Improving survival in metastatic castration-resistant prostate cancer (CRPC) is no longer an elusive goal. With the expansion of knowledge regarding the biology of the disease, we are witnessing a plethora of novel therapeutics that are undergoing testing in clinical trials. Since the approval of docetaxel for metastatic CRPC in 2004, three additional agents have demonstrated improvements in overall survival in randomized phase III trials: two agents (cabazitaxel and sipuleucel-T) were approved by the FDA in 2010, and a third (abiraterone) was approved in April of 2011. A threshold has clearly been crossed in the management of advanced prostate cancer; however, the impact on survival has been relatively modest, and efforts at personalized therapy have lagged behind those for other solid tumors. Further meaningful advances are needed, and the foundation for future clinical trials must be high-quality, high-impact translational science that focuses on disease biology, the defining of relevant pathways and validated predictive biomarkers, and adequate preclinical characterization of agents and combinations that will facilitate more personalized therapy.
Prior to 2004, major treatment options for advanced prostate cancer were limited to hormonal therapy for hormone-sensitive disease, mitoxantrone (Novantrone) and strontium-89 (Metastron) for pain palliation, and zoledronic acid (Zometa) to minimize skeletal-related events (SREs) in castration-resistant prostate cancer (CRPC).[1-4] The landmark studies demonstrating a survival improvement for patients treated with docetaxel (Taxotere) not only dramatically influenced the management of CRPC but also energized more research in this setting, leading to more FDA-approved agents available for use (Table 1).[5,6]
Just in 2010, three agents were approved by the FDA: cabazitaxel (Jevtana) and sipuleucel-T (Provenge) for the treatment of metastatic CRPC based on improvements in overall survival, and denosumab (XGEVA) for the supportive management of bone disease.[7-9] In April 2011, the FDA approved abiraterone (Zytiga) for the treatment of metastatic CRPC post docetaxel. These agents work by quite distinct mechanisms; they thus reflect the complex nature of CRPC and the potential therapeutic opportunities. The expansion in the understanding of the biology of CRPC has led to a plethora of agents that are currently under clinical investigation in a variety of advanced disease settings (Tables 2 and 3). This review will discuss recently FDA-approved agents for advanced prostate cancer and those under investigation in phase III trials.
Based on cumulative scientific clinical data, particularly data on docetaxel, the microtubule is considered a validated therapeutic target in metastatic CRPC. Microtubules have numerous cellular functions, including preservation of cellular shape, intracellular transport, and formation of the mitotic spindle for movement of sister chromatids during mitosis. The most widely tested microtubule inhibitors are the taxanes and the epothilones, both of which suppress microtubule activity, leading to mitotic arrest and apoptosis. The epothilones (eg, ixabepilone, patupilone) have been studied in phase II trials in patients with metastatic CRPC with variable efficacy.[11-14] The nanoparticle albumin-bound (nab) formulations of docetaxel and paclitaxel are being evaluated in CRPC.[15,16]
Cabazitaxel is the microtubule inhibitor most recently approved by the FDA. The preclinical activity of cabazitaxel in tumor models resistant to docetaxel and paclitaxel led to clinical studies demonstrating antitumor activity in metastatic CRPC refractory to docetaxel.[10,17] This paved the way for an international, multicenter, phase III study that randomly assigned 755 men with metastatic CRPC with disease progression after docetaxel to receive prednisone plus either mitoxantrone or cabazitaxel. While all patients were previously treated with docetaxel, 16% in the cabazitaxel group and 13% in the mitoxantrone group had received two or more docetaxel-containing regimens. The median time from the last docetaxel dose to disease progression was 0.8 months in the cabazitaxel group and 0.7 months in those receiving mitxantrone. Patients treated with cabazitaxel had a median overall survival of 15.1 months (95% confidence interval [CI], 14.1-16.3), compared with 12.7 months (95% CI, 11.6-13.7) in the mitoxantrone-treated patients, with a hazard ratio (HR) for death of 0.7 (95% CI, 0.59-0.83, P < .0001) for men receiving cabazitaxel. The cabazitaxel-treated patients had a median progression-free survival of 2.8 months (95% CI, 2.4-3.0) compared with 1.4 months (95% CI, 1.4-1.7) in those receiving mitoxantrone (HR, 0.74; 95% CI, 0.64-0.86; P < .0001). In patients with measurable disease, 14.4% (95% CI, 9.6-19.3) of cabazitaxel-treated patients had an objective response, compared with only 4.4% (95% CI, 1.6-7.2%) in the mitoxantrone group (P < .0005). Nearly all patients experienced some degree of myelosuppression, but more patients treated with cabazitaxel experienced grade 3 or higher neutropenia (82% vs 58%) and neutropenic fever (8% vs 1%). Grade 3 or higher anemia and diarrhea were also seen more often in patients treated with cabazitaxel (11% vs 5%, and 6% vs < 1%, respectively). In addition, more deaths occurred within 30 days of receiving the last dose of drug in cabazitaxel-treated patients (18 deaths [5%], including 7 from neutropenia and its consequences and 5 from cardiac causes) than in the mitoxantrone group (9 deaths [2%], 6 of which were due to disease progression).
Cabazitaxel was approved by the FDA in 2010 for salvage therapy after disease progression following docetaxel-based therapy. However, the toxicities associated with this treatment, notably myelosuppression, warrant particular caution. Careful monitoring of blood counts is needed, and growth factor support is recommended for patients, including the elderly, who are at high risk for complications from myelosuppression. In addition, the increase in cardiac deaths seen with cabazitaxel compared with mitoxantrone warrants careful administration and monitoring in patients with underlying cardiac disease.
The immune system is heavily involved in the development and progression of cancer. Over the past several years, several strategies have been developed exploiting this concept in a multitude of malignancies, including prostate cancer.
Sipuleucel-T is an active cellular immunotherapy agent composed of autologous antigen-presenting cells (APCs) that have been cultured with the fusion protein PA2024, which consists of prostatic acid phosphatase and granulocyte–macrophage colony-stimulating factor, and which is designed to stimulate an immune response against prostate cancer cells.
The initial phase III study using sipuleucel-T in prostate cancer, published in 2006, randomly assigned 127 patients with asymptomatic metastatic CRPC to treatment with sipuleucel-T or to a control group (in which patients received APCs cultured in the absence of PA2024). The difference in median time to disease progression (the primary endpoint) between the two groups was not statistically significant (11.7 weeks in the sipuleucel-T group vs 10.0 weeks in the control group). However, the median overall survival, a secondary endpoint, was 25.9 months in the sipuleucel-T group compared with 21.4 months in the control group (HR, 1.71 [95% CI, 1.13-2.58];P = .01). Another small phase III study of patients with asymptomatic metastatic CRPC showed a non-statistically significant trend towards increased overall survival (a secondary endpoint) with sipuleucel-T (19.7 months vs 15 months), but with no significant difference in the time to disease progression, the primary endpoint of the study. A third phase III trial, with overall survival as the primary endpoint, randomly assigned patients with asymptomatic or minimally symptomatic metastatic CRPC in a 2:1 ratio to treatment with sipuleucel-T or to a control arm (in which patients received APCs cultured in the absence of PA2024). Patients randomly assigned to the control arm who developed progressive disease were unblinded and offered treatment with sipuleucel-T manufactured using the patient’s cryopreserved APCs. Of the 171 patients in the control arm, a total of 109 (63.7%) received sipuleucel-T as salvage therapy, with 84 of these (49.1%) receiving it as initial therapy following disease progression. Most patients in both cohorts received additional therapy beyond sipuleucel-T. In the experimental arm, 81.8% received additional treatment and 57.2% received docetaxel after a median of 12.3 months, whereas 73.1% in the control arm received additional therapy, 50.3% of whom received docetaxel after a median 13.9 months. The results showed that sipuleucel-T–treated patients had a four-month improvement in overall survival (25.8 months vs 21.7 months; HR, 0.78 [95% CI, 0.61-0.98]; P = .03). As in the other two studies, no antitumor effect was seen, as reflected by the lack of difference in time to disease progression, symptom improvement, decrease in PSA level, or other measure of disease response.
The most common adverse reaction seen with sipuleucel-T was an infusion reaction, occurring within 24 hours in 71.2% of patients (3.5% had grade 3 reactions) and manifested by chills, fever, fatigue, nausea, tachycardia, and hypertension.[19-21] Other common side effects included headache, back pain, and joint pain. Overall, grade 3 or 4 adverse events occurred in 23.6% and 4% of patients, respectively, with the most common being back pain and chills. In one trial, cerebrovascular events occurred in 7.5% of patients treated with sipuleucel-T (11 of 147) vs 2.6% of patients in the control group (2 of 76).
A common concern regarding sipuleucel-T has been the lack of any demonstrable antitumor effect in any of the randomized trials as compared with results in the control groups—and therefore, the inability to assess response at the individual patient level.[22,23] It remains to be proven whether conventional response measures are appropriate with this class of agents or not. If not, then until adequate efficacy assessment measures are established, we strongly recommend that future phase III testing of such agents include an active control arm proven to be of benefit so as to allow confidence in the trial results with regard to comparable or superior outcome. This is especially important considering the per-patient cost of treatment with sipuleucel-T and the fact that it does not obviate the need for chemotherapy. Proponents of this agent argue that the cost is comparable to that of other biologic agents approved by the FDA and that the price may be offset by the more favorable side-effect profile of sipuleucel-T (compared to chemotherapy). However, since this agent was tested in a different patient population than that included in the docetaxel trials (which allowed accrual of patients with pain and visceral disease), and since none of the trials compared sipuleucel-T to an active control with established clinical benefit, the fact remains that thousands of patients will receive a full course of therapy without the certainty of knowing who may be benefiting.
Under normal conditions, activation of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) leads to inhibition of T-cell activation. Ipilimumab (Yervoy) is a human monoclonal antibody against CTLA-4. Early work on prostate cancer has shown that this agent potentiates a sustained T-cell immune response and leads to clinical benefit. Recent reports demonstrate activity in advanced prostate cancer when ipilimumab is combined with androgen ablation; 55% of patients in one study achieved undetectable PSA levels after 3 months of combined therapy compared with 38% of patients treated with androgen ablation alone.[27,28] Side effects included diarrhea (4.5%); colitis (4.5%); and cutaneous changes, such as localized vitiligo, etc (27.7%). A phase III study evaluating the effect of ipilimumab on overall survival in patients with metastatic CRPC is ongoing.
1. Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993;25:805-13.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Sipuleucel-T (PROVENGE). US Food and Drug Administration; [cited 2010 November 14]; Available from: http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210012.htm.
8. Cabazitaxel (JEVTANA). US Food and Drug Administration; [cited 2010 November 14]; Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
9. Fizazi K. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2010;28:Abstract LBA4507.
10. Attard G, Greystoke A, Kaye S, De Bono J. Update on tubulin-binding agents. Pathol Biol (Paris). 2006;54:72-84.
11. 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.
12. Rosenberg JE, Ryan CJ, Weinberg VK, et al. Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium. J Clin Oncol. 2009;27:2772-8.
13. Rosenberg JE, Weinberg VK, Kelly WK, et al. 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;110:556-63.
14. 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.
15. ABI-008 trial in patients with hormone-refractory prostate cancer. US National Institues of Health; [cited 2011 January 27]; Available from: http://www.clinicaltrials.gov/.
16. Kolevska T, Ryan CJ, Huey V, et al. Phase II trial of nab-paclitaxel as first-line therapy of hormone refractory metastatic prostate cancer (HRPC). J Clin Oncol. 2009;27:Abstract 5152.
17. 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.
18. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.
19. Small EJ, Schellhammer PF, Higano CS, et al. 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;24:3089-94.
20. 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;115:3670-9.
21. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.
22. Batchelor J. Provenge wild ride blazes trail for immunotherapy. Oncol News Intl. 2010 November 29.
23. Longo DL. New therapies for castration-resistant prostate cancer. N Engl J Med. 2010;363:479-81.
24. Nabhan C. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:1966-7; author reply 8.
25. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445-50.
26. Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810-5.
27. Granberg CF, Karnes RJ, Tollefson MK, et al. Conversion of advanced prostate cancer to organ-confined minimal residual disease using CTLA-4 blockade (ipilimumab) immunotherapy. ASCO Genitourinary Cancers Symposium. 2010:Abstract 33.
28. Tollefson MK, Karnes RJ, Thompson RH, et al. A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer. ASCO Genitourinary Cancers Symposium. 2010:Abstract 168.
29. Phase 3 study of immunotherapy to treat advanced prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.
30. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407-15.
31. Mohler JL, Gregory CW, Ford OH, 3rd, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440-8.
32. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54.
33. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;
34. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.
35. el-Rayes BF, Hussain MH. Hormonal therapy for prostate cancer: past, present and future. Expert Rev Anticancer Ther. 2002;2:37-47.
36. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-8.
37. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57:836-42.
38. 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.
39. 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;28:1496-501.
40. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-95.
41. 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;28:1481-8.
42. de Bono JS, Logothetis C, Fizazi K, et al. Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized double-blind placebo-controlled phase III study. Ann Oncol. 2010;21:LBA5.
43. Abiraterone acetate in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.
44. Matsunaga N, Kaku T, Ojida A, et al. C(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17,20)-lyase inhibitors. Bioorg Med Chem. 2004;12:4313-36.
45. Safety and efficacy study of TAK-700 in patients with nonmetastatic castration-resistant prostate cancer and a rising prostate-specific antigen. US National Institutes of Health; [cited 2011 January 2]; Available from: http://www.clinicaltrials.gov/.
46. Study comparing orteronel plus prednisone in patients with metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.
47. Study comparing orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.
48. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437-46.
49. A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer (PREVAIL). US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.
50. Safety and efficacy study of MDV3100 in patients with castration-resistant prostate cancer who have been previously treated with docetaxel-based chemotherapy (AFFIRM). US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.
51. Bradley DA, Hussain M, Dipaola RS, Kantoff P. Bone directed therapies for prostate cancer. J Urol. 2007;178:S42-8.
52. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-76.
53. Nelson J, Bagnato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer. 2003;3:110-6.
54. 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.
55. 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.
56. Banerjee S, Hussain M, Wang Z, et al. In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. Cancer Res. 2007;67:3818-26.
57. 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. [cited 2011 January 29]; Available from: http://www.clinicaltrials.gov/.
58. 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;55:1112-23.
59. Results of zibotentan phase III trial in castration resistant prostate cancer. Astra-Zeneca; [cited 2011 January 29]; Available from: http://www.astrazeneca.com/Media/Press-releases/Article/Results-of-Zibotentan-Phase-III-trial-in-castration-resistant-pr.
60. A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) in non-metastatic hormone resistant prostate cancer (ENTHUSE M0). US National Institutes of Health; [cited 2010 November 29]; Available from: http://www.clinicaltrials.gov/.
61. A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) and docetaxel in metastatic hormone resistant prostate cancer (ENTHUSE M1C). US National Institutes of Health; [cited 2010 November 28]; Available from: http://www.clinicaltrials.gov/.
62. 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.
63. Denosumab (XGEVA). US Food and Drug Administration; [cited 2011 January 29]; Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s007lbl.pdf.
64. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97:798-804.
65. Hwang C, Heath EI. Angiogenesis inhibitors in the treatment of prostate cancer. J Hematol Oncol. 2010;3.
66. Liang WC, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006;281:951-61.
67. 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.
68. Picus J, Halabi S, Kelly WK, et al. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer. 2011;117:526-33.
69. Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:2070-6.
70. Kelly WK, Halabi S, Carducci MA, et al. 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. J Clin Oncol 2010;28:Abstract LBA4511.
71. 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.
72. 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.
73. Bratt O, Haggman M, Ahlgren G, et al. Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. Br J Cancer. 2009;101:1233-40.
74. Pili R. A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naïve patients with metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 2010;28:Abstract 4510.
75. 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.
76. A multicenter, randomized, double blind study comparing the efficacy and safety of aflibercept versus placebo administered every 3 weeks in patients treated with docetaxel/ prednisone for metastatic androgen-independent prostate cancer. US National Institutes of Health; [cited 2010 November 27]; Available from: http://www.clinicaltrials.gov/.
77. Smith DC, Smith MR, Small EJ, et al. Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease. J Clin Oncol. 2011;29:abstract 127.
78. Knudsen BS, Gmyrek GA, Inra J, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60:1113-7.
79. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995;147:386-96.
80. Verras M, Lee J, Xue H, et al. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res. 2007;67:967-75.
81. Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res. 2009;15:5020-5.
82. Shojaei F, Lee JH, Simmons BH, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090-100.
83. Fizazi K. The role of Src in prostate cancer. Ann Oncol. 2007;18:1765-73.
84. 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.
85. Randomized study comparing docetaxel plus dasatinib to docetaxel plus placebo in castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 November 29]; Available from: http://www.clinicaltrials.gov/.
86. Chi KN, Zoubeidi A, Gleave ME. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin for the treatment of cancer. Expert Opin Investig Drugs. 2008;17:1955-62.
87. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:4247-54.
88. A randomized, placebo-controlled, double-blind, phase 3 study evaluating the benefit of adding custirsen to docetaxel retreatment as second-line therapy in men with castrate resistant prostate cancer. US National Institutes of Health; [cited 2010]; Available from: http://www.clinicaltrials.gov/.
89. A randomized phase 3 study comparing standard first-line docetaxel/prednisone to docetaxel/prednisone in combination with custirsen (OGX-011) in men with metastatic castrate resistant prostate cancer. US National Institutes of Health; [cited 2010 November 28]; Available from: http://www.clinicaltrials.gov/.
90. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63:940-5.
91. ClinicalTrials.gov. US National Institutes of Health; [cited 2011 January 30]; Available from: http://www.clinicaltrials.gov/.