immunotherapy. Curr Opin Oncol 2012; 24: 258–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005; 175: 2741–2753.

    Article  CAS  PubMed  Google Scholar 

  98. Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA 2001; 98: 14565–14570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gao J, Sun J, Ward JF, Rao P, Troncoso P, Araujo JC et al. Combination therapy with anti-CTLA-4 plus leuprolide acetate in the pre-surgical setting of patients with regional, high-risk prostate cancer. Cancer Res 2012; 72 (Suppl 8)(abstract no. 4388).

    Article  Google Scholar 

  100. Aparicio A, Sun J, Tang DN, Arap W, Araujo J, Corn P et al. A phase II study of ipilimumab plus androgen deprivation therapy in castration-sensitive prostate carcinoma. Cancer Res 2012; 72 (Suppl 8)(abstract no. 5368).

    Article  Google Scholar 

  101. Antonarakis ES, Kibel AS, Adams G, Karsh LI, Elfiky A, Shore ND et al. A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): immune results. J Clin Oncol 2013; 31: 312s (abstract 5016).

    Article  Google Scholar 

  102. Small EJ, Lance RS, Redfern CH, Millard FE, Gardner TA, Karsh LI et al. A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol 2013; 31: 319s (abstract 5047).

    Google Scholar 

  103. Levy MY, Sidana A, Chowdhury WH, Solomon SB, Drake CG, Rodriguez R et al. Cyclophosphamide unmasks an antimetastatic effect of local tumor cryoablation. J Pharmacol Exp Ther 2009; 330: 596–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vanneman M, Dranoff G. . Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 2012; 12: 237–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dickinson M, Johnstone RW, Prince HM. . Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs 2010; 28 (Suppl 1): S3–S20.

    Article  PubMed  Google Scholar 

  107. Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 2012; 7: e30815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Angelergues A, Maillet D, Flechon A, Ozguroglu M, Mercier F, Guillot A et al. Prognostic factors of survival in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel: sequencing might matter. J Clin Oncol 2013; 31: 323s (abstract 5063).

    Article  Google Scholar 

  109. Stevenson R, Ford D, Zarkar AM, Glaholm J, Porfiri E, Tew A et al. The sequential use of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: experience from Birmingham, United Kingdom. J Clin Oncol 2013; 31: (abstract e16048).

  110. Clinical Trials.gov identifier NCT01650194. A study to determine safety and tolerability of enzalutamide (MDV3100) in combination with abiraterone acetate in bone metastatic castration-resistant prostate cancer patientshttp://clinicaltrials.gov/ct2/show/NCT01650194?term=NCT01650194&rank=1 Accessed 4 June 2013.

  111. Danila DC, Pantel K, Fleisher M, Scher HI. . Circulating tumors cells as biomarkers: progress toward biomarker qualification. Cancer J 2011; 17: 438–450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. McCourt CM, Boyle D, James J, Salto-Tellez M. . Immunohistochemistry in the era of personalised medicine. J Clin Pathol 2013; 66: 58–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Professional medical writing and editorial assistance was provided by Ami P. Modi, PhD, at StemScientific, and funded by Bristol-Myers Squibb (BMS).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C G Drake.

Ethics declarations

Competing interests

CG Drake has served as a consultant for Amplimmune, BMS, CoStim, Dendreon and Pfizer, and has patents/potential royalties licensed by Amplimmune. P Sharma has served as a paid consultant for BMS, Dendreon, Helsinn, Jounce and MedImmune, serves on the board of directors for Society for Immunotherapy of Cancer and has stock in Jounce. W Gerritsen serves on advisory boards for Aglaia Biomedical Ventures, Amgen, Bayer, BMS, Ipsen, Janssen, Merck and Sanofi, and has received speaker’s honoraria from Astellas, BMS and Janssen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drake, C., Sharma, P. & Gerritsen, W. Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy. Oncogene 33, 5053–5064 (2014). https://doi.org/10.1038/onc.2013.497

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.497

Keywords

This article is cited by

Search

Quick links