Trending Topic

Breast Cancer
29 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Endocrine therapy (ET) has changed the natural history of hormone receptor-positive (HR+) breast cancer (BC) and is the cornerstone of the treatment of HR+ BC. There are several ETs approved for the treatment of BC, including selective oestrogen receptor modulators (SERMs; tamoxifen), aromatase inhibitors (AIs; anastrazole, letrozole and exemestane) and selective oestrogen receptor degraders (SERDs; fulvestrant […]

Castration-resistant Prostate Cancer – Chemotherapies and Molecular Targets

Amit Bahl
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Aug 14th 2013 European Oncology & Haematology, 2013;9(1):27–33 DOI: https://doi.org/10.17925/EOH.2013.09.1.27
Select a Section…
1

Abstract

Overview

Castration-resistant prostate cancer has a poor prognosis: current chemotherapeutic approaches ultimately result in resistance and are associated with survival rates of less than 2 years. However, the last decade has seen an expansion in the number of therapeutic options for CRPC and the regulatory approval of several agents, including the chemotherapy drug cabazitaxel and the targeted agents abiraterone acetate, enzalatumide and denosumab. Novel targeted agents inhibit androgen receptor-mediated signalling, and non-hormonal targets, including apoptosis, signal transduction pathway inhibitors, angiogenesis and bone and immune microenvironments. Clinical trials of these agents, however, have demonstrated varied efficacy. Among the drugs in clinical development, custirsen, cabozantinib and dasatinib are among the most promising. There is a requirement for studies directly comparing agents, and for improved patient selection to identify patients benefitting from a particular therapy.
Acknowledgements: Technical editorial assistance was provided by Katrina Mountfort from Touch Medical Media.

Keywords

Castration-resistant prostate cancer, chemotherapy, clusterin, custirsen, targeted therapy

2

Article

Prostate cancer is the most common noncutaneous malignancy. It is the sixth leading cause of cancer-related death in men worldwide,1 and the second most common cause of cancer death in US men.2 In 2012, it was estimated that 241,740 cases would be diagnosed and 28,170 would die of the disease.3 Prostate cancer responds to androgen-deprivation therapy (ADT). However, most cases become refractory after 1 to 3 years and resume growth despite hormone therapy, leading to the state of castration-resistant prostate cancer (CRPC), for which the prognosis is poor.4 Many patients enter the disease at an early stage when the only sign of resistance to ADT is a progressive elevation of prostate-specific antigen (PSA). Progression to CRPC occurs via reactivation of androgen receptor (AR) activity,5 alternative mitogenic growth factor pathways,6 stress-induced survival genes7 and cytoprotective chaperone networks.8 Following CRPC development, the patient population is likely to continue progression to metastatic disease (mCRCP).

During the past decade, a number of new approaches have been developed for the treatment of CRPC, including hormonal agents, cytotoxic chemotherapeutic drugs, targeted therapeutics and immunotherapy. These developments have led to the regulatory approval of five new therapeutic agents: sipuleucel-T, denosumab, abiraterone acetate, cabazitaxel and enzalatumide (see Table 1). This article will review recent advances in chemotherapy and discuss the potential molecular targets for new therapeutic approaches.

Chemotherapy
Historically, prostate cancer was considered refractory to cytotoxic chemotherapy,9 and chemotherapy options for the treatment of CRPC were limited. Until 2004, only mitoxantrone was approved, providing palliation but no survival benefit. In 2004, docetaxel received approval from the US Food and Drug Administration (FDA) after clinical studies showed that prednisone and docetaxel showed an overall survival (OS) benefit compared with mitoxantrone plus prednisone, as well as a significant improvement of quality of life and pain reduction.10,11

Docetaxel and prednisone in combination are currently considered the standard of care for men with CRPC with detectable metastatic disease.12 However, survival rates remain low: less than 2 years13,14 and less than a year in metastatic cases.15 Moreover, a significant proportion of men with CRPC do not respond to docetaxel-based therapy, and all patients will ultimately develop resistance.16 Mitoxantrone has been the standard treatment following docetaxel failure.17 New chemotherapeutic agents have recently been evaluated for CRPC. Cabazitaxel was approved by the FDA in 2010 for second-line use in CRPC following docetaxel-based treatment. The approval was based on results of the phase III TROPIC trial in which it improved OS in patients whose disease had progressed during or after docetaxel-based therapy.18

Other new chemotherapeutic agents include a novel class of tubulepolymerising agents – epothilones. One agent in this class, ixabepilone, has demonstrated activity in phase II trials in patients with chemotherapynaïve metastatic CRPC19 and as second-line chemotherapy.20 Satraplatin, an oral platinum analogue, was not approved by the FDA as a result of significant toxicities.21

The role of chemotherapy in CRPC has evolved over the last decade. However, to date, docetaxel remains the only first-line chemotherapy option that improves survival, and treatment with docetaxel inevitably results in resistance. Targeting the processes responsible for resistance presents an alternative therapeutic strategy for CPRC.

Potential Molecular Targets for New Therapeutic Approaches to Castration-resistant Prostate Cancer
The advent of molecular-based therapy has resulted in a large number of new therapeutic approaches to CRPC. Potential molecular targets include hormonal and non-hormonal intracellular pathways, such as the apoptotic pathway, signal transduction pathways, angiogenesis, and other oncogenic survival pathways (see Figure 1).

Androgen Receptor Pathway
There is evidence to suggest that although ADT removes the gonadal testosterone in CRPC, androgens originating from other sources, including the adrenal gland and the tumour itself, may continue to act as a ligand and result in AR signalling.22,23 Therefore the AR pathway represents a therapeutic target for CRPC. Established antiandrogen therapy includes AR antagonists, such as bicalutamide and flutamide, and antiandrogenic drugs, such as ketoconolazone, but these result in increased levels of AR, which confer resistance.24 This has led to the development of new antiandrogens. In addition to AR, novel therapies have targeted cytochrome P450 c17 (CYP17) an enzyme involved in androgen synthesis.25 Conversion of testosterone to the more potent dihydrotestosterone (DHT) by 5-α-reductase in tumour tissue also results in continued AR activation, and provides another therapeutic target.26

Apoptosis
Non-hormonal strategies for the treatment of CRPC include inducing stress responses that target apoptosis. Antiapoptotic stress-induced factors include heat shock proteins and chaperone proteins. Elevated levels of the stress-activated cytoprotective chaperone protein clusterin (CLU) have been observed in several cancers, including prostate cancer.27,28 CLU is upregulated in response to many anticancer therapies and confers broad-spectrum resistance by inhibiting protein aggregation and proteotoxic stress, cytochrome C release and activation of apoptotic proteins.29 Expression of CLU in prostate tumours increases after treatment with ADT30 or chemotherapy.7

Survivin antagonists also act through the apoptotic pathway. Survivin inhibits apoptosis, enhances cell proliferation and promotes tumour angiogenesis in a number of tumour types including prostate cancer.31 It is upregulated in malignant tissue and its suppression leads to tumour growth, making it a potentially important therapeutic target.

Insulin-like growth factor receptor-1 (IGF-1R) also has antiapoptotic activity; its other mechanisms of action involve mitogenesis and cellular transformation. Several studies have suggested that it may be important in prostate carcinogenesis and is often overexpressed in prostate tumours.32,33

Signal Transduction Pathway Inhibitors
Upregulation of the phosphatidylinositol 3-kinase (PI3K/AKT) pathway is important in the pathogenesis in prostate carcinogenesis.34 A critical component of this oncogenic survival pathway is activation of the mammalian target of rapamycin (mTOR ) pathway, providing a rationale for the use of mTOR inhibitors in CRPC. P13K activation is regulated by phosphatase and tensin homologue (PTEN). Recent findings suggest that the PTEN tumour suppressor gene may be a useful predictive biomarker in this setting.35

Angiogenesis
Angiogenesis is thought to have an important role in the progression of prostate cancer and provides several potential therapeutic targets in CRPC. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a major role in promoting angiogenesis and tumour progression in a number of tumour types. Plasma VEGF levels are significantly elevated in patients with CRPC compared with patients with localised disease.36 Hepatocyte growth factor also promotes angiogenesis. Overexpression of hepatocyte growth factor and its receptor protein, c-MET, has been observed in prostate cancer,37 and androgen suppression has been shown to increase MET expression.38

The Bone Microenvironment
The bone is an important target in advanced CRPC since most patients will develop bone metastases during the course of their disease, and most disease-related symptoms are directly related to bone metastases The nuclear factor κB ligand (RANKL) is involved in the regulation of bone metabolism and is overexpressed in osteoblasts.39Targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.

Src kinase signalling is another potential molecular target in CRPC. Src kinases are non-receptor tyrosine kinases that affect several molecular pathways involved in neuropeptide-induced prostate cancer growth and migration, including angiogenesis, survival and transition to CRPC.40 Overexpression of Src and Src kinases has been observed during prostate tumour growth and metastasis, and high Src kinase activity has been associated with shorter OS.41 Src signalling is also involved in the development of bone metastasis, as it regulates different osteoclast functions including bone resorption.42

Endothelin-1 (ET-1), part of the endothelin family of peptides, promotes prostate cancer progression by a number of mechanisms, including angiogenesis, and may predict OS in CRPC.43 It also has an important role in the pathogenesis of bone metastases: ET-1 produced by metastatic cancer cells stimulates the endothelin-A receptor in osteoblastic cells.44

Immune Targets
The field of cancer immunotherapy is rapidly evolving. One promising approach involves augmentation of cell-mediated immunity by interrupting T-cell pathways responsible for immune down-regulation or tolerance. This has provided a number of potential therapeutic targets, including the signalling molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4).45

Epigenetic Regulation of Androgen Receptor Gene Expression
Epigenetic regulation of AR gene expression may also present novel molecular targets in CRCP therapy. Regulation mechanisms include DNA methylation and histone deacetylation.46

Targeted Agents Recently Approved or in Clinical Development
Numerous targeted agents are currently in clinical development; published studies of phase II and III clinical trials are summarised in Table 2. Clinical endpoints include progression-free survival (PFS), OS and levels of PSA, an indicator of disease progression.47 Recently developed antiandrogen therapies target androgen production from both endocrine and autocrine sources. Abiraterone acetate is a selective, irreversible inhibitor of CYP17 and has been approved by the FDA for first- and second-line therapy in the treatment of CRPC following the results of two phase III clinical trials.48,49 Other CYP17 inhibitors in clinical development include TA K-700 (orteronel).50

Enzalutamide (MDV3100), an AR antagonist, significantly improved OS in men with CRPC following docetaxel treatment in a recent phase III clinical trial and received FDA approval in 2012 for the treatment of patients with mCRPC who have previously received docetaxel.51 Dutasteride, a 5α-reductase inhibitor that is used in benign prostatic hypertrophy, has shown only modest efficacy in phase II trials.52,53

Among the numerous targeted therapies in clinical development for CRPC, custirsen is one of the most promising. Custirsen is an intravenously administered antisense oligonucleotide that has demonstrated high affinity for CLU messenger RNA (mRNA) and decreases CLU expression.54,55 In preclinical studies, treatment with custirsen enhanced the effects of cytotoxic drugs, including docetaxel and mitoxantrone.55,56 In a phase II clinical trial, treatment with custirsen plus docetaxel and prednisolone was well-tolerated and associated with a significant improvement in OS.57 In another phase II clinical trial, combined therapy of custirsen plus either docetaxel retreatment (DPC) or mitoxantrone (MPC) was evaluated in patients with progressive mCRPC following first-line docetaxel therapy.58 The results showed improved OS and time to pain progression in the DPC arm compared with the MPC arm. Ongoing phase III trials, one with a primary endpoint of survival and one with an endpoint of pain palliation, are evaluating the addition of custirsen to second-line cabazitaxel/prednisone treatment (AFFINITY trial)59 and to docetaxel/ prednisone in the first-line setting (SYNERGY trial).60

In addition to custirsen, other agents that target the apoptotic pathway are currently being developed. These include two survivin antagonists: LY -218130, an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumour tissue,61 and YM-155, a small molecule surviving inhibitor. YM-155 has shown modest clinical efficacy in a phase II trial62 and is being investigated in combination with docetaxel. Three human monoclonal antibodies that specifically target IGF-1R are also in clinical development. Cixutumumab63 and figitumumab64 have shown clinical efficacy in phase II trials. Ganitumab (AMG-479) is in the early stages of development.65

The importance of the PI3K/AKT pathway has led to investigation of the use of mTOR inhibitors in CRPC. However, a recent phase II study failed to show significant clinical benefit for the combination of everolimus and bicalutamide in men with CRPC.66 A more recent phase II study has suggested that the PTEN tumour suppressor gene may be a predictive biomarker for response.35 Temsirolimus is also being evaluated, and appears to demonstrate activity in chemotherapy-naïve patients with CRPC.67 A novel mTOR inhibitor, ridaforlolimus,68 and an oral pan-PI3K inhibitor, BKM-120, are also in clinical development.34

Despite a strong rationale for the use of anti-angiogenic strategies in CRCP, a phase III clinical study failed to show a survival advantage for the VEGF inhibitor bevacizumab in combination with docetaxel compared with docetaxel alone.69 However, the combination of bevacizumab and satraplatin showed efficacy in a phase II trial of mCRPC patients.70 Tyrosine kinase inhibitors have also failed to show significant clinical benefit to date. A phase III trial of sunitinib was terminated early when interim analysis revealed no significant improvement in OS.71 In a recent Pphase II trial, a combined treatment regimen involving sunitinib and docetaxel showed more promising clinical activity.72 Sorefanib showed limited clinical activity as monotherapy in a phase II trial,73 although a more recent phase II trial of sorefanib in combination with bicalutamide showed encouraging results.74

Cabozantinib, a tyrosine kinase inhibitor with activity against MET and VEGFR 2, has demonstrated efficacy in CRPC in a recent phase II trial.75 Another angiogenesis-inhibiting agent, tasquinimod, has slowed progression and improved PFS in a phase II study of CRPC,76 though its exact mechanism of action is not clear. Two phase III trials of cabozantinib, COMET-1 and COMET-2, are underway.77,78

Denosumab, a fully human anti-RANKL monoclonal antibody, was approved by the FDA in 2010 for the prevention of skeletal-related events (SREs) in patients with bone metastases from CRPC. In a recent phase III trial, despite showing no improvement in OS, it significantly delayed time to first bone metastasis.79 However, the FDA rejected an application for approval for the use of denosumab in this indication; the effect on bone metastasis-free survival was considered of insufficient magnitude to outweigh the risks of the treatment, which include osteonecrosis of the jaw.80 In another phase III trial, denosumab demonstrated superiority over zoledronic acid for the prevention of SREs.81

Several Src kinases are in clinical development. Dasatinib in combination with docetaxel has shown efficacy in a phase I/II clinical trial,82 and is currently being investigated in a phase III trial. Saracatinib showed limited clinical efficacy in a phase II trial.83

Atrasentan, an inhibitor of the endothelin-A receptor, showed promise in phase II trials, but failed to show significant clinical benefit in patients with CRPC in a phase III trial.84 The phase III SWOG 0421 trial of atrasentan plus docetaxel as first-line therapy was terminated early due to failure to meet primary endpoints.85 Another endothelin-A receptor antagonist, zibotentan, is no longer under investigation as a potential treatment for CRPC following two recent phase III trials in which it failed to demonstrate efficacy.81,86 Immune checkpoint inhibitors, such as ipilimumab, have shown significant efficacy in melanoma. As a result, a number of ongoing clinical trials are investigating the role of ipilimumab in CRCP, either alone or in combination with immunomodulating agents, such as radiation and chemotherapy, and in combination with cancer vaccines.87 In a phase I/II trial, ipilimumab in combination with radiotherapy showed clinical efficacy with manageable adverse events.88 Among the epigenetic therapeutic approaches to CRPC, histone deacetylase inhibitors have been the most widely studied. In a phase II trial, vorinostat was associated with significant toxicities.89 Panobinostat in combination with docetaxel has recently completed phase I testing and a phase II trial is ongoing.90 Azacitidine is an inhibitor of DNA methylation and has shown encouraging results in a phase II trial of chemotherapy-naïve CRPC patients.91

Summary and Concluding Remarks
The field of CRPC therapy is rapidly evolving as a result of the large number of therapies in clinical development. However, clinical trials have demonstrated varied efficacy, with several phase III trials being terminated early for futility, most likely owing to the biological heterogeneity of CRPC. Among the new agents for which phase III trial data are available, the chemotherapeutic agent cabazitaxel and the targeted therapies abiraterone acetate and enzalatumide have shown improvements in OS. Denosumab has delayed the time to bone metastasis. Of the agents being investigated in Phase III trials, custirsen, cabozantinib and dasatinib appear to be the most promising.

The growing number of approved and experimental therapies in CRCP raises many questions. It is difficult to compare clinical trial data for these therapies because of differences in study designs such as heterogeneous patient populations and control arms. There is a lack of studies directly comparing therapies in order to better evaluate their clinical efficacy. The failure of several clinical trials of targeted therapies for CRCP highlights the need for improved design of clinical trials in order to identify agents that have limited efficacy, while enabling more promising therapies to progress more quickly to the approval process. The mixed clinical trial data also illustrates the fact that CRPC is a heterogeneous condition, and patient subgroups may exist that are characterised by varying degrees of involvement of different signalling pathways. There is a need for improved patient selection based on clinical or molecular characteristics, to identify those most likely to benefit from a particular therapy.

The development of molecular targeted therapy calls into the question the future of traditional chemotherapeutic strategies. However, the need for cytotoxic approaches is likely to remain; their optimum utility will be best achieved in combination with targeted therapies. Considerable research is required to determine to optimum sequencing and combinations of these drugs to overcome resistance to monotherapies.

The advent of targeted therapies has brought new treatment paradigm of CRPC. In the future, identification of different molecular subtypes of CRPC, as well as predictive biomarkers of therapeutic response, will allow clinicians to optimise therapy of CRPC through individualised approaches.

2

References

  1. Baade PD, Youlden DR, Krnjacki LJ, International epidemiology of prostate cancer: geographical distribution and secular trends, Mol Nutr Food Res, 2009;53:171–84.
  2. Jemal A, Siegel R, Xu J, et al., Cancer statistics, 2010, CA Cancer J Clin, 2010;60:277–300.
  3. Siegel R, Naishadham D, Jemal A, Cancer statistics, 2012, CA Cancer J Clin, 2012;62:10–29.
  4. Kirby M, Hirst C, Crawford ED, Characterising the castrationresistant prostate cancer population: a systematic review, Int J Clin Pract, 2011;65:1180–92.
  5. Knudsen KE, Scher HI, Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer, Clin Cancer Res, 2009;15:4792–8.
  6. C ulig Z, Androgen receptor cross-talk with cell signalling pathways, Growth Factors, 2004;22:179–84.
  7. M iyake H, Nelson C, Rennie PS, et al., Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models, Cancer Res, 2000;60:2547–54.
  8. R occhi P, So A, Kojima S, et al., Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer, Cancer Res, 2004;64:6595–602.
  9. Y agoda A, Petrylak D, Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer, Cancer, 1993;71:1098–109.
  10. T annock 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.
  11. P etrylak 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.
  12. Saad F, Hotte SJ, Guidelines for the management of castrateresistant prostate cancer, Can Urol Assoc J, 2010;4:380–84.
  13. O h WK, Manola J, Babcic V, et al., Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes, Urology, 2006;67:1235–40.
  14. M ichels J, Montemurro T, Murray N, et al., First- and secondline chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter?, Cancer, 2006;106:1041–6.
  15. Berthold DR, Pond GR, de Wit R, et al., Survival and PSA response of patients in the TA X 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa, Ann Oncol, 2008;19:1749–53.
  16. Hwang C, Overcoming docetaxel resistance in prostate cancer: a perspective review, Ther Adv Med Oncol, 2012;4:329–40.
  17. A ragon-Ching JB, Dahut WL, Chemotherapy in Androgen- Independent Prostate Cancer (AIPC): What’s next after taxane progression?, Cancer Ther, 2007;5A:151–60.
  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. 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.
  20. R osenberg 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.
  21. L atif T, Wood L, Connell C, et al., Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC), Invest New Drugs, 2005;23:79–84.
  22. A ttar RM, Takimoto CH, Gottardis MM, Castration-resistant prostate cancer: locking up the molecular escape routes, Clin Cancer Res, 2009;15:3251–5.
  23. . C hen Y, Sawyers CL, Scher HI, Targeting the androgen receptor pathway in prostate cancer, Curr Opin Pharmacol, 2008;8:440–48.
  24. C hen CD, Welsbie DS, Tran C, et al., Molecular determinants of resistance to antiandrogen therapy, Nat Med, 2004;10:33–9.
  25. A ggarwal R, Ryan CJ, Castration-resistant prostate cancer: targeted therapies and individualized treatment, Oncologist, 2011;16:264–75.
  26. C hang KH, Li R, Papari-Zareei M, et al., Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer, Proc Natl Acad Sci U S A, 2011;108:13728–33.
  27. Zellweger T, Kiyama S, Chi K, et al., Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumour model, BJU Int, 2003;92:463–9.
  28. M iyake H, Hara I, Kamidono S, et al., Resistance to cytotoxic chemotherapy-induced apoptosis in human prostate cancer cells is associated with intracellular clusterin expression, Oncol Rep, 2003;10:469–73.
  29. Zoubeidi A, Chi K, Gleave M, Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer, Clin Cancer Res, 2010;16:1088–93.
    30. July LV, Akbari M, Zellweger T, et al., Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy, Prostate, 2002;50:179–88.

  30. R yan BM, O’Donovan N, Duffy MJ, Survivin: a new target for anti-cancer therapy, Cancer Treat Rev, 2009;35:553–62.
  31. Krueckl SL, Sikes RA, Edlund NM, et al., Increased insulinlike growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model, Cancer Res, 2004;64:8620–9.
  32. C han JM, Stampfer MJ, Ma J, et al., Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advancedstage prostate cancer, J Natl Cancer Inst, 2002;94:1099–106.
  33. Sarker D, Reid AH, Yap TA , et al., Targeting the PI3K/AKT pathway for the treatment of prostate cancer, Clin Cancer Res, 2009;15:4799–805.
  34. T empleton AJ, Dutoit V, Cathomas R, et al., Phase 2 Trial of Single-agent Everolimus in Chemotherapy-naive Patients with Castration-resistant Prostate Cancer (SAKK 08/08), Eur Urol, 2013;64(1):150–58.
  35. G eorge 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.
  36. C hristensen JG, Burrows J, Salgia R, c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention, Cancer Lett, 2005;225:1–26.
  37. 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.
  38. Fizazi K, Yang J, Peleg S, et al., Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts, Clin Cancer Res, 2003;9:2587–97.
  39. Wheeler DL, Iida M, Dunn EF, The role of Src in solid tumors, Oncologist, 2009;14:667–78.
  40. Fizazi K, The role of Src in prostate cancer, Ann Oncol, 2007;18:1765–73.
  41. M iyazaki T, Sanjay A, Neff L, et al., Src kinase activity is essential for osteoclast function, J Biol Chem, 2004;279:17660–66.
  42. Strijbos MH, Gratama JW, Schmitz PI, et al., Circulating endothelial cells, circulating tumour cells, tissue factor, endothelin-1 and overall survival in prostate cancer patients treated with docetaxel, Eur J Cancer, 2010;46:2027–35.
  43. Y in 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.
  44. O ’Day SJ, Hamid O, Urba WJ, Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies, Cancer, 2007;110:2614–27.
  45. N akayama T, Watanabe M, Suzuki H, et al., Epigenetic regulation of androgen receptor gene expression in human prostate cancers, Lab Invest, 2000;80:1789–96.
  46. Hussain M, Goldman B, Tangen C, et al., Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916, J Clin Oncol, 2009;27:2450–56.
  47. R yan CJ, Smith MR, de Bono JS, et al., Abiraterone in metastatic prostate cancer without previous chemotherapy, N Engl J Med, 2013;368:138–48.
  48. Fizazi K, Scher HI, Molina A, et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study, Lancet Oncol, 2012;13:983–92.
  49. Dreicer R, Agus, DB, MacVicar, GR, et al. , Safety, pharmacokinetics, and efficacy of TA K-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study [abstract 3084] J Clin Oncol, 2010;28:(15 Suppl.):254s.
  50. Scher HI, Fizazi K, Saad F, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, N Engl J Med, 2012;367:1187–97.
  51. Shah SK, Trump DL, Sartor O, et al., Phase II study of Dutasteride for recurrent prostate cancer during androgen deprivation therapy, J Urol, 2009;181:621–6.
  52. T aplin 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.
  53. G leave ME, Monia BP, Antisense therapy for cancer, Nat Rev Cancer, 2005;5:468–79.
  54. Sowery RD, Hadaschik BA, So AI, et al., Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy, BJU Int, 2008;102:389–97.
  55. M iyake H, Hara I, Kamidono S, et al., Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model, Clin Cancer Res, 2001;7:4245–52.
  56. C hi 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.
  57. Saad F, Hotte S, North S, et al., Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c, Clin Cancer Res, 2011;17:5765–73.
  58. C omparison of Docetaxel/Prednisone to Docetaxel/ Prednisone in Combination With OGX-011 in Men With Prostate Cancer (SYNERGY), 2013. Available at: https:// clinicaltrials.gov/show/NCT01188187 (accessed ).
  59. C omparison of Cabazitaxel/Prednisone Alone or in Combination With Custirsen for 2nd Line Chemotherapy in Prostate Cancer (AFFINITY), 2013. Available at: https:// clinicaltrials.gov/show/NCT01578655 (accessed ).
  60. T anioka M, Nokihara H, Yamamoto N, et al., Phase I study of LY 2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors, Cancer Chemother Pharmacol, 2011;68:505–11.
  61. T olcher AW, Quinn DI, Ferrari A, et al., A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer, Ann Oncol, 2012;23:968–73.
  62. Higano C, Alumkal J, Ryan CJ, et al, A phase II study evaluating the efficacy and safety of single-agent IMC-A12, a monoclonal antibody against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastastic, asymptomatic castration-resistant prostate cancer, J Clin Oncol, 2009;27(Suppl.):abstract 5142.
  63. C hi KN, Gleave ME, Fazli L, et al., A phase II pharmacodynamic study of preoperative figitumumab in patients with localized prostate cancer, Clin Cancer Res, 2012;18:3407–13.
  64. Fahrenholtz CD, Beltran PJ, Burnstein KL, Targeting IGF-IR with Ganitumab Inhibits Tumorigenesis and Increases Durability of Response to Androgen-Deprivation Therapy in VCaP Prostate Cancer Xenografts, Mol Cancer Ther, 2013;12(4): 394–404.
  65. N akabayashi M, Werner L, Courtney KD, et al., Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer, BJU Int, 2012;110:1729–35.
  66. N abhan C, A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naïve castration-resistant prostate cancer (CRPC): First report of suggested activity, presented at the ASCO 2012 Genitourinary Cancers Symposium, 2–4 February 2012, San Francisco, CA, Abstract 165.
  67. A mato RJ, Wilding G, Bubley G, et al., Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-treated, castration-resistant prostate cancer, Clin Genitourin Cancer, 2012;10:232–8.
  68. Kelly W, Halabi, S, Carducci, MA, et al. , A randomized, doubleblind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer: survival results of CALGB 90401, J Clin Oncol, 2010;28 (Suppl):Abstract LBA4511.
  69. Vaishampayan UN, Fontana J, Heilbrun LK, et al., Phase II trial of bevacizumab and satraplatin in docetaxel-pretreated metastatic castrate-resistant prostate cancer, Urol Oncol, 2013; [Epub ahead of print].
  70. P fizer, Pfizer discontinues phase 3 trial of sutent, in combination with prednisolone, for advanced castrationresistant prostate cancer. Available at: https://oncology. healthace.com/092710/Oncology_Report_092710_S5.pdf; (accessed 22 July 2013).
  71. Zurita AJ, George DJ, Shore ND, et al., Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial, Ann Oncol, 2012;23:688–94.
  72. A ragon-Ching JB, Jain L, Gulley JL, et al., Final analysis of a phase II trial using sorafenib for metastatic castrationresistant prostate cancer, BJU Int, 2009;103:1636–40.
  73. Beardsley EK, Hotte SJ, North S, et al., A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer, Invest New Drugs, 2012;30:1652–9.
  74. Smith DC, Smith MR, Sweeney C, et al., Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial, J Clin Oncol, 2013;31:412–19.
  75. P ili R, Haggman M, Stadler WM, et al., Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer, J Clin Oncol, 2011;29:4022–8.
  76. https://clinicaltrials.gov/ct2/show/NCT01522443, Study of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2), .
  77. Study of Cabozantinib (XL184) Versus Prednisone in Men With Metastatic Castration-resistant Prostate Cancer Previously Treated With Docetaxel and Abiraterone or MDV3100 (COMET-1). Available at: https://clinicaltrials.gov/ct2/show/ NCT01605227 (accessed ).
  78. Smith MR, Saad F, Coleman R, et al., Denosumab and bonemetastasis- free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial, Lancet, 2012;379:39–46.
  79. A mgen, Amgen Receives Complete Response Letter From FDA for XGEVA® sBLA for Prevention of Bone Metastases. Avaialbe at: https://www.amgen.com/media/media_pr_detail. jsp?releaseID=1688335, 2012 (accessed 22 July 2013).
  80. . Fizazi KS, Higano CS, Nelson JB, et al., Phase III, Randomized, Placebo-Controlled Study of Docetaxel in Combination With Zibotentan in Patients With Metastatic Castration-Resistant Prostate Cancer, J Clin Oncol, 2013;31(14):1740–47.
  81. A raujo JC, Mathew P, Armstrong AJ, et al., Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1–2 study, Cancer, 2012;118:63–71.
  82. L ara PN Jr, Longmate J, Evans CP, et al., A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study, Anticancer Drugs, 2009;20:179–84.
  83. C arducci 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.
  84. SWOG, S0421 closes early; interim analysis finds no benefit in adding atrasentan to prostate chemotherapy. Available at: https://swog.org/visitors/newsletters/2011/04/index. asp?a=s0421, 2011 (accessed
  85. M iller K, Moul JW, Gleave M, et al., Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castrationresistant prostate cancer, Prostate Cancer Prostatic Dis, 2013;16(2):187–92.
  86. Singh N, Madan RA, Gulley JL, Ipilimumab in prostate cancer, Expert Opin Biol Ther, 2013;13:303–13.
  87. Slovin SF, Higano CS, Hamid O, et al., Ipilimumab alone or in combination with radiotherapy in metastatic castrationresistant prostate cancer: results from an open-label, multicenter phase I/II study, Ann Oncol, 2013;24(7):1813–21.
  88. Bradley D, Rathkopf D, Dunn R, et al., Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium, Cancer, 2009;115:5541–9.
  89. R athkopf D, Wong BY, Ross RW, et al., A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer, Cancer Chemother Pharmacol, 2010;66:181–9.
  90. Sonpavde G, Aparicio AM, Zhan F, et al., Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaive castration-resistant prostate cancer, Urol Oncol, 2011;29:682–9.
  91. Fizazi K, Carducci M, Smith M, et al., Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, doubleblind study, Lancet, 2011;377:813–22.
  92. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, N Engl J Med, 2010;363:411–22.
  93. Small EJ, Schellhammer PF, Higano CS, et al., Placebocontrolled 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.
  94. Scher H, Fizazi, K, Saad F et al, Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study, J Clin Oncol, 2012;30:suppl 5; abstr LBA1.
  95. Dahut WL, Madan RA, Karakunnel JJ, et al., Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer, BJU Int, 2013;111(8):1269–80.
3

Article Information

Disclosure

Amit Bahl is on the advisory boards and honorarium of Sanofi, Astellas, Takeda, Janssen, Amgen, Pfizer and Roche.

Correspondence

Amit Bahl, Consultant Oncologist and Clinical Director, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Horfield Rd, Bristol, Avon BS2 8ED UK. E: Amit.Bahl@UHBristol.nhs.uk

Support

The publication of this article was supported by TEVA. The views and opinions expressed are those of the authors and not necessarily those of TEVA.

Received

2013-04-18T00:00:00

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF

This Functionality is for
Members Only

Explore the latest in medical education and stay current in your field. Create a free account to track your learning.

Close Popup