Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18–24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

Keywords:
Targeted agents, Prostate cancer, Chemotherapy, Hormonal therapy
1.
Bergerat JP, Ceraline J: Pleiotropic functional properties of androgen receptor mutants in prostate cancer. Hum Mutat 2009;30:145–157.
2.
LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V, Gerald WL: Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res 2002;62:4499–4506.
3.
Edwards J, Krishna NS, Grigor KM, Bartlett JM: Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 2003;89:552–556.
4.
Marcias G, Erdmann E, Lapouge G, Siebert C, Barthelemy P, Duclos B, Bergerat JP, Ceraline J, Kurtz JE: Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22rv1 hormone-refractory prostate cancer (PCA) cell line. Hum Mutat 2010;31:74–80.
5.
Brooke GN, Parker MG, Bevan CL: Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression. Oncogene 2008;27:2941–2950.
6.
Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 1993;11:1566–1572.
7.
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324:787–790.
8.
Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 2010;375:1437–1446.
9.
Yap TA, Carden CP, Attard G, de Bono JS: Targeting cyp17: established and novel approaches in prostate cancer. Curr Opin Pharmacol 2008;8:449–457.
10.
Galsky MD, Simon K, Sonpavde G, Hutson TE, Fleming M, Kondagunta GV, Berry W: Ketoconazole retains activity in patients with docetaxel-refractory prostate cancer. Ann Oncol 2009;20:965–966.
11.
O’Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, Harland S, Robbins A, Halbert G, Nutley B, Jarman M: Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (cb7630) in patients with prostate cancer. Br J Cancer 2004;90:2317–2325.
12.
Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS: Phase I clinical trial of a selective inhibitor of cyp17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008;26:4563–4571.
13.
Attard G, Reid AH, A’Hern R, Parker C, Oommen NB, Folkerd E, Messiou C, Molife LR, Maier G, Thompson E, Olmos D, Sinha R, Lee G, Dowsett M, Kaye SB, Dearnaley D, Kheoh T, Molina A, de Bono JS: Selective inhibition of cyp17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009;27:3742–3748.
14.
Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C, Molina A, Anand A, Koscuiszka M, Larson SM, Schwartz LH, Fleisher M, Scher HI: Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010;28:1496–1501.
15.
Shah S, Ryan C, Kilian C, Hubbell A, Kheoh T, Haqq C, Molina A, Small E: Bone scan ‘flare’ in patients receiving abiraterone acetate (Aa) for metastatic castration resistant prostate cancer (MCRPC): analysis of data from a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium (abstract). J Clin Oncol 2010;28(15s):4545.
16.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512.
17.
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.
18.
Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, Logothetis CJ, Pignon JP, Michiels S: Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data. Lancet Oncol 2007;8:994–1000.
19.
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–1520.
20.
Eymard JC, Oudard S, Gravis G, Ferrero JM, Theodore C, Joly F, Priou F, Krakowski I, Zannetti A, Thill L, Beuzeboc P: Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU Int 2010;106:974–978.
21.
Ansari J, Hussain SA, Zarkar A, Tanguay JS, Bliss J, Glaholm J: Docetaxel chemotherapy for metastatic hormone refractory prostate cancer as first-line palliative chemotherapy and subsequent re-treatment: Birmingham experience. Oncol Rep 2008;20:891–896.
22.
Berthold DR, Pond GR, de Wit R, Eisenberger M, Tannock IF: Survival and psa response of patients in the tax 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa. Ann Oncol 2008;19:1749–1753.
23.
Caffo O, Sava T, Comploj E, Giampaolo MA, Segati R, Valduga F, Cetto G, Galligioni E: Estramustine plus docetaxel as second-line therapy in patients with hormone-refractory prostate cancer resistant to docetaxel alone. Urol Oncol 2010;28:152–156.
24.
Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, Forouzesh B, Beeram M, Patnaik A, Molpus K, Semiond D, Besenval M, Tolcher AW: Phase I and pharmacokinetic study of xrp6258 (rpr 116258a), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009;15:723–730.
25.
Pivot X, Koralewski P, Hidalgo JL, Chan A, Goncalves A, Schwartsmann G, Assadourian S, Lotz JP: A multicenter phase ii study of xrp6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol 2008;19:1547–1552.
26.
Sartor SO, Ozguroglu M, Hansen S, Machiels JH, Shen L, Gupta S, De Bono JS, TROPIC Investigators: Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (MCRPC) previously treated with docetaxel: final results of a multinational phase III trial (tropic) (abstract). J Clin Oncol 2010;28(15s):4508.
27.
Rosenberg JE, Weinberg VK, Kelly WK, Michaelson D, Hussain MH, Wilding G, Gross M, Hutcheon D, Small EJ: Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 2007;110:556–563.
28.
Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, Beuzeboc P, Demkow T, Oudard S: Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol 2004;15:1613–1621.
29.
Hussain A, DiPaola RS, Baron AD, Higano CS, Tchekmedyian NS, Johri AR: Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Ann Oncol 2009;20:492–497.
30.
De Souza PL, Mellado B, Pfister C, Rosenthal M, Castellano DE, Weber D, Ferrara S, Shaikh N, Tan E, Patterson SG: Randomized phase II trial of patupilone plus prednisone versus docetaxel plus prednisone in patients with chemotherapy-naive, metastatic, castrate-resistant prostate cancer (CRPC) (abstract). J Clin Oncol 2010;28(15s):4553.
31.
Sternberg CN, Whelan P, Hetherington J, Paluchowska B, Slee PH, Vekemans K, Van Erps P, Theodore C, Koriakine O, Oliver T, Lebwohl D, Debois M, Zurlo A, Collette L: Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer. Oncology 2005;68:2–9.
32.
Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabro F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M: Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 2009;27:5431–5438.
33.
Qi L, Robinson WA, Brady BM, Glode LM: Migration and invasion of human prostate cancer cells is related to expression of VEGF and its receptors. Anticancer Res 2003;23:3917–3922.
34.
Chen J, De S, Brainard J, Byzova TV: Metastatic properties of prostate cancer cells are controlled by VEGF. Cell Commun Adhes 2004;11:1–11.
35.
Aragon-Ching JB, Dahut WL: VEGF inhibitors and prostate cancer therapy. Curr Mol Pharmacol 2009;2:161–168.
36.
Picus J, Halabi S, Rini B, Vogelzang NJ, Whang Y, Kaplan E, Kelly W, Small E: The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006 (abstract 1578). Proc Am Soc Clin Oncol 2003;22:393.
37.
Di Lorenzo G, Figg WD, Fossa SD, Mirone V, Autorino R, Longo N, Imbimbo C, Perdona S, Giordano A, Giuliano M, Labianca R, De Placido S: Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008;54:1089–1094.
38.
Heidenreich A, Pfister DJ, Thüer D, Brehmer B: Docetaxel versus docetaxel plus bevacizumab in progressive castration-resistant prostate cancer following first-line docetaxel (abstract). J Clin Oncol 2010;28(15s):e15006.
39.
Kelly WK, Halabi S, Carducci MA, George DJ, Mahoney JF, Stadler WM, Morris MJ, Kantoff P, Monk JP, Small E: A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (MCRPC): survival results of CALGB 90401 (abstract). J Clin Oncol 2010;28(18s):LBA4511.
40.
Olsson A, Bjork A, Vallon-Christersson J, Isaacs JT, Leanderson T: Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors. Mol Cancer 2010;9:107.
41.
Dalrymple SL, Becker RE, Isaacs JT: The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts. Prostate 2007;67:790–797.
42.
Bratt O, Haggman M, Ahlgren G, Nordle O, Bjork A, Damber JE: Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. Br J Cancer 2009;101:1233–1240.
43.
Pili R, Haggman M, Stadler W, Gingrich J, Assikis V, Björk A, Forsberg G, Carducci M, Armstrong AJ: A randomized, multicenter, international phase II study of tasquinim- od in chemotherapy naive patients with metastatic castrate-resistant prostate cancer (CRPC) (abstract). J Clin Oncol 2010;28(15s):4510.
44.
Zonnenberg BA, Groenewegen G, Janus TJ, Leahy TW, Humerickhouse RA, Isaacson JD, Carr RA, Voest E: Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer. Clin Cancer Res 2003;9:2965–2972.
45.
Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD, Schulman CC, Nabulsi AA, Humerickhouse RA, Weinberg MA, Schmitt JL, Nelson JB: 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;21:679–689.
46.
Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ, Isaacson JD, Nelson JB: A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007;110:1959–1966.
47.
Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, Qian J, Steinberg J, Carducci M: Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 2008;113:2478–2487.
48.
Armstrong AJ, Creel P, Turnbull J, Moore C, Jaffe TA, Haley S, Petros W, Yenser S, Gockerman JP, Sleep D, Hurwitz H, George DJ: A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2008;14:6270–6276.
49.
James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T, Phung D, Dawson NA: Safety and efficacy of the specific endothelin-a receptor antagonist zd4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol 2009;55:1112–1123.
50.
Chu QS: Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin Biol Ther 2009;9:263–271.
51.
Dahut WL, Aragon-Ching JB, Woo S, Tohnya TM, Gulley JL, Arlen PM, Wright JJ, Ventiz J, Figg WD: Phase I study of oral lenalidomide in patients with refractory metastatic cancer. J Clin Pharmacol 2009;49:650–660.
52.
Mathew P, Tannir N, Tu SM, Carter CM, Bekele NB, Pagliaro L: A modular phase I study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer following prior taxane therapy. Cancer Chemother Pharmacol 2010;65:811–815.
53.
Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M: 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;96:879–882.
54.
Karabulut B, Erten C, Gul MK, Cengiz E, Karaca B, Kucukzeybek Y, Gorumlu G, Atmaca H, Uzunoglu S, Sanli UA, Baran Y, Uslu R: Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic bcl-2 protein level in hormone-refractory prostate cancer cells. Cell Biol Int 2009;33:239–246.
55.
Fizazi K, Carducci M, Smith MR, Damiao R, Brown JE, Karsh L, Milecki P, Wang H, Dansey RD, Goessl CD: A randomized phase II trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer (abstract). J Clin Oncol 2010;28(18s)LBA4507.
56.
Kantoff P, Higano CS, Shore ND, Berger ER, Small E, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich M, Schellhammer P: Sipuleucel-T immunotherapy for castration-resistant prostate cancer N Engl J Med 2010;363:411–422.
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2011
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