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New Frontiers in Treatment

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Bone Metastases from Prostate Cancer

Abstract

In the United States, prostate cancer is the most common cancer in men, with an estimated 220,000 cases diagnosed in 2015 [1]. With a percentage of involvement of more than 80 %, the bone represents the preferential site of metastases for this disease. As a consequence, patients experiencing advanced stage castration-resistant prostate cancer (CRPC) are at increased risk of developing skeletal-related events, including pathologic fractures and spinal cord compression [2].

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References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29

    Article  PubMed  Google Scholar 

  2. Weinfurt KP, Li Y, Castel LD et al (2005) The significance of skeletal related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 16:579–584

    Article  CAS  PubMed  Google Scholar 

  3. Duque JLF, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR (1999) Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology 54:523–527

    Article  CAS  PubMed  Google Scholar 

  4. Bok RA, Halabi S, Fei DT, Rodriquez CR, Hayes DF, Vogelzang NJ, Kantoff P, Shuman MA, Small EJ (2001) Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study. Cancer Res 61:2533–2536

    CAS  PubMed  Google Scholar 

  5. Street J, Lenehan B (2009) Vascular endothelial growth factor regulates osteoblast survival -evidence for an autocrine feedback mechanism. J Orthop Surg Res 4:19

    Article  PubMed  PubMed Central  Google Scholar 

  6. Picus J, Halabi S, Kelly WK, Vogelzang NJ, Whang YE, Kaplan EB, Stadler WM, Small EJ, Cancer and Leukemia Group B (2011) A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer. Cancer 117:526–533

    Article  CAS  PubMed  Google Scholar 

  7. Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in Men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sonpavde G, Periman PO, Bernold D, Weckstein D, Fleming MT, Galsky MD, Berry WR, Zhan F, Boehm KA, Asmar L, Hutson TE (2010) Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol 21:319–324

    Article  CAS  PubMed  Google Scholar 

  9. Michaelson MD, Regan MM, Oh WK, Kaufman DS, Olivier K, Michaelson SZ, Spicer B, Gurski C, Kantoff PW, Smith MR (2009) Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol 20:913–920

    Article  PubMed  PubMed Central  Google Scholar 

  10. Michaelson MD, Oudard S, Ou Y, Sengelov F, Saad F, Houede N, Ostler PJ, Stenzl A, Daugaard G, Jones RJ, Laestadius F, Bahl A, Castellano DE, Gschwend J, Maurina T, Ye D, Chen I, Wang S, Maneval EC (2011) Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU + P) versus prednisone (P) alone in men with progressive metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 29(Suppl):Abstr 4515

    Google Scholar 

  11. Lu L, Payvandi F, Wu L, Zhang L-H, Hariri RJ, Man H-W, Chen RS, Muller GW, Hughes CCW, Stirling DI, Schafer PH, Bartlett JB (2009) The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 77:78–86

    Article  CAS  PubMed  Google Scholar 

  12. Petrylak DP, Fizazi K, Sternberg CN, Budnik N, Wit Rd, Wiechno PJ, Bellmunt J, Barton D, Fandi A, Jungnelius U, Li S, Vogelzang NJ, Investigators M (2012) A phase 3 study to evaluate the efficacy and safety of Docetaxel and Prednisone (DP) with or without lenalidomide in patients with Castrate-resistant Prostate Cancer (CRPC): the MAINSAIL trial. ESMO 2012 Congress Abstract LBA24

    Google Scholar 

  13. Dahut WL, Gulley JL, Arlen PM, Liu Y, Fedenko KM et al (2004) Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 22:2532–2539

    Article  CAS  PubMed  Google Scholar 

  14. Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A et al (2013) Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 14:760–768

    Article  CAS  PubMed  Google Scholar 

  15. Pili R, Haggman M, Stadler WM, Gingrich JR, Assikis VJ, Bjork A, Nordle O, Forsberg G, Carducci MA, Armstrong AJ (2011) Phase II randomized, double-blind, placebo-controlled study of tasquinimod in Men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol 29:4022–4028

    Article  CAS  PubMed  Google Scholar 

  16. Carducci M, Armstrong A, Pili R, et al. A phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castrate resistant prostate cancer (mCRPC). Presented at: 2015 European Cancer Congress; Vienna. Abstract 4BA

    Google Scholar 

  17. Humphrey PA, Zhu X, Swanson PE, Ratliff TL, Vollmer RT, Day ML (1995) Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147:386–396

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM, Kattan MW, Gerald WL, Vande Woude GF (2002) High expression of the Met receptor in prostate cancer metastasis to bone. Urology 60:1113–1117

    Article  PubMed  Google Scholar 

  19. Ryan CJ, Rosenthal M, Ng S, Alumkal JJ, Picus J, Gravis G, Fizazi K, Forget F, Machiels J-PH, Zhu M, Jiang J, Dubey S, Loh E, Gerritsen WR (2012) A multicenter, randomized phase II study of rilotumumab (R) (AMG 102) or placebo (Pbo) plus mitoxantrone (M) and prednisone (P) in patients (pts) with previously treated castrate-resistant prostate cancer (CRPC). J Clin Oncol 30(Suppl 5):Abstr 115

    Google Scholar 

  20. Monk P, Liu G, Stadler WM, Geyer SM, Sexton JL, Joseph Wright J, Villalona-Calero MA, Wade JL, Szmulewitz RZ et al (2015) Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol 33(Suppl 7):Abstr 146

    Google Scholar 

  21. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou Y-C, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308

    Article  CAS  PubMed  Google Scholar 

  22. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schoffski P, Scheffold C, Weitzman A, Hussain M (2013) Cabozantinib for metastatic castration-resistant prostate cancer: results of a Phase II placebo-controlled randomized discontinuation study. J Clin Oncol 31:412–419

    Article  CAS  PubMed  Google Scholar 

  23. Smith RM, De Bono JS, Sternberg C, Le Moulec S, Oudard S, De Giorgi U et al (2015) Final analysis of COMET-1: cabozantinib versus prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with docetaxel and abiraterone and/or enzalutamide. J Clin Oncol 33(Suppl 7):Abstr 139

    Google Scholar 

  24. Basch EM, Scholz MC, De Bono JS, Vogelzang NJ, DeSouza PL, Marx GM et al (2015) Final analysis of COMET-2: cabozantinib versus mitoxantrone/prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients with moderate to severe pain who were previously treated with docetaxel and abiraterone and/or enzalutamide. J Clin Oncol 33(Suppl 7):Abstr 141

    Google Scholar 

  25. Vasaitis T, Belosay A, Schayowitz A, Khandelwal A (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther 7(8):2348–2357. doi:10.1158/1535-7163.MCT-08-0230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC (2013) Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem 56(12):4880–4898. doi:10.1021/jm400048v. Epub 2013 Jun 7

  27. Antonarakis ES, Lu C, Wang H (2014) Commentary on “AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer”. N Engl J Med 371(11):1028–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Montgomery RB, Eisenberger MA, Rettig M et al (2012) Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen and CYP17 inhibitor in castration resistant prostate cancer (CRPC). J Clin Oncol 30(Suppl): Abstr 4665

    Google Scholar 

  29. Montgomery B, Eisenberger MA, Rettig MB, Chu F, Pili R, Stephenson JJ, Vogelzang NJ, Koletsky AJ, Nordquist LT, Edenfield WJ, Mamlouk K, Ferrante KJ, Taplin ME (2016) Androgen Receptor Modulation Optimized for Response (ARMOR) phase I and II studies: galeterone for the treatment of castration-resistant prostate cancer. Clin Cancer Res 22(6):1356–1363. doi:10.1158/1078-0432.CCR-15-1432, Epub 2015 Nov 2

    Article  CAS  PubMed  Google Scholar 

  30. Clegg NJ, Wongvipat J, Joseph JD et al (2012) Discovery and development of ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72:1494–1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rathkopf DE, Morris MJ, Danila DC et al (2012) A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 30(Suppl): Abstr 4548

    Google Scholar 

  32. Rathkopf DE, Antonarakis ES, Shore ND et al (2013) ARN-509 in men with metastatic castration-resistant prostate cancer. J Clin Oncol 31:3525–3530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith MR, Antonarakis ES, Ryan CJ et al (2013) ARN-509 in men with high-risk non-metastatic castration reistant prostate cancer. J Clin Oncol 31(Suppl 6): Abstract 7

    Google Scholar 

  34. Efstathiou E, Titus M, Tsavachidou D (2012) Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J clin Oncol 30:637–643

    Article  CAS  PubMed  Google Scholar 

  35. Moilanen A, Riikonen R, Oksala R et al (2015) Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signalling-directed prostate cancer therapies. Sci Rep 5:12007

    Article  PubMed  PubMed Central  Google Scholar 

  36. Joseph JD, Lu N, Qian J et al (2013) A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov 3:1020–1029

    Article  CAS  PubMed  Google Scholar 

  37. Korpal M, Korn JM, Gao X et al (2013) An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 3:1030–1043

    Article  CAS  PubMed  Google Scholar 

  38. Fizazi K, Massard C, Bono P et al (2014) ARADES study group. An open-label, phase I/II safety, pharmacokinetic, and proof-of concept study of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (CRPC). Lancet Oncol 15(9):975–985

    Article  CAS  PubMed  Google Scholar 

  39. Fizazi K, Albiges L, Loriot Y, Massard C (2015) ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther 15(9):1007–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Massard C, Penttinen H, Bono P et al (2015) Pharmacokinetics, activity, and safety of ODM-201 in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: An open-label phase I trial with long-term extension. J Clin Oncol 33(Suppl 7):Abstr 230

    Google Scholar 

  41. Tammela L, Massard C, Bono P et al (2014) European Urology Supplements Safety and efficacy of ODM-201 in chemotherapy and CYP17-inhibitor naïve patients: Analysis of data from the ARADES and the ARAFOR trials (abstract 862). Presented at the 29th Annual European Association of Urology Congress; Stockholm

    Google Scholar 

  42. Bradbury RH, Acton DG et al (2013) Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett 23(7):1945–1948

    Article  CAS  PubMed  Google Scholar 

  43. Loddick SA, Ross SJ, Thomason AG et al (2013) AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. Mol Cancer Ther 12:1715–1727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Omlin A, Jones RJ, van der Noll R et al (2013) A first-in-human study of the oral selective androgen receptor down-regulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC). J Clin Oncol 31(Suppl): Abstr 4511

    Google Scholar 

  45. Myung JK, Banuelos CA, Fernandez JG et al (2013) An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest 123:2948–2960. 25(9)

    Google Scholar 

  46. Saad F, Fizazi K, Jinga V, Efstathiou E et al; ELM-PC 4 Investigators (2015) Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol 16(3):338–348. doi:10.1016/S1470-2045(15)70027-6

  47. Tanej S et al (2015) Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Urol 194(4):990

    Article  CAS  Google Scholar 

  48. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bracarda S, Altavilla A, Hamzaj A, Sisani M, Marrocolo F, Del Buono S, Danielli R (2015) Immunologic checkpoints blockade in renal cell, prostate, and urothelial malignancies. Semin Oncol 42(3):495–505

    Article  PubMed  Google Scholar 

  50. Tollefson MK, Karnes RJ, Thompson RH, et al (2010) A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer [abstract]. Genitourinary Cancer Symposium (Meeting Abstracts) 168

    Google Scholar 

  51. Small E, Higano C, Tchekmedyian N et al (2006) 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 cance r[abstract]. J Clin Oncol (Meeting Abstracts) 24:4609

    Google Scholar 

  52. Harzstark AL, Fong L, Weinberg VK et al (2010) Final results of a phase I study of CTLA-4 blockade in combination with GM-CSF for metastatic castration resistant prostate cancer (mCRPC) [abstract]. J clin Oncol (Meeting Abstracts) 28:4689

    Google Scholar 

  53. Fong L, Kwek S, O’Brien S et al (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69:609–615

    Article  CAS  PubMed  Google Scholar 

  54. Kwon ED, Drake CG, Scher HI et al (2014) Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15(7):700–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tomillero A, Moral MA (2008) Gateways to clinical trials. Methods Find Exp Clin Pharmacol 30(8):643–672

    CAS  PubMed  Google Scholar 

  56. Poust J et al (2008) Targeting metastatic melanoma. Am J Health Syst Pharm 65(24 Suppl 9):S9–S15

    Article  CAS  PubMed  Google Scholar 

  57. McNeel DG, Smith HA, Eickhoff JC et al (2012) Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother 61:1137–1147

    Article  CAS  PubMed  Google Scholar 

  58. Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Le DT, Pardoll DM, Jaffee EM (2010) Cellular vaccine approaches. Cancer J 16:304–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Higano C, Corman J, Smith D et al (2008) Phase I/II dose escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 113:975–984

    Article  CAS  PubMed  Google Scholar 

  61. Higano C, Saad F, Somer B et al (2009) A phase III trial of GVAX immunotherapy for prostate cancer vs. docetaxel plus prednisone in asymptomatic castration-resistant prostate cancer (CRPC). Presented at ASCO GU

    Google Scholar 

  62. Small E, Demkow T, Gerritson W et al (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel vs. docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). GU ASCO

    Google Scholar 

  63. Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL et al (2000) Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 6:2175–2182

    CAS  PubMed  Google Scholar 

  64. 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(19):3089–3094

    Article  CAS  PubMed  Google Scholar 

  65. Higano C, Burch P, Small E et al (2005) Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial. 13th European Cancer Conference. Paris

    Google Scholar 

  66. Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422

    Article  CAS  PubMed  Google Scholar 

  67. Di Paola RS, Plante M, Kaufman H et al (2006) .A phase I trial of pox PSA vaccines (PROSTVAC) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer. J Translat Med 4, article 1

    Google Scholar 

  68. Sanda MG, Smith DC, Charles LG et al (1999) Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer. Urology 53(2):260–266

    Article  CAS  PubMed  Google Scholar 

  69. Gulley JL, Arlen PM, Madan RA et al (2010) Immunologic and prognostic factors associated with OS employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 59:663–674

    Article  CAS  PubMed  Google Scholar 

  70. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M et al (2010) OS analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 28(7):1099–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Bracarda, S., Hamzaj, A., Andrikou, K. (2017). New Frontiers in Treatment. In: Bertoldo, F., Boccardo, F., Bombardieri, E., Evangelista, L., Valdagni, R. (eds) Bone Metastases from Prostate Cancer . Springer, Cham. https://doi.org/10.1007/978-3-319-42327-2_17

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