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Challenges for the Development of New Agents in Prostate Cancer

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Drug Management of Prostate Cancer

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Abstract

Development of novel therapeutic agents in advanced prostate cancer presents particular challenges due to multiple factors including advanced age at diagnosis with competing causes of death and difficulties in assessing responses in bone (the predominant site of metastatic disease). Over the last 2 decades, few non hormonal drugs have met the regulatory requirements for approval in advanced prostate cancer. These include mitoxantrone (1996), zoledronic acid (2002) and docetaxel (2004). Sipuleucel-T, an autologous cell based vaccine and cabazitaxel were approved in 2010. Despite these breakthroughs, the general landscape for new and effective treatments in prostate cancer remains challenging. The aim of this review is to discuss the specific obstacles in the development of novel agents in prostate cancer and potential strategies to overcome them.

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References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Schmidt JD, Gibbons RP, Johnson DE, Prout GR, Scott WW, Murphy GP. Chemotherapy of advanced prostatic cancer. Evaluation of response parameters. Urology 1976;7:602–10.

    Article  PubMed  CAS  Google Scholar 

  3. Slack NH, Murphy GP. Criteria for evaluating patient responses to treatment modalities for prostatic cancer. Urol Clin North Am 1984;11:337–42.

    PubMed  CAS  Google Scholar 

  4. Slack NH, Brady MF, Murphy GP. Stable versus partial response in advanced prostate cancer. Prostate 1984;5:401–15.

    Article  PubMed  CAS  Google Scholar 

  5. Eisenberger MA. Chemotherapy for prostate carcinoma. NCI Monogr 1988;(7):151–63.

    Google Scholar 

  6. Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 1993;71:1098–109.

    Article  PubMed  CAS  Google Scholar 

  7. Tannock IF. Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate? J Clin Oncol 1985;3:1013–21.

    PubMed  CAS  Google Scholar 

  8. Shah RB, Mehra R, Chinnaiyan AM, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004;64:9209–16.

    Article  PubMed  CAS  Google Scholar 

  9. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.

    Article  PubMed  CAS  Google Scholar 

  10. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.

    Article  PubMed  CAS  Google Scholar 

  11. Tannock IF, Osoba D, Stockler MR, et al. 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 1996;14:1756–64.

    PubMed  CAS  Google Scholar 

  12. Kantoff PW, Halabi S, Conaway M, et al. 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 1999;17:2506–13.

    PubMed  CAS  Google Scholar 

  13. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–68.

    Article  PubMed  CAS  Google Scholar 

  14. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–82.

    Article  PubMed  CAS  Google Scholar 

  15. Petrylak DP, Macarthur R, O’Connor J, et al. Phase I/II studies of docetaxel (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer. Semin Oncol 1999;26:28–33.

    PubMed  CAS  Google Scholar 

  16. Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001;19:2509–16.

    PubMed  CAS  Google Scholar 

  17. Kreis W, Budman D. Daily oral estramustine and intermittent intravenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormone-refractory prostate cancer. Semin Oncol 1999;26:34–8.

    PubMed  CAS  Google Scholar 

  18. Petrylak DP, Macarthur RB, O’Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17:958–67.

    PubMed  CAS  Google Scholar 

  19. Galsky MD, Small EJ, Oh WK, 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. J Clin Oncol 2005;23:1439–46.

    Article  PubMed  CAS  Google Scholar 

  20. Hussain M, Tangen CM, Lara PN, Jr., 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. J Clin Oncol 2005;23:8724–9.

    Article  PubMed  Google Scholar 

  21. Ferro MA, Gillatt D, Symes MO, Smith PJ. High-dose intravenous estrogen therapy in advanced prostatic carcinoma. Use of serum prostate-specific antigen to monitor response. Urology 1989;34:134–8.

    Article  PubMed  CAS  Google Scholar 

  22. Seidman AD, Scher HI, Petrylak D, Dershaw DD, Curley T. Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 1992;147:931–4.

    PubMed  CAS  Google Scholar 

  23. Smith DC, Dunn RL, Strawderman MS, Pienta KJ. Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J Clin Oncol 1998;16:1835–43.

    PubMed  CAS  Google Scholar 

  24. Vollmer RT, Dawson NA, Vogelzang NJ. The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate. Cancer 1998;83:1989–94.

    Article  PubMed  CAS  Google Scholar 

  25. Kelly WK, Scher HI, Mazumdar M, Vlamis V, Schwartz M, Fossa SD. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 1993;11:607–15.

    PubMed  CAS  Google Scholar 

  26. Scher HI, Kelly WM, Zhang ZF, et al. Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer. J Natl Cancer Inst 1999;91:244–51.

    Article  PubMed  CAS  Google Scholar 

  27. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461–7.

    PubMed  CAS  Google Scholar 

  28. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505–12.

    Article  PubMed  CAS  Google Scholar 

  29. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34.

    Article  PubMed  CAS  Google Scholar 

  30. Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1995;1:944–9.

    Article  PubMed  CAS  Google Scholar 

  31. Yin JJ, Mohammad KS, Kakonen SM, et al. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 2003;100:10954–9.

    Article  PubMed  CAS  Google Scholar 

  32. Pirtskhalaishvili G, Nelson JB. Endothelium-derived factors as paracrine mediators of prostate cancer progression. Prostate 2000;44:77–87.

    Article  PubMed  CAS  Google Scholar 

  33. Thakkar SG, Choueiri TK, Garcia JA. Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 2006;8:108–13.

    Article  PubMed  CAS  Google Scholar 

  34. Carducci MA, Padley RJ, Breul J, 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. J Clin Oncol 2003;21:679–89.

    Article  PubMed  CAS  Google Scholar 

  35. Lipton A, Sleep DJ, Hulting SM, Isaacson JD, Allen AR. Benefit of atrasentan in men with hormone refractory prostate cancer metastatic to bone. J Clin Oncol 2004;22:4687.

    Article  Google Scholar 

  36. Sleep DJ, Nelson JB, Petrylak DP, Isaacson JD, Carducci MA. Clinical benefit of atrasentan for men with metastatic hormone-refractory prostate cancer metastatic to bone. J Clin Oncol 2006;24:4630.

    Google Scholar 

  37. Scher HI, Halabi S, Tannock I, et al. 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;26:1148–59.

    Article  PubMed  Google Scholar 

  38. Sternberg CN, Petrylak D, Witjes F, et al. Satraplatin (S) demonstrates significant clinical benefits for the treatment of patients with HRPC: results of a randomized phase III trial. J Clin Oncol 2007;25:abstract 5019.

    Article  Google Scholar 

  39. Sartor A, Petrylak D, Witjes J, et al. Satraplatin in patients with advanced hormone-refractory prostate cancer (HRPC): overall survival (OS) results from the phase III satraplatin and prednisone against refractory cancer (SPARC) trial. J Clin Oncol 2008;20 Suppl:abstract 5003.

    Google Scholar 

  40. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95.

    Article  Google Scholar 

  41. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989;8:431–40.

    Article  PubMed  CAS  Google Scholar 

  42. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24:3984–90.

    Article  PubMed  Google Scholar 

  43. Petrylak DP, Ankerst DP, Jiang CS, et al. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 2006;98:516–21.

    Article  PubMed  Google Scholar 

  44. Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al. Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 2007;25:3965–70.

    Article  PubMed  Google Scholar 

  45. Eisenberger M, Crawford E, McLeod D, Hussain M, Loehrer P, Blumenstein B. The prognostic significance of prostate specific antigen (PSA) in stage D2 prostate cancer (PC) interim evaluation of intergroup study 0105 (Meeting abstract). Proceedings of the 1995 ASCO Annual Meeting 1995;14:abstract 613.

    Google Scholar 

  46. Hussain M, Goldman B, Tangen C, Higano C, Petrylak D, Crawford E. Use of prostate-specific antigen progression (PSA-P) to predict overall survival (OS) in patients (pts) with metastatic prostate cancer (PC): data from S9346 and S9916. J Clin Oncol 2008;20 Suppl:abstract 5015.

    Google Scholar 

  47. Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97:59–69.

    Article  PubMed  CAS  Google Scholar 

  48. Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005;23:4925–35.

    Article  PubMed  CAS  Google Scholar 

  49. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem 2004;91:718–29.

    Article  PubMed  CAS  Google Scholar 

  50. Berruti A, Piovesan A, Torta M, et al. Biochemical evaluation of bone turnover in cancer patients with bone metastases: relationship with radiograph appearances and disease extension. Br J Cancer 1996;73:1581–7.

    Article  PubMed  CAS  Google Scholar 

  51. Vinholes J, Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment. Cancer Treat Rev 1996;22:289–331.

    Article  PubMed  CAS  Google Scholar 

  52. Percival RC, Urwin GH, Harris S, et al. Biochemical and histological evidence that carcinoma of the prostate is associated with increased bone resorption. Eur J Surg Oncol 1987;13:41–9.

    PubMed  CAS  Google Scholar 

  53. Zhang J, Dai J, Qi Y, et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Invest 2001;107:1235–44.

    Article  PubMed  CAS  Google Scholar 

  54. Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000;88:2989–94.

    Article  PubMed  CAS  Google Scholar 

  55. Karsenty G. Bone formation and factors affecting this process. Matrix Biol 2000;19:85–9.

    Article  PubMed  CAS  Google Scholar 

  56. Parfitt AM. The mechanism of coupling: a role for the vasculature. Bone 2000;26:319–23.

    Article  PubMed  CAS  Google Scholar 

  57. Boyce BF, Hughes DE, Wright KR, Xing L, Dai A. Recent advances in bone biology provide insight into the pathogenesis of bone diseases. Lab Invest 1999;79:83–94.

    PubMed  CAS  Google Scholar 

  58. Pectasides D, Nikolaou M, Farmakis D, et al. Clinical value of bone remodelling markers in patients with bone metastases treated with zoledronic acid. Anticancer Res 2005;25:1457–63.

    PubMed  CAS  Google Scholar 

  59. Vogelzang N, Nelson J, Schulman C, et al. Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer. J Clin Oncol 2005;23:4563.

    Google Scholar 

  60. Carducci M, Nelson JB, Saad F, et al. Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: phase 3 study. J Clin Oncol 2004;22:4508.

    Google Scholar 

  61. Lara PN, Jr., Stadler WM, Longmate J, et al. A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases. Clin Cancer Res 2006;12:1556–63.

    Article  PubMed  CAS  Google Scholar 

  62. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781–91.

    Article  PubMed  CAS  Google Scholar 

  63. Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006;12:4218–24.

    Article  PubMed  CAS  Google Scholar 

  64. Moreno JSD, Shaffer D, Montgomery B, et al. Multi-center study evaluating circulating tumor cells (CTCs) as a surrogate for survival in men treated for castration refractory prostate cancer (CRPC). J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. 2007;25(20 Suppl):5016.

    Google Scholar 

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Authors and Affiliations

  1. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Maha Hussain

Authors
  1. Ajjai S. Alva
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  2. Deborah A. Bradley
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  3. Maha Hussain
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Correspondence to Maha Hussain .

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Editors and Affiliations

  1. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    William D. Figg

  2. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    Cindy H. Chau

  3. School of Medicine, Dept. Urology, University of California, San Francisco, Divisadero Street 1600, San Francisco, 94115, California, USA

    Eric J. Small

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Alva, A.S., Bradley, D.A., Hussain, M. (2010). Challenges for the Development of New Agents in Prostate Cancer. In: Figg, W., Chau, C., Small, E. (eds) Drug Management of Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-60327-829-4_34

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  • DOI: https://doi.org/10.1007/978-1-60327-829-4_34

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