Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC. 1. Introduction Prostate cancer is the most common malignancy in males in Western countries, representing the second leading cause of cancer death [1]. Advances in screening and diagnosis have allowed detection of the disease in early stages (approximately 85% of cases diagnosed), stages at which the therapeutic options are curative and include surgery, radiation and, in some cases, active surveillance only [2–4]. However, for late-stage disseminated disease, current therapies are merely palliative. In 1941, a study of Huggins and Hodges showed the close relationship of androgens with prostate tumor growth and androgen-deprivation therapy (castration) became the key treatment for these stages in monotherapy or in combination with other methods [2, 4, 5]. Initial responses to castration therapy are quite favorable, with a significant clinical regression and rapid biochemical responses, as assessed by decline in levels of serum marker, prostate-specific antigen (PSA) in 80–90% of patients with metastatic disease [2, 4, 6]. Despite a good initial response, remissions last on average 2-3 years, with eventual progression occurring despite castration [4, 5, 7]. In these cases prostate cancer will progress to a castration-insensitive phase of disease (Castration-Resistant Prostate Cancer—CRPC) which carries a worse prognosis and translates into a survival time of 16–18 months in average from the beginning of progression [2, 4–6]. Systemic therapies have also been an option in the management to these patients. However, chemotherapy is not well tolerated by all CRPC patients, who were often elderly men with limited bone marrow reserve and concurrent medical conditions [8]. In 2004 the result of two major phase 3 clinical trials established docetaxel as the first-line
References
[1]
N. Howlader, A. M. Noone, M. Krapcho, et al., SEER Cancer Statistics Review, 1975–2008, National Cancer Institute, Bethesda, Md, USA, 2011, based on November 2010 SEER data submission, posted to the SEER web site, http://seer.cancer.gov/csr/1975_2008/.
[2]
R. B. Marques, N. F. Dits, S. Erkens-Schulze, W. M. Weerden, and G. Jenster, “Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models,” PLoS ONE, vol. 5, no. 10, Article ID e13500, 2010.
[3]
G. Attard, D. Sarker, A. Reid, R. Molife, C. Parker, and J. S. De Bono, “Improving the outcome of patients with castration-resistant prostate cancer through rational drug development,” British Journal of Cancer, vol. 95, no. 7, pp. 767–774, 2006.
[4]
W. P. Harris, E. A. Mostaghel, P. S. Nelson, and B. Montgomery, “Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion,” Nature Clinical Practice Urology, vol. 6, no. 2, pp. 76–85, 2009.
[5]
R. M. Attar, C. H. Takimoto, and M. M. Gottardis, “Castration-resistant prostate cancer: locking up the molecular escape routes,” Clinical Cancer Research, vol. 15, no. 10, pp. 3251–3255, 2009.
[6]
S. Sun, C. C. T. Sprenger, R. L. Vessella et al., “Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant,” Journal of Clinical Investigation, vol. 120, no. 8, pp. 2715–2730, 2010.
[7]
P. A. Watson, Y. F. Chen, M. D. Balbas et al., “Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 39, pp. 16759–16765, 2010.
[8]
C. J. Paller and E. S. Antonarakis, “Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer,” Drug Design, Development and Therapy, no. 5, pp. 117–124, 2011.
[9]
J. E. Ang, D. Olmos, and J. S. De Bono, “CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer,” British Journal of Cancer, vol. 100, no. 5, pp. 671–675, 2009.
[10]
S. S. Dutt and A. C. Gao, “Molecular mechanisms of castration-resistant prostate cancer progression,” Future Oncology, vol. 5, no. 9, pp. 1403–1413, 2009.
[11]
E. D. Crawford, M. A. Eisenberger, D. G. McLeod et al., “A controlled trial of leuprolide with and without flutamide in prostatic carcinoma,” New England Journal of Medicine, vol. 321, no. 7, pp. 419–424, 1989.
[12]
M. A. Eisenberger, B. A. Blumenstein, E. D. Crawford et al., “Bilateral orchiectomy with or without flutamide for metastatic prostate cancer,” New England Journal of Medicine, vol. 339, no. 15, pp. 1036–1042, 1998.
[13]
I. F. Tannock, R. De Wit, W. R. Berry et al., “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1502–1512, 2004.
[14]
S. K. Pal, P. Twardowski, and O. Sartor, “Critical appraisal of cabazitaxel in the management of advanced prostate cancer,” Clinical Interventions in Aging, vol. 5, pp. 395–402, 2010.
[15]
P. W. Kantoff, C. S. Higano, N. D. Shore et al., “Sipuleucel-T immunotherapy for castration-resistant prostate cancer,” New England Journal of Medicine, vol. 363, no. 5, pp. 411–422, 2010.
[16]
E. J. Small, S. Halabi, N. A. Dawson et al., “Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583),” Journal of Clinical Oncology, vol. 22, no. 6, pp. 1025–1033, 2004.
[17]
D. R. Berthold, C. N. Sternberg, and I. F. Tannock, “Management of advanced prostate cancer after first-line chemotherapy,” Journal of Clinical Oncology, vol. 23, no. 32, pp. 8247–8252, 2005.
[18]
S. J. Kim and S. I. Kim, “Current treatment strategies for castration-resistant prostate cancer,” Korean Journal of Urology, vol. 52, no. 3, pp. 157–165, 2011.
[19]
H. Suzuki, K. Okihara, H. Miyake et al., “Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade,” Journal of Urology, vol. 180, no. 3, pp. 921–927, 2008.
[20]
W. Kassouf, S. Tanguay, and A. G. Aprikian, “Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails,” Journal of Urology, vol. 169, no. 5, pp. 1742–1744, 2003.
[21]
R. Joyce, M. A. Fenton, P. Rode et al., “High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy,” Journal of Urology, vol. 159, no. 1, pp. 149–153, 1998.
[22]
O. Kucuk, E. Fisher, C. M. Moinpour et al., “Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235),” Urology, vol. 58, no. 1, pp. 53–58, 2001.
[23]
M. Lodde, L. Lacombe, and Y. Fradet, “Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer,” Urology, vol. 76, no. 5, pp. 1189–1193, 2010.
[24]
G. Sonpavde, T. E. Hutson, and W. R. Berry, “Hormone refractory prostate cancer: management and advances,” Cancer Treatment Reviews, vol. 32, no. 2, pp. 90–100, 2006.
[25]
D. C. Smith, B. G. Redman, L. E. Flaherty, L. LI, M. Strawderman, and K. J. Pienta, “A Phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer,” Urology, vol. 52, no. 2, pp. 257–260, 1998.
[26]
J. S. De Bono, C. J. Logothetis, A. Molina et al., “Abiraterone and increased survival in metastatic prostate cancer,” New England Journal of Medicine, vol. 364, no. 21, pp. 1995–2005, 2011.
[27]
G. A. Potter, S. Elaine Barrie, M. Jarman, and M. G. Rowlands, “Novel steroidal inhibitors of human cytochrome P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer,” Journal of Medicinal Chemistry, vol. 38, no. 13, pp. 2463–2471, 1995.
[28]
G. Attard, A. S. Belldegrun, and J. S. De Bono, “Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer,” British Journal of Urology International, vol. 96, no. 9, pp. 1241–1246, 2005.
[29]
S. E. Barrie, B. P. Haynes, G. A. Potter et al., “Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P45017α inhibitors,” Journal of Steroid Biochemistry and Molecular Biology, vol. 60, no. 5-6, pp. 347–351, 1997.
[30]
M. Jarman, S. Elaine Barrie, and J. M. Liera, “The 16,17-double bond is needed for irreversible inhibition of human cytochrome P45017α by abiraterone (17-(3-Pyridyl)androsta-5,16-dien-3β-ol) and related steroidal inhibitors,” Journal of Medicinal Chemistry, vol. 41, no. 27, pp. 5375–5381, 1998.
[31]
P. Vishnu and W. W. Tan, “Update on options for treatment of metastatic castration-resistant prostate cancer,” OncoTargets and Therapy, vol. 3, pp. 39–51, 2010.
[32]
A. O. Sartor, “Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space,” Journal of Hematology and Oncology, vol. 4, article 18, 2011.
[33]
D. Bianchini, A. Zivi, S. Sandhu, and J. S. de Bono, “Horizon scanning for novel therapeutics for the treatment of prostate cancer,” Annals of Oncology, vol. 21, supplement 7, pp. vii43–vii55, 2010.
[34]
H. I. Scher, A. Anand, D. Rathkopf et al., “Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study,” The Lancet, vol. 375, no. 9724, pp. 1437–1446, 2010.
[35]
L. Zarour and J. Alumkal, “Emerging therapies in castrate-resistant prostate cancer,” Current Urology Reports, vol. 11, no. 3, pp. 152–158, 2010.
[36]
F. Saad, D. M. Gleason, R. Murray et al., “A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma,” Journal of the National Cancer Institute, vol. 94, no. 19, pp. 1458–1468, 2002.
[37]
K. P. Weinfurt, K. J. Anstrom, L. D. Castel, K. A. Schulman, and F. Saad, “Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer,” Annals of Oncology, vol. 17, no. 6, pp. 986–989, 2006.
[38]
F. Saad, D. M. Gleason, R. Murray et al., “Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer,” Journal of the National Cancer Institute, vol. 96, no. 11, pp. 879–882, 2004.
[39]
T. H. Diamond, J. Winters, A. Smith et al., “The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study,” Cancer, vol. 92, no. 6, pp. 1444–1450, 2001.
[40]
R. S. Israeli, S. J. Rosenberg, D. R. Saltzstein et al., “The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy,” Clinical Genitourinary Cancer, vol. 5, no. 4, pp. 271–277, 2007.
[41]
M. R. Smith, J. Eastham, D. M. Gleason, D. Shasha, S. Tchekmedyian, and N. Zinner, “Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer,” Journal of Urology, vol. 169, no. 6, pp. 2008–2012, 2003.
[42]
K. Fizazi, M. Carducci, M. Smith et al., “Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study,” The Lancet, vol. 377, no. 9768, pp. 813–822, 2011.
[43]
E. Steenland, J. Leer, H. Van Houwelingen et al., “The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis study,” Radiotherapy and Oncology, vol. 52, no. 2, pp. 101–109, 1999.
[44]
Y. M. Van Der Linden, J. J. Lok, E. Steenland et al., “Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment,” International Journal of Radiation Oncology Biology Physics, vol. 59, no. 2, pp. 528–537, 2004.
[45]
W. F. Harstell, C. B. Scott, D. W. Bruner et al., “Randomized trial of short-versus long-course radiotherapy for palliation of painful bone metastases,” Journal of the National Cancer Institute, vol. 97, no. 11, pp. 798–804, 2005.
[46]
E. Chow, K. Harris, G. Fan, M. Tsao, and W. M. Sze, “Palliative radiotherapy trials for bone metastases: a systematic review,” Journal of Clinical Oncology, vol. 25, no. 11, pp. 1423–1436, 2007.
[47]
O. M. Salazar, T. Sandhu, N. W. Da Motta et al., “Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA),” International Journal of Radiation Oncology Biology Physics, vol. 50, no. 3, pp. 765–775, 2001.
[48]
D. P. Dearnaley, R. J. Bayly, R. P. A'Hern, J. Gadd, M. M. Zivanovic, and V. J. Lewington, “Palliation of bone metastases in prostate cancer. Hemibody irradiation or strontium-89?” Clinical Oncology, vol. 4, no. 2, pp. 101–107, 1992.
[49]
V. J. Lewington, A. J. McEwan, D. M. Ackery et al., “A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone,” European Journal of Cancer, vol. 27, no. 8, pp. 954–958, 1991.
[50]
K. Buchali, H. J. Correns, M. Schuerer, D. Schnorr, H. Lips, and K. Sydow, “Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma,” European Journal of Nuclear Medicine, vol. 14, no. 7-8, pp. 349–351, 1988.
[51]
A. T. Porter, A. J. B. McEwan, J. E. Powe 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,” International Journal of Radiation Oncology Biology Physics, vol. 25, no. 5, pp. 805–813, 1993.
[52]
P. M. Quilty, D. Kirk, J. J. Bolger, et al., “A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer,” Radiotherapy and Oncology, vol. 31, no. 1, pp. 33–40, 1994.
[53]
G. O. N. Oosterhof, J. T. Roberts, T. M. De Reijke et al., “Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group,” European Urology, vol. 44, no. 5, pp. 519–526, 2003.
[54]
A. N. Serafini, S. J. Houston, I. Resche et al., “Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial,” Journal of Clinical Oncology, vol. 16, no. 4, pp. 1574–1581, 1998.
[55]
O. Sartor, R. H. Reid, P. J. Hoskin et al., “Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer,” Urology, vol. 63, no. 5, pp. 940–945, 2004.
[56]
C. Parker, D. Heinrich, J. M. O'Sullivan, et al., “Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer: a phase III randomized trial (ALSYMPCA),” European Journal of Cancer, vol. 47, supplement 2, abstract 1LBA, p. 3, 2011.
[57]
D. P. Petrylak, C. M. Tangen, M. H. A. Hussain et al., “Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1513–1520, 2004.
[58]
M. D. Galsky and N. J. Vogelzang, “Docetaxel-based combination therapy for castration-resistant prostate cancer,” Annals of Oncology, vol. 21, no. 11, pp. 2135–2144, 2010.
[59]
M. D. Galsky, E. J. Small, W. K. Oh 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,” Journal of Clinical Oncology, vol. 23, no. 7, pp. 1439–1446, 2005.
[60]
M. Hussain, C. M. Tangen, P. N. Lara 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,” Journal of Clinical Oncology, vol. 23, no. 34, pp. 8724–8729, 2005.
[61]
J. E. Rosenberg, W. K. Kelly, M. D. Michaelson, et al., “A randomized phase II study of ixabepilone (Ix) or mitoxantrone and prednisone (MP) in patients with taxane (T)-resistant hormone refractory prostate cancer (HRPC),” Journal of Clinical Oncology, vol. 23, no. 16S, abstract #5166, p. 4566, 2005.
[62]
K. N. Chi, E. K. Beardsley, P. M. Venner, et al., “A phase II study of patupilone in patients with metastatic hormone refractory prostate cancer (HRPC) who have progressed after docetaxel,” Journal of Clinical Oncology, vol. 26, no. 15s, Abstract #5166, 2008.
[63]
E. K. Beardsley, F. Saad, and B. Eigl, “A phase II study of patupilone in patients (patients) with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel,” Journal of Clinical Oncology, vol. 27, no. 15s, abstract #5139, 2009.
[64]
J. E. Rosenberg, V. K. Weinberg, W. K. Kelly 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, vol. 110, no. 3, pp. 556–563, 2007.
[65]
J. S. Bono, P. Maroto, E. Calvo, et al., “Phase II study of eribulin mesylate (E7389) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC) stratified by prior taxane therapy,” Annals of Oncology, pp. mdr380v1–mdr380, 2011.
[66]
J. S. De Bono, S. Oudard, M. Ozguroglu et al., “Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial,” The Lancet, vol. 376, no. 9747, pp. 1147–1154, 2010.
[67]
E. J. Small, P. F. Schellhammer, C. S. Higano et al., “Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3089–3094, 2006.
[68]
C. S. Higano, P. F. Schellhammer, E. J. Small 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, vol. 115, no. 16, pp. 3670–3679, 2009.
[69]
E. J. Small, N. Sacks, J. Nemunaitis et al., “Granulocyte macrophage colony-stimulating factor-secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer,” Clinical Cancer Research, vol. 13, no. 13, pp. 3883–3891, 2007.
[70]
M. Hussain, M. R. Smith, C. Sweeney, et al., “Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial,” Journal of Clinical Oncology, vol. 29, supplement, abstract 4516, 2011.
[71]
E. Cha and L. Fong, “Therapeutic vaccines for prostate cancer,” Current Opinion in Molecular Therapeutics, vol. 12, no. 1, pp. 77–85, 2010.
[72]
P. W. Kantoff, T. J. Schuetz, B. A. Blumenstein et al., “Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1099–1105, 2010.
[73]
G. Sonpave, K. M. Slawin, D. M. Spencer, and J. M. Levitt, “Emerging vaccine therapy approaches for prostate cancer,” Reviews in Urology, vol. 12, pp. 25–34, 2010.
[74]
M. A. Carducci and A. Jimeno, “Targeting bone metastasis in prostate cancer with endothelin receptor antagonists,” Clinical Cancer Research, vol. 12, no. 20, pp. 6296s–6300s, 2006.
[75]
M. A. Carducci, F. Saad, P.-A. Abrahamsson et al., “A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer,” Cancer, vol. 110, no. 9, pp. 1959–1966, 2007.
[76]
W. K. Kelly, S. Halabi, M. A. Carducci, et al., “A randomized, double-bind, placebo-controlled phase III trial comparing docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): survival results of CALGB 90401,” Journal of Clinical Oncology, vol. 28, no. 18s, abstract LBA4511, 2010.
[77]
NCT01057810 Randomized, Double-Blind, Phase 3 Trial to Compare the Efficacy of Ipilumumab vs Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Na？ve Castration Resistant Prostate Cancer.
[78]
G. Sonpavde, P. O. Periman, D. Bernold et al., “Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy,” Annals of Oncology, vol. 21, no. 2, pp. 319–324, 2010.
[79]
M. A. Carducci, R. J. Padley, J. Breul 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,” Journal of Clinical Oncology, vol. 21, no. 4, pp. 679–689, 2003.
[80]
Phase III Study of Docetaxel and Atrasentan Versus Docetaxel and Placebo for Patients With Advanced Hormone Refractory Prostate Cancer National Institutes of Health. Clinical Trials 2011, http://clinicaltrials.gov/.
[81]
N. D. James, A. Caty, H. Payne et al., “Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial,” British Journal of Urology International, vol. 106, no. 7, pp. 966–973, 2010.
[82]
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Non-metastatic Hormone Resistant Prostate Cancer (ENTHUSE M0) NCT00626548.
[83]
A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer (ENTHUSE M1C) NCT00617669.
[84]
W. L. Dahut, J. L. Gulley, P. M. Arlen et al., “Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer,” Journal of Clinical Oncology, vol. 22, no. 13, pp. 2532–2539, 2004.
[85]
G. Di Lorenzo, W. D. Figg, S. D. Fossa et al., “Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study,” European Urology, vol. 54, no. 5, pp. 1089–1096, 2008.
[86]
J. Picus, S. Halabi, W. K. Kelly et al., “A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer,” Cancer, vol. 117, no. 3, pp. 526–533, 2011.
[87]
Y. M. Ning, J. L. Gulley, P. M. Arlen et al., “Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer,” Journal of Clinical Oncology, vol. 28, no. 12, pp. 2070–2076, 2010.
[88]
National Institutes of Health Clinical Trials database, http://clinicaltrials.gov/.
[89]
E. J. Small, N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison, “A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer,” Clinical Cancer Research, vol. 13, no. 6, pp. 1810–1815, 2007.
[90]
L. Fong, S. S. Kwek, S. O'Brien et al., “Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF,” Cancer Research, vol. 69, no. 2, pp. 609–615, 2009.
[91]
NCT00861614 A Randomized, Double-Blind, Phase 3 Trial Comparing Ipilumumab vs. Placebo Following Radiotherapy in Subjects With Castration Resistant Prostate Cancer That Have Received Prior Treatment With Docetaxel.
[92]
W. L. Dahut, C. Scripture, E. Posadas et al., “A phase II clinical trial of sorafenib in androgen-independent prostate cancer,” Clinical Cancer Research, vol. 14, no. 1, pp. 209–214, 2008.
[93]
J. B. Aragon-Ching, L. Jain, J. L. Gulley et al., “Final analysis of a phase II trial using sorafenib for metastaticcastration-resistant prostate cancer,” British Journal of Urology International, vol. 103, no. 12, pp. 1636–1640, 2009.
[94]
S. Steinbild, K. Mross, A. Frost et al., “A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV,” British Journal of Cancer, vol. 97, no. 11, pp. 1480–1485, 2007.
[95]
K. N. Chi, S. L. Ellard, S. J. Hotte et al., “A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer,” Annals of Oncology, vol. 19, no. 4, pp. 746–751, 2008.
[96]
A. J. Zurita, G. Liu, T. Hutson, et al., “Sunitinib in combination with docetaxel and prdnisone in patients (pts) with metastatic hormone-refrectory prostate cancer (mHRPC),” Journal of Clinical Oncology, vol. 27, no. 15s, abstract 5166, 2009.
[97]
T. A. Yap, D. Olmos, A. T. Brunetto et al., “Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies,” Journal of Clinical Oncology, vol. 29, no. 10, pp. 1271–1279, 2011.
