NIH Public Access
`Author Manuscript
`Cancer Lett. Author manuscript; available in PMC 2014 May 21.
`Published in final edited form as:
`Cancer Lett. 2010 May 1; 291(1): 1–13. doi:10.1016/j.canlet.2009.08.012.
`
`Novel targeted therapeutics for metastatic castration-resistant
`prostate cancer
`
`Emmanuel S. Antonarakis*, Michael A. Carducci, and Mario A. Eisenberger
`Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, United
`States
`
`Abstract
`Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease.
`Although docetaxel is the standard of care for these patients and is associated with a modest
`prolongation of survival, there is an urgent need for novel treatment strategies for metastatic
`prostate cancer. In the last several years, great strides have been made in our understanding of the
`biological and molecular mechanisms driving prostate cancer growth and progression, and this has
`resulted in widespread clinical testing of numerous new targeted therapies. This review discusses
`some of the key therapeutic agents that have emerged for the treatment of metastatic castration-
`resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and
`clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway
`inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like
`growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists,
`receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues,
`cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine
`therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.
`
`Keywords
`Metastatic castration-resistant prostate; cancer; Targeted therapies; Immune therapies; Molecular
`targets; Clinical trials; Drug development
`
`1. Introduction
`
`Prostate cancer is the most common malignancy in men worldwide. In the United States,
`there were an estimated 186,300 new diagnoses of prostate cancer and 28,700 prostate
`cancer deaths in 2008, representing 25% of new cancer cases and 10% of male cancer deaths
`
`© 2009 Elsevier Ireland Ltd. All rights reserved.
`*Corresponding author. Address: Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins
`University, 1650 Orleans Street, CRB1-191, Baltimore, MD 21231, United States. Tel.: +1 410 614 4459; fax: +1 410 955 0125.
`eantona1@jhmi.edu (E.S. Antonarakis).
`Conflict of interest
`ESA indicates no financial or other conflicts of interest. MAC has served as a consultant for Sanofi-Aventis, Abbott, Pfizer,
`Genentech, AstraZeneca, Novartis, Wyeth, and Cougar Biotechnology (now Johnson & Johnson); he has received honoraria from
`Sanofi-Aventis and Abbott. MAE has served as a consultant for Sanofi-Aventis, Ipsen, Celgene, and Centocor (now Centocor Ortho
`Biotech).
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`[1]. This makes prostate cancer the second leading cause of cancer death in men. While the
`disease can potentially be cured when localized, metastatic prostate cancer remains
`incurable.
`
`Treatment of localized prostate cancer is usually centered around surgery and/or radiation
`therapy. However, even after definitive local therapy, approximately 30–50% of patients
`will have a local or distant recurrence [2,3]. Patients with metastatic prostate cancer have a
`median survival of 3–7 years, and most men die of it [2]. Treatment for metastatic disease
`involves surgical castration or hormonal manipulation using gonadotropin-releasing
`hormone (GnRH) agonists, antiandrogens, or both. Although the majority of these patients
`initially respond to androgen deprivation therapy, all eventually progress to a state of
`castration-resistant prostate cancer (CRPC). Treatment options for these men are limited.
`Secondary hormonal manipulations, such as ketoconazole, are often used but these produce
`short-lived responses and do not improve survival [4]. Other acceptable approaches in these
`men include watchful waiting until the development of symptoms, or the initiation of
`cytotoxic chemotherapy. In this regard, the chemotherapeutic agent docetaxel has been
`shown to improve overall survival in patients with CRPC, but only by a median of 2.9
`months (median survival 19.2 months versus 16.3 months using mitoxantrone, P = .004)
`[5,6]. Novel therapies for this patient population are urgently needed.
`
`Since the approval of docetaxel by the Food and Drug Administration (FDA) in 2004, no
`new anti-cancer therapies have entered the market for the treatment of metastatic CRPC. On
`the other hand, the number of agents for CRPC in various stages of clinical development is
`higher than ever before. This has been made possible due to our accelerated understanding
`of the biological and molecular mechanisms underpinning prostate cancer growth and
`spread, which has fueled an expansion in research on new therapeutic approaches. This
`review will highlight novel targeted therapies that have emerged for CRPC in the last 5
`years, focusing on the mechanism of action and developmental status of some key clinical
`compounds that have reached phase II and III clinical trials (Table 1). Advances in
`chemotherapeutic drugs, hormonal agents, and bisphosphonates will not be discussed herein.
`
`2. Targeted treatments
`
`Although a prostate cancer stem cell has yet to be conclusively demonstrated, prostate
`cancer clearly progresses from an androgen-dependent tumor (with features similar to the
`luminal differentiated glands of the prostate) to a castration-resistant tumor that has features
`of adult stem cells, including anti-apoptotic mechanisms, chemotherapy resistance, and
`reliance on nonhormonal signaling pathways [7]. Candidate prostate cancer progression
`pathways under investigation include epidermal growth factor receptor (EGFR) signaling,
`vascular endothelial growth factor (VEGF) receptor-mediated pathways,
`phosphatidylinositol 3-kinase (PI3K)/Akt signaling, the insulin-like growth factor (IGF)
`axis, Hedgehog signaling, mitogen-activated protein (MAP) kinase signaling, the endothelin
`axis, and others. Given the molecular complexity of these pathways in the prostate cancer
`cell and the potential redundancy of individual pathways in the process of cancer
`progression, the simultaneous inhibition of multiple pathways remains a common strategy to
`induce sustained and clinically meaningful responses in metastatic CRPC.
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`The major biologic processes under therapeutic investigation in CRPC involve growth and
`survival, nutrition, apoptosis, chemotherapy and hormone therapy resistance, extra-gonadal
`androgen production, modulation of the androgen receptor, angiogenesis, the bone interface,
`epigenetic regulation, immune surveillance and escape, and stem cell renewal. This article
`provides an overview of these pathways as they pertain to prostate cancer rational targets
`and the approaches that are currently being developed for therapeutic purposes (Table 1).
`
`2.1. PI3K/Akt/mTOR pathway
`
`In advanced prostate cancer, loss of the tumor suppressor gene PTEN occurs in more than
`50% of metastatic lesions and in approximately 20% of locally advanced lesions [8,9]. Loss
`of PTEN correlates with high Gleason score and stage, chemotherapy resistance, and other
`features of advanced prostate cancers [8]. PTEN is a negative regulator of the
`phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway, and advanced prostate cancers
`frequently have elevated levels of phosphorylated (activated) Akt [10]. The Akt pathway is
`involved in signal transduction from multiple cell surface receptors, including the insulin
`receptor, epidermal growth factor receptor, insulin-like growth factor receptor, platelet-
`derived growth factor receptor, and interleukin-6 receptor, and it is likely to function as a
`cellular sensor for nutrient and growth signals [11]. In addition to promoting cell survival
`through the inhibition of apoptosis, the Akt pathway regulates cell growth, proliferation, and
`angiogenesis through the mTOR (mammalian target of rapamycin) pathway and the
`facilitated translation of signals such as c-Myc, cyclin D, and vascular endothelial growth
`factor [10]. Restoration of functional PTEN activity or inhibition of mTOR activity can
`block the growth of PTEN−/− prostate cancer xenografts in mice and restore chemotherapy
`(and possibly hormonal) sensitivity [12,13].
`
`Rapamycin is a natural compound derived from soil samples containing the bacterium
`Streptomyces hygroscopicus, and has been used as a potent immunosuppressive agent in
`solid organ transplantation. Its antiproliferative properties and anti-tumor activity in cell
`lines also led to its clinical development in cardiology as a means of preventing stent
`restenosis and in oncology, in which a wide variety of tumors were found to exhibit
`sensitivity to this agent and its analogue, temsirolimus [14–16]. Temsirolimus has now been
`approved for the treatment of metastatic renal cell carcinoma [17]. Toxicities with
`rapamycin and its analogues are predictable and are not dose-related; they include
`maculopapular rash, hypertriglyceridemia, hyperglycemia, allergic reactions, pedal edema,
`mucositis, and thrombocytopenia [14,17–19].
`
`Although mTOR inhibitors probably have little single-agent activity in advanced CRPC
`[20], the combination of these agents with docetaxel is an attractive option given their ability
`to reverse chemotherapy resistance in prostate cancer cell lines [21]. In addition, these
`agents induce apoptosis when they are given in combination with chemotherapy in patients
`who have demonstrable activation of the Akt pathway as a result of PTEN mutation/loss or
`other genetic alterations [22]. To this end, the mTOR inhibitor, everolimus, is currently
`being evaluated in combination with docetaxel for the first-line treatment of metastatic
`CRPC in a phase I/II clinical trial [23]. Everolimus is already approved for the treatment of
`advanced renal cell carcinoma [24]. A new mTOR inhibitor, deforolimus (AP23573), is also
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`being investigated in the phase II setting as single-agent therapy for men with advanced
`taxanerefractory CRPC.
`
`2.2. Angiogenesis targets
`
`Tumor angiogenesis is likely to be an important biologic component of prostate cancer
`metastasis, and elevated levels of the potent angiogenic molecule, vascular endothelial
`growth factor (VEGF), have been shown to correlate with advanced clinical stage and
`survival [25,26]. In a retrospective study of archived serum samples, VEGF levels were
`independently associated with survival from prostate cancer [27]. Similarly, antibodies to
`VEGF have slowed prostate xenograft growth rates, especially in combination with
`chemotherapy [28,29].
`
`These findings led to the phase II CALGB 90006 trial, which added bevacizumab to
`docetaxel and estramustine in men with metastatic CRPC. Among 79 treated patients in this
`study, a fall in PSA of 50% or more was seen in 65% of men, median time to progression
`was 9.7 months, and overall median survival was 21 months [30]. Other phase II trials
`combining docetaxel and bevacizumab have also shown promising results [31,32]. These
`favorable trials have led to the design of a phase III randomized study (CALGB 90401)
`evaluating docetaxel 75 mg/m2 every 3 weeks and prednisone 10 mg daily plus either
`bevacizumab 15 mg/kg or placebo given every 3 weeks. The primary endpoint of this trial is
`overall survival, and accrual of 1020 patients with metastatic CRPC has been completed.
`The initial results of this pivotal trial are awaited.
`
`Thalidomide was originally developed in the 1960s for treatment of morning sickness and
`subsequently linked to teratogenic effects resulting in phocomelia and dysmelia. Whereas
`the exact mechanism of teratogenesis is unproven, the metabolites of thalidomide have been
`shown to inhibit angiogenesis through multiple potential mechanisms, including inhibition
`of pro-angiogenic signals such as VEGF, basic fibroblast growth factor (bFGF),
`interleukin-6, and tumor necrosis factor-α [33,34]. Preclinical studies suggest that
`thalidomide also has T-cell co-stimulatory activity and immunomodulatory properties. Phase
`I/II studies using high doses of thalidomide as a single agent have yielded low PSA response
`rates in the order of 20% [33,35]. However, in a randomized phase II trial of weekly
`docetaxel and low-dose thalidomide versus docetaxel alone, PSA responses, time to disease
`progression, and overall survival were greater in the combination arm [36]. Although this
`trial was underpowered to detect a difference from the standard arm, the clinical activity and
`manageable toxicity of this agent have led to the development of more potent thalidomide
`analogues for combination therapy, and these are currently undergoing clinical evaluation.
`Finally, a recent report of a phase II trial using a three-drug combination of docetaxel,
`thalidomide and bevacizumab showed PSA responses in approximately 80% of patients;
`however neurotoxicity was significant with this combination [37].
`
`Toxicities with thalidomide include deep venous thrombosis, sedation, neuropathy,
`constipation, and fatigue. Newer thalidomide analogues with immunomodulatory features
`have been developed that lack the neurotoxicity of thalidomide but retain many of the T-cell
`modulatory effects, anti-angiogenic properties, and even direct pro-apoptotic functions [34].
`Lenalidomide and CC-4047 are second-generation compounds with much more potent
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`tumor necrosis factor-α inhibition than the parent compound, and clinical testing with these
`agents has begun. For example, several phase I and II studies have revealed PSA responses
`and partial radiological responses with lenalidomide, both when used alone and when
`combined with ketoconazole or docetaxel [38–40]. However, phase III trials using
`thalidomide or lenalidomide in CRPC have not yet been conducted.
`
`There has been a recent interest in the evaluation of tyrosine kinase inhibitors (TKIs), agents
`which block angiogenic growth factor targets such as the VEGF and PDGF receptors. The
`drug sorafenib is an oral inhibitor of RAF kinase, VEGFR, and PDGFR, which has been
`approved for use in metastatic renal cell carcinoma and hepatocellular carcinoma [41,42]. In
`phase II studies using sorafenib in men with metastatic CRPC, this agent was shown to
`prevent radiological progression and cause regression of bone metastases in some patients,
`but without affecting PSA levels [43,44]. The agent sunitinib and a novel multi-kinase
`inhibitor, vatalinib, are currently being tested in phase II studies in combination with
`docetaxel for chemotherapy-naïve CRPC; radiological responses rather than PSA responses
`have been chosen as primary endpoints in these trials. Finally, single-agent sunitinib is being
`evaluated in a phase III study of patients with docetaxel-refractory disease.
`
`An alternative anti-angiogenic strategy is the use of VEGF decoy receptors (VEGF-Trap) to
`saturate circulating VEGF and prevent it from binding to its natural transmembrane receptor.
`One such agent is aflibercept (AVE0005), a novel recombinant decoy fusion protein of
`VEGFR and the Fc fragment of IgG1 [45]. In a phase I/II study of intravenous aflibercept
`combined with docetaxel in 54 heavily-pretreated patients with advanced solid tumors, the
`optimal dose of aflibercept was determined to be 6 mg/kg given every 3 weeks [46].
`Toxicities from this combination regimen included neutropenia, hypertension, proteinuria,
`epistaxis, and dysphonia. Five patients (9%) achieved partial radiological responses, and 32
`(59%) had stable disease. A multicenter, randomized, placebo-controlled phase III study of
`docetaxel with or without aflibercept in men with chemotherapy-naïve metastatic CRPC is
`now accruing patients.
`
`A final approach to angiogenesis inhibition involves the use of tumor-vascular disrupting
`agents, drugs that primarily act against established tumor blood vessels by disrupting
`vascular endothelial cells and causing a range of subsequent antivascular effects [47]. The
`prototype in this class of agents is 5,6-dimethylxanthenoine-4-acetic acid (DMXAA).
`Motivated by experiments showing that DMXAA functioned synergistically with docetaxel
`in human prostate cancer xenografts [48], a multicenter randomized phase II trial of
`docetaxel plus or minus DMXAA (1200 mg/m2 intravenously every 3 weeks) was
`conducted for men with metastatic CRPC in the first-line setting. In that study of 71 patients,
`PSA responses (>30% PSA reduction) at 3 months were 47% and 63% in the docetaxel-
`alone and docetaxel-DMXAA arms, respectively, and radiological response rates were 9%
`and 23% in the monotherapy-arm and the combination-arm, respectively [49]. Adverse
`events with DMXAA-docetaxel included neutropenia/febrile neutropenia, cardiac toxicities
`(supraventricular tachycardia, myocardial ischemia), gastrointestinal effects, and infectious
`complications.
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`2.3. EGFR and PDGFR pathways
`
`The rapid development in the last several years of small molecules that inhibit tyrosine
`kinases has yielded encouraging results in a host of cancers. Demonstration of tumor
`response has sometimes correlated with mutation in the target tyrosine kinase, such as
`epidermal growth factor receptor (EGFR), Bcr-Abl, and c-Kit. In these cases, the target
`mutation has played a central role in the pathogenesis of these tumors. In prostate cancer, no
`such mutations have been identified, perhaps explaining why early trials of tyrosine kinase
`inhibitors in prostate cancer have been disappointing.
`
`EGFR is overexpressed in 40–80% of prostate cancer cells, and over-expression may be
`more common in African American men with prostate cancer [50]. Furthermore, preclinical
`data suggested a correlation of EGFR expression with Gleason sum and androgen
`independence [51]. In phase II studies of approximately 100 patients with castration-
`resistant disease evaluating the EGFR tyrosine kinase inhibitor gefitinib, minimal activity
`and no PSA responses were reported [52,53]. Gefitinib resistance may be related to
`overactivity of the PI3K/Akt pathway in prostate cancer, and thus combinations of agents
`that target multiple pathways may be more beneficial [54]. In an effort to overcome this
`resistance, trials combining EGFR or dual kinase inhibitors with other novel agents are in
`development. For example, gefitinib is currently being tested in combination with the Akt/
`mTOR inhibitor, everolimus, in a phase II trial as first-line therapy for metastatic CRPC.
`
`Prostate cancer cells express high levels of platelet-derived growth factor receptor
`(PDGFR), and signaling through this mechanism converges with the PI3K/Akt pathway
`which has been implicated in prostate cancer progression. Single-agent activity with the
`PDGFR inhibitor imatinib has been disappointing [55]; however, encouraging results in
`combination with weekly docetaxel have been reported in the phase I setting [56]. A phase
`II randomized trial of this combination compared with docetaxel alone is in progress, but
`early results from this study suggested a lack of improvement in median progression-free
`survival in men receiving docetaxel plus imatinib [57]. Plans to move forward with imatinib
`as a potential therapeutic agent for prostate cancer in the future are lacking.
`
`Another potential target in this family of receptors is the HER2/neu tyrosine kinase, whose
`expression has been shown to increase androgen receptor activation leading to prostate
`cancer growth and survival [58]. However, phase II studies using the anti-HER2 monoclonal
`antibody trastuzumab showed minimal efficacy in CRPC, perhaps due to a low frequency of
`HER2 over-expression [59]. Studies using the dual EGFR/HER2 small molecule inhibitor
`lapatinib in asymptomatic CRPC are now being conducted, but early results have shown
`PSA responses in only about 10% of participants [60].
`
`2.4. Apoptosis
`
`Apoptosis is regulated by pro-apoptotic and anti-apoptotic proteins that are recruited as a
`result of apoptotic stimuli such as DNA damage, chemo- and hormonal therapy, and
`irradiation. Bcl-2, an anti-apoptotic factor, is an attractive molecular target in the treatment
`of CRPC. In human prostate carcinoma cell lines as well as in clinical prostate cancer
`specimens, increased Bcl-2 expression induces the transition to androgen-independent cell
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`growth [61], and confers resistance to many antineoplastic agents including taxanes [62].
`These findings suggest that Bcl-2 over-expression may mediate clinical resistance to both
`androgen deprivation and chemotherapy in prostate cancer patients.
`
`Oblimersen is a synthetic antisense oligonucleotide that hybridizes to bcl-2 mRNA and
`inhibits Bcl-2 protein expression [63]. In mice bearing xenograft tumors from androgen-
`independent human prostate cancer cell lines, oblimersen markedly enhanced the anti-tumor
`activity of docetaxel resulting in increased rates of complete tumor regression compared
`with animals treated with docetaxel alone [64]. Because docetaxel itself partially inactivates
`the Bcl-2 protein (by phosphorylation), the addition of oblimersen to docetaxel is a rational
`therapeutic strategy. To this end, a phase I/II study using oblimersen (given by continuous
`intravenous infusion on days 1–8) with docetaxel (on day 6) every 3 weeks in patients with
`CRPC showed that 14/27 men (52%) achieved PSA responses while 4/12 men (33%) with
`measurable disease achieved partial radiological responses [65]. Adverse events with this
`combination were myelosuppression (including febrile neutropenia), alopecia, fatigue,
`diarrhea, and nausea/vomiting. Toxicities specifically attributed to oblimersen were fever
`(beginning 2–3 days after drug initiation), aspartate aminotransferase elevations,
`hypophosphatemia, and deep vein thrombosis. A randomized phase II trial evaluating
`docetaxel (given on day 5) with or without oblimersen (by continuous intravenous infusion
`on days 1–7) in patients with metastatic CRPC was recently reported. Discouragingly, this
`study revealed that PSA responses were similar in the docetaxel–oblimersen arm and in the
`docetaxel-alone arm (46% and 37%, respectively), and partial radiological responses were
`also similar (18% and 24%, respectively) [66]. In addition, docetaxel–oblimersen was
`associated with an increased incidence of grade 3–4 fatigue, mucositis, and
`thrombocytopenia; and caused more major toxic events (40.7% versus 22.8%, respectively).
`
`AT-101 (R-gossypol acetate) is a polyphenolic compound derived from the cottonseed plant
`that inhibits the function of all Bcl-2 – related proteins (Bcl-2, Bcl-xL, Mcl-1, and Bcl-w)
`[67]. By blocking the binding of Bcl-2 family members with pro-apoptotic proteins and up-
`regulating specific pro-apoptotic factors, AT-101 lowers the threshold for cancer cells to
`undergo apoptosis [68]. Preclinically, AT-101 has shown anti-tumor activity in a variety of
`tumor types including prostate cancer [69]. A phase I/II study of oral AT-101 used alone
`was conducted in men with CRPC and no prior chemotherapy. In that study, the optimal
`dose was determined to be 20 mg/day for 21 out of 28 days, and common toxicities included
`diarrhea, fatigue, nausea, anorexia, and small bowel obstruction [70]. Two of 23 patients
`(9%) had a ≥50% PSA decline, but no patient achieved a radiological response. A second
`phase I/II study was performed by combining AT-101 (on days 1–3 of each cycle) with
`docetaxel (given every 3 weeks) in men with docetaxel-naïve CRPC. In that study, the
`optimal dose of AT-101 was found to be 40 mg twice daily on days 1–3 of each
`chemotherapy cycle, and adverse events of this combination included neutropenia,
`lymphopenia, fatigue, nausea, diarrhea, and hypophosphatemia [71]. Eight of nine patients
`treated at the optimal dose (89%) had a ≥50% PSA decline, and 2 of 6 patients with
`measurable disease (33%) had a partial radiologic response. A multicenter randomized
`phase II study evaluating docetaxel plus or minus oral AT-101 in the first-line treatment of
`metastatic CRPC is now underway.
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`The insulin-like growth factor type-1 receptor (IGF-1R) and its ligands may also play a key
`role in prostate cancer carcinogenesis through mechanisms that involve mitogenesis, anti-
`apoptosis, and cellular transformation. Epidemiological studies have shown that increased
`circulating insulin-like growth factor type-1 (IGF-1) levels and decreased insulin-like
`growth factor binding protein-3 (IGFBP-3) levels are associated with higher risk of
`developing prostate cancer [72]. Conversely, partial inactivation of the IGF-1R seems well
`tolerated and may protect individuals from prostate cancer. In addition, IGF-1R is often
`overexpressed in prostate tumors and can mediate prostate cancer cell proliferation and
`resistance to androgen ablation therapy [73,74]. A promising strategy to inhibit the function
`of the IGF-1R is the use of monoclonal antibodies that bind to the extracellular domain of
`this transmembrane receptor [75]. In prostate cancer cell lines as well as in xenograft
`models, such antibodies can inhibit growth of both androgen-dependent and -independent
`tumors [76,77].
`
`IMC-A12 (cixutumumab) is a fully human IgG1 monoclonal antibody that specifically
`targets the IGF-1R, inhibiting ligand binding and IGF signaling [78]. A phase II study of
`intravenous IMC-A12 (10 mg/kg every 2 weeks) used as monotherapy in men with
`asymptomatic metastatic CRPC was recently reported. In that study, 9 of 31 patients (29%)
`demonstrated lack of radiographic progression after 6 months of treatment, and an even
`greater number had PSA responses [79]. Adverse events related to this agent were fatigue,
`hyperglycemia (usually asymptomatic), thrombocytopenia, hyperkalemia, and pneumonia. A
`phase II study combining IMC-A12 (6 mg/kg on days 1, 8, and 15 of a 3-week cycle) with
`mitoxantrone in the second-line treatment of docetaxel-refractory metastatic CRPC is
`currently underway.
`
`CP-751,871 (figitumumab) is the second fully human anti-IGF-1R IgG2 monoclonal
`antibody to enter clinical trials [80]. A phase I study of intravenous CP-751,871 given in
`combination with docetaxel to men with metastatic CRPC has been completed. In that study,
`4 of 18 patients (22%) had a radiographic partial response to therapy, and an additional 2
`men (11%) had disease stabilization for >6 months [81]. Toxicities of this combination
`regimen were neutropenia (including neutropenic fever), diarrhea, and transient
`hyperglycemia. A phase II study of CP-751,871 (20 mg/kg on day 1 of a 21-day cycle)
`combined with docetaxel in men with chemotherapy-naïve (arm A) and docetaxel-resistant
`(arm B) CRPC is now open.
`
`2.6. Bone interface
`
`An emerging target with a prominent role in prostate cancer progression and development of
`bone metastases is endothelin-1, a peptide that also plays an important role in vascular tone
`[82]. Preclinical studies suggest that endothelin A receptors are overexpressed in prostate
`cancer, and higher tissue endothelin receptor levels in patients with prostate cancer correlate
`with advanced tumor stage, grade, and metastases [83]. Endothelin-1 is a potent
`vasoconstrictor, and antagonists have been developed for the treatment of pulmonary
`hypertension. In oncology, endothelin is likely to be involved in the paracrine signals
`between osteoblasts and prostate cancer cells that regulate the development of bone
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`metastases and have been shown to influence cell growth and proliferation, regulate
`osteoblast activity, and inhibit apoptosis [84–86]. These observations suggest that this
`pathway may be a rational target for the interference of tumor-stromal interactions.
`
`Atrasentan is a highly selective endothelin A receptor antagonist and has been extensively
`tested in prostate cancer [87]. In phase II trials, a 10-mg dose of oral atrasentan was found to
`prolong time to progression compared with placebo in men with metastatic CRPC (196
`versus 129 days, respectively; P = .02) [88]. Adverse events with atrasentan were mild and
`related to vasomotor reactions including headache, rhinitis, flushing, and peripheral edema.
`In addition, favorable effects were seen in markers of bone deposition and resorption.
`However, in a placebo-controlled double-blind phase III trial involving 809 patients with
`metastatic CRPC, atrasentan (10 mg/day) did not reduce the risk of disease progression (P
`= .14), despite evidence of biologic effects on PSA and bone alkaline phosphatase [89]. A
`second phase III trial in non-metastatic CRPC that randomized 467 men to atrasentan and
`474 to placebo also failed to improve time to metastatic progression (P = .29) or overall
`survival [90]. A large cooperative group phase III clinical trial evaluating docetaxel with or
`without atrasentan as first-line therapy for metastatic CRPC is now underway. This study
`was fueled by promising results of early phase II trials evaluating this combination [91], and
`from preclinical data showing synergism between docetaxel and atrasentan in vitro and in
`vivo [92].
`
`A novel small molecule endothelin receptor inhibitor, zibotentan (ZD4054), has shown
`initial promising results [93]. In a phase II trial of zibotentan versus placebo in men with
`metastatic CRPC, this agent did not improve time to disease progression (the primary study
`endpoint) (P = .55); however overall survival was longer on the zibotentan arm (P = .01)
`[94]. Although survival was a secondary endpoint in that trial, this has led to the design of
`several ongoing placebo-controlled phase III clinical studies evaluating zibotentan either
`alone or in combination with docetaxel in patients with metastatic CRPC. A further phase III
`trial is investigating single-agent zibotentan in men with non-metastatic castration-resistant
`disease.
`
`2.7. RANK ligand inhibitors
`
`Interactions between tumor cells and the bone marrow microenvironment have been
`postulated as an additional important mechanism in the pathogenesis of bone metastasis.
`Tumor-associated cytokines have been shown to induce the expression of RANKL (the
`receptor activator of nuclear factor κB ligand), which binds and activates RANK which is
`found in osteoclasts [95]. Inhibition of the RANKL system has recently been the focus of
`much research and represents an evolving bone-targeted strategy. Among the approaches
`employed are monoclonal antibodies to RANKL and the use of recombinant osteoprotegerin
`(the natural decoy receptor of RANKL), both of which significantly inhibit osteoclastic
`function in vitro and in vivo [96].
`
`Denosumab, a fully human monoclonal antibody against RANKL, has entered clinical trials
`in prostate and breast cancers [97]. In a phase II randomized study evaluating 50 patients
`with metastatic prostate cancer, denosumab (180 mg subcutaneously every 4 weeks)
`produced a reduction in bone resorption over that of zoledronate as indicated by a lowering
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`Cancer Lett. Author manuscript; available in PMC 2014 May 21.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`of urinary N-telopeptide levels, and also resulted in less skeletal-related events (SREs) [98].
`A multi-center phase III double-blind study comparing denosumab with zoledronate in the
`prevention of SREs in patients with metastatic CRPC has recently completed accrual of 745
`men.
`
`2.8. Vitamin D analogue