Abstract
Until very recently, docetaxel was the only approved agent in castration-resistant prostate cancer (CRPC) and other effective therapeutic options are urgently needed. In recent years, several new agents with promising activity and a favourable toxicity profile have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy. In particular, recent results from two large phase III trials of sipuleucel-T and cabazitaxel show that these two agents significantly prolong overall survival in CRPC. Indeed, sipuleucel-T has recently been approved by the US FDA for the treatment of CRPC. Many other pharmaceuticals, which are presented in this review, have been investigated recently or are being investigated in phase III trials and might prove to be effective in the future. Reviewed articles are discussed in light of the innovations in study design brought by the Prostate Cancer Clinical Trials Working Group (PCWG2), which updated the Prostate-Specific Antigen Working Group (PCWG1) guidelines, in order to allow better identification of potentially active drugs in clinical trials.
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References
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225–49
Di Lorenzo G, Autorino R, Figg WD, et al. Hormonerefractory prostate cancer: where are we going? Drugs 2007; 67: 1109–24
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
Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005; 23: 8253–61
Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15: 2928–38
Taplin ME, Regan MM, Ko YJ, et al. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res 2009; 15: 7099–105
Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004; 22: 1025–33
Yap TA, Carden CP, Attard G, et al. Targeting CYP17: established and novel approaches in prostate cancer. Curr Opin Pharmacol 2008; 8: 449–57
Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 2010; 28(9): 1481–8
Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27: 3742–8
Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the cyp 17 inhibitor abiraterone acetate. J Clin Oncol 2010; 28(9): 1489–95
Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010; 28(9): 1496–501
Abiraterone acetate in castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy [ClinicalTrials.gov identifier NCT00638690]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Jan 1]
Abiraterone acetate in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer [ClinicalTrials.gov identifier NCT00887198]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Jan 1]
Scher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC) [abstract]. J Clin Oncol (Meeting Abstracts) 2009; 27: 5011
Russo A, Bronte G, Rizzo S, et al. Anti-endothelin drugs in solid tumors. Expert Opin Emerg Drugs 2010; 15(1): 27–40
Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group Trial (SWOG 9426). Cancer 2008; 112: 2393–400
James ND, Caty A, Borre M, et al. 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: 1112–3
James ND, Morris T, Phung D, et al. Phase II trial of the specific endothelin A receptor antagonist zibotentan (ZD4054) in pain-free or mildly symptomatic patients with hormone-resistant prostate cancer and bone metastases: final analysis of safety and efficacy [abstract no. 7013]. Eur J Cancer Suppl 2009; 7: 410
Dawson N, Payne H, Battersby C, et al. Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054). J Cancer Res Clin Oncol. Epub 2010 Apr 14
Trump DL, Payne H, Miller K et al. Safety and efficacy of the specific endothelin A receptor antagonist zibotentan (ZD4054) plus docetaxel in patients with metastatic hormone-resistant prostate cancer: results of a phase I study [abstract no. 193]. 2010 ASCO Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)
Phase III trial of ZD4054 (endothelin A antagonist) in non-metastatic hormone resistant prostate cancer (ENTHUSE M0) [ClinicalTrials.gov identifier NCT00626548]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 22]
Phase III trial of ZD4054 (endothelin A antagonist) in hormone resistant prostate cancer with bone metastases (ENTHUSE M1) [ClinicalTrials.gov identifier NCT00554229]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 22]
Phase III Trial of ZD4054 (endothelin A antagonist) and docetaxel in metastatic hormone resistant prostate cancer (ENTHUSE M1C) [ClinicalTrials.gov identifier NCT0061 7669]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 22]
Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; 110: 1959–66
Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 2008; 113: 2478–87
Armstrong AJ, Creel P, Turnbull J, et al. A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2008; 14: 6270–6
Docetaxel and prednisone with or without atrasentan in treating patients with stage IV prostate cancer and bone metastases that did not respond to previous hormone therapy [ClinicalTrials.gov identifier NCT00134056]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 23]
Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev 2006; 25: 541–9
Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009; 27: 1564–71
Double-blind study of denosumab compared with zole-dronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer [ClinicalTrials.gov identifier NCT00321620]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 26]
Study on prolonging bone metastasis-free survival in men with hormone refractory prostate cancer [ClinicalTrials. gov identifier NCT00286091]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 26]
Amgen. Denosumab demonstrated superiority over zometa(R) in pivotal phase 3 head-to-head trial in prostate cancer patients with bone metastases [press release]. 2010 Feb 8 [online]. Available from URL: http://www.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1385163 [Accessed 2010 Apr 4]
Cortés-Funes H. The role of antiangiogenesis therapy: bevacizumab and beyond. Clin Transl Oncol 2009; 11: 349–55
George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 2001; 7: 1932–6
Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008; 54: 1089–94
Docetaxel and prednisone with or without bevacizumab in treating patients with prostate cancer that did not respond to hormone therapy [ClinicalTrials.gov identifier NCT00110214]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 26]
Roche provides update on phase III study of Avastin in men with late stage prostate cancer [media release]. Basel: 2010 Mar 12 [online]. Available from URL: http://www.roche.com/media/media_releases/med-cor-2010-03-12.htm [Accessed 2010 Apr 1]
Lockhart AC, Rothenberg ML, Dupont J et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010; 28: 207–14
Aflibercept in combination with docetaxel in metastatic androgen independent prostate cancer (VENICE) [Clinical Trials.gov identifier NCT00519285]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 26]
Dror Michaelson M, Regan MM, Oh WK, et al. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol 2009; 20: 913–20
Sonpavde G, Periman PO, Bernold D, et al. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol 2010; 21: 319–24
Sunitinib plus prednisone in patients with metastatic hormone-refractory prostate cancer after failure of docetaxel chemotherapy (SUN 1120). [ClinicalTrials.gov identifier NCT00676650]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Apr 20]
Nam S, Kim D, Cheng JQ, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 2005; 65: 9185–9
Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 2009; 15: 7421–8
Araujo J, Gallick G, Trudel G, et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: a phase 1/2 study (CA180-086) [abstract no. 5061]. J Clin Oncol 2009; 27: 15s
Randomized study comparing docetaxel plus dasatinib to docetaxel plus placebo in castration-resistant prostate cancer [ClinicalTrials.gov identifier NCT00744497]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 Feb 26]
Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res 2010; 16: 1088–93
Chi KN, Hotte SJ, Yu E, et al. Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer [abstract]. J Clin Oncol (Meeting Abstracts) 2009; 27: 5012
Saad F, Hotte SJ, North SA, et al. A phase II randomized study of custirsen (OGX-011) combination therapy in patients with poor-risk hormone refractory prostate cancer (HRPC) who relapsed on or within six months of 1st-line docetaxel therapy [abstract]. J Clin Oncol 2008; 20 Suppl.: 5002
Mita AC, Denis LJ, Rowinsky EK, et al. 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: 723–30
Sartor AO, Oudard S, Ozguroglu M, et al. 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 no. 9]. 2010 ASCO Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)
Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel retreatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int. In press
Lee JJ, Kelly WK. Epothilones: tubulin polymerization as a novel target for prostate cancer therapy. Nat Clin Pract Oncol 2009; 6: 85–92
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
Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line chemotherapy in docetaxel-refractory hormonerefractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 2007; 110: 556–63
Small E, Harzstark A, Weinberg VK, et al. Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: a phase II study of the DOD Prostate Cancer Clinical Trials Consortium [abstract]. J Clin Oncol (Meeting Abstracts) 2009; 27: 5058
Hussain A, DiPaola RS, Baron AD, et al. Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Ann Oncol 2009; 20: 492–7
Beardsley EK, Saad F, Eigl B, et al. A phase II study of patupilone in patients (pts) with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel [abstract]. J Clin Oncol (Meeting Abstracts) 2009; 27: 5139
Beer TM, Smith DC, Hussain A, et al. Phase II study of first-line sagopilone combined with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC) [abstract]. J Clin Oncol (Meeting Abstracts) 2009; 27: 5059
Sternberg CN, Petrylak DP, Sartor O, et al. 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: 5431–8
Kelland L. Broadening the clinical use of platinum drug-based chemotherapy with new analogues. Satraplatin and picoplatin. Expert Opin Investig Drugs 2007; 16(7): 1009–21
De Jager RL, Roman LD, Lopatkin NA, et al. Phase II study of picoplatin with docetaxel and prednisone in first-line treatment of castration-resistant prostate cancer (CRPC) [abstract no. 37]. 2010 ASCO Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)
Small EJ, Schellhammer PF, Higano CS. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006 Jul 1; 24: 3089–94
Higano CS, Schellhammer PF, Small EJ, 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 2009 Aug 15; 115(16): 3670–9
Kantoff P, Higano CS, Berger ER, et al. Updated survival results of the IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer (CRPC) [abstract no. 8]. 2010 ASCO Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)
Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al. Prostatespecific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 2007; 25: 3965–70
Halabi S, Vogelzang NJ, Ou SS, et al. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol 2009; 27: 2766–71
Armstrong AJ, Tannock IF, de Wit R, et al. The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival. Eur J Cancer 2010; 46: 517–25
Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003; 21: 1232–7
Acknowledgements
Dr Di Lorenzo and Dr Buonerba equally contributed to this work. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
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Di Lorenzo, G., Buonerba, C., Autorino, R. et al. Castration-Resistant Prostate Cancer. Drugs 70, 983–1000 (2010). https://doi.org/10.2165/10898600-000000000-00000
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DOI: https://doi.org/10.2165/10898600-000000000-00000