Antiangiogenic agents in the treatment of prostate cancer

Drug Discovery Today: Therapeutic Strategies

Vol. 7, No. 1–2 2010

Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY

TODAY THERAPEUTIC

STRATEGIES

Prostate cancer

Antiangiogenic agents in the treatment of prostate cancer David E. Adelberg*, William L. Dahut Medical Oncology Branch, National Cancer Institute, Building 10, Rm12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA

Prostate cancer remains the most commonly diagnosed noncutaneous malignancy among men in the United States. Once prostate cancer becomes metastatic, there is no curative therapy. Angiogenesis, the process of new blood vessel formation, plays a central

Section editor: James L. Gulley – Laboratory of Tumor Immunology and Biology & Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

role in prostate cancer growth and metastasis and

Tumor angiogenesis

angiogenic markers have been shown to correlate with

In 1971, Folkman proposed that tumor growth and metastasis are angiogenesis-dependent [9] and that blocking angiogenesis may arrest tumor growth [9]. Clinically occult, avascular tumors are limited in their growth potential [10]. When able to recruit their own blood supply, tumor cells may undergo rapid expansion and metastasis. This has been termed the ‘angiogenic switch’ [11] and depends on a variety of processes (reviewed in [12]), one of the earliest being the hypoxic-induction of pro-angiogenic gene expression. This is part of an overall shift in the balance of endothelial cell (EC) activator and inhibitor molecules that ultimately leads to tumor neovascularization [13]. Pro-angiogenic mediators include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), placental growth factor (PlGF), transforming growth factor-b (TGF-b) and angiopoietin-1 (ANG1), among others. The most widely studied of the pro-angiogenic growth factors is VEGF, of which there are at least seven isoforms [14]. VEGF-A appears to have the central role in tumor angiogenesis [14] by increasing vascular permeability and EC survival, as well as stimulating microvascular EC migration and proliferation [13]. Of the three different VEGF receptor tyrosine kinases (VEGFR-1, -2, and -3), it is the binding of VEGF-A to VEGFR-1 and -2 that appears to be most crucial for tumor angiogenesis [10,15,16].

prostate cancer prognosis. Several therapeutic strategies targeting angiogenesis in prostate cancer have been undertaken and will be reviewed here. Introduction Prostate cancer is the leading noncutaneous malignancy in American men [1,2] and the second leading cause of cancerrelated deaths in this population [2]. In 2010, estimates are just over 210,000 men will be diagnosed and more than 32,000 will die of metastatic disease [2]. For patients who either present with, or develop metastatic disease, first-line androgen-deprivation therapy provides a median duration of response of only 14–20 months [3]. Castration resistant prostate cancer (CRPC) is marked by either a rising prostatespecific antigen (PSA) level or new metastatic disease despite castrate levels of testosterone [4]. For symptomatic metastatic CRPC, therapeutic options are limited. Docetaxel [5], cabazitaxel [6], sipuleucel-T [7] and abiraterone [8] have each been shown to modestly prolong survival in this setting. However, clinical responses are not durable and disease progression inevitably ensues. Thus, there is a continued need for new therapeutic strategies in metastatic CRPC. *Corresponding author: D.E. Adelberg ([email protected]) 1740-6773/$ ß 2011 Published by Elsevier Ltd.

DOI: 10.1016/j.ddstr.2011.02.005

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Rationale for targeting angiogenesis in prostate cancer Many preclinical studies have implicated angiogenesis as a crucial factor in prostate cancer progression. VEGF expression by immunohistochemistry is markedly higher in prostate cancer specimens compared to non-neoplastic prostatic tissue controls [17] and plasma VEGF levels are significantly higher with metastatic versus localized disease [18]. Both plasma and urine VEGF levels have been inversely correlated with survival in patients with CRPC [19,20]. Higher microvessel density, a surrogate histological measure of tumor angiogenesis [10], has been shown to significantly correlate with metastasis [21], Gleason grade, stage, disease-specific survival and overall survival (OS) [22,23]. In addition to VEGF, other pro-angiogenic pathways may be contributing to prostate cancer progression. Serum bFGF was shown to be significantly higher in men with prostate cancer compared to controls without evidence of disease [24]. The pro-angiogenic molecule CD105 (endoglin) may also play a role in prostate cancer. CD105 is a transmembrane protein that is selectively and highly expressed on the surface of proliferating vascular ECs [25,26] and is strongly expressed in blood vessels of prostate cancer specimens [27,28]. It acts as an accessory protein to the TGF-b signaling receptor complex, re-routing normally inhibitory TGF-b signals down a stimulatory pathway involving Alk-1 and SMAD proteins 1, 5 and 8. This ultimately leads to EC proliferation, migration and transcription of pro-angiogenic genes [29]. Increased tumor microvessel density (MVD), as assessed by anti-CD105 antibodies, correlates with Gleason score, tumor stage, metastasis, tumor cell proliferation index and shorter survival in prostate cancer [27,28]. Higher levels of urinary CD105 are present in biopsyproven prostate cancer compared with biopsy-negative patients [30]. Anti-VEGF therapy upregulates CD105 expression [31], indicating that a therapeutic strategy which targets CD105 may complement VEGF-inhibition. Upregulation of CD105 may represent one possible mechanism for resistance to angiogenesis therapies based on antagonism of VEGF. These findings highlight the central importance of angiogenesis to prostate cancer progression. When considered with preclinical data that have shown the capability of antiangiogenic therapy to mediate tumor regressions [32], the rationale for an antiangiogenic approach to prostate cancer becomes evident. This approach can be roughly divided into two strategies: indirectly blocking tumor angiogenesis through antagonism of soluble pro-angiogenic growth factors or receptor tyrosine kinases or directly attacking the microvascular EC [33].

Indirect angiogenesis inhibitors: anti-VEGF monoclonal antibody Bevacizumab (Avastin1; Genentech, Inc., South San Francisco, CA) is a recombinant humanized IgG1 monoclonal antibody with high affinity and specificity for all isoforms of 10

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VEGF-A [15,34]. Upon binding to soluble VEGF-A, bevacizumab limits ligand binding to EC receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR), thus blocking the transduction of proangiogenic intracellular signals [34]. Currently, bevacizumab, in combination with chemotherapy, is FDA approved for the treatment of metastatic colon, lung and renal cell cancer [33,35]. Single-agent bevacizumab has been approved as second-line treatment for glioblastoma [35]. The activity of single-agent bevacizumab in CRPC was evaluated by Reese et al. in a phase II study published in 2001 [36]. 15 chemotherapy-naı¨ve patients with metastatic CRPC received bevacizumab at 10 mg/kg every 14 days for six cycles. None of the 15 evaluable patients achieved objective responses as assessed by either standard radiographic RECIST criteria or PSA declines of at least 50% [37]. Four patients (27%) had a PSA decline of <50%. The most common toxicities noted in the trial were fatigue (60%) and hyponatremia (13%). Combinations of bevacizumab with standard of care chemotherapy such as first-line docetaxel or even estramustine have been undertaken. The Cancer and Leukemia Group B (CALGB) phase II 90006 trial enrolled 79 patients with metastatic CRPC (median Gleason score of eight), each of whom received docetaxel (70 mg/m2 every 21 days), bevacizumab (15 mg/kg every 21 days) and estramustine (280 mg on days 1–5 of the 21-day cycle). 14 of 33 (42%) patients with measurable disease achieved a partial response with 79% of patients achieving a PSA decline of >50% [37]. These response rates are higher than what had been previously reported in multi-institutional studies with docetaxel and estramustine without bevacizumab [15,37]. DiLorenzo et al. conducted a phase II trial in which 20 patients with metastatic CRPC, all of whom had evidence of prior disease progression on docetaxel, were re-challenged with the combination of docetaxel (60 mg/m2 every three weeks) and bevacizumab (10 mg/kg every three weeks). The objective response rate was 37.5% and 11 of 20 patients (55%) achieved a PSA decline of >50%; four of these 11 patients had not achieved significant PSA responses on prior docetaxel alone [38]. CALGB recently reported results of a randomized, doubleblind, placebo-controlled phase III trial in which 1050 patients with metastatic CRPC were randomized to receive docetaxel (75 mg/m2 every 21 days), prednisone (5 mg twice daily), and either bevacizumab (15 mg/kg every 21 days) or placebo [39]. All patients received dexamethasone 8 mg by mouth 12, three one hour before docetaxel. The primary endpoint was OS and the study was powered to detect a 21% decrease in the hazard rate of death. Despite an improvement in the secondary endpoints of progression-free survival (PFS), measurable disease response and post-therapy PSA decline, the study did not meet its stated primary endpoint of improvement in OS. Median OS for the bevacizumab arm was 22.6 months (95% confidence interval of 21.1–24.5)

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versus 21.5 months (95% CI 20.0–23.0) in the placebo arm, translating into a non-significant HR of 0.91 (0.78–1.05). Improvements in PFS [9.9 months versus 7.5 months, HR 0.77], objective response rate [53.2% versus 42.1%] and PSA response rate (50% decline) [69.5% versus 57.9%] all met statistical significance. Of note, there was a statistically significant increase in morbidity and mortality in the bevacizumab arm. Grade three or higher treatment-related adverse events occurred in 74.8% of the bevacizumab group versus 55.3% in the placebo group. Treatment-related deaths occurred in 4.4% of the experimental arm versus 1.1% in the placebo arm. Bevacizumab has also recently been added to immunotherapy with encouraging results. A phase II trial combined the dendritic-cellular based therapeutic cancer vaccine sipuleucel-T (Provenge1; Dendreon, Seattle, WA) with bevacizumab. The basis for this combination came from preclinical data which suggested that VEGF in the tumor microenvironment may be inhibiting dendritic cell function. Addition of bevacizumab was hypothesized to minimize this dendritic cell suppression and enhance the immune response to tumor [15]. Results showed a statistically significant increase in median PSA doubling time with all evaluable patients having evidence of specific immune responses [40]. Monoclonal antibodies have also been developed against specific VEGF receptors and are being tested in phase I or II studies. IMC-1121, a monoclonal antibody to VEGFR-2, has shown tolerability in phase I testing and is being evaluated in the phase II setting in combination with mitoxantrone and prednisone in docetaxel-resistant metastatic CRPC patients. IMC-18F1, a monoclonal antibody to VEGFR-1, is being evaluated in the phase I setting [15,37].

Indirect angiogenesis inhibitors: anti-VEGF fusion protein Fusion proteins typically contain an Fc fragment of a human antibody fused with the binding domain of a specific growth factor receptor. They are similar to monoclonal antibodies in that they function as soluble decoy receptors, binding ligand and preventing stimulation of cell surface receptors [15]. As they are fully humanized protein molecules, the fusion proteins have been better tolerated than the less-than-fully humanized monoclonal antibodies [15]. VEGF-Trap (Aflibercept1; Sanofi-Aventis, Paris, France and Regeneron, Tarrytown, New York) contains the Fc fragment of IgG1 fused to domain 2 of VEGFR-1 and domain 3 of VEGFR-2 [37]. This fusion protein has high affinity for many of the isoforms of VEGF, exerting its antiangiogenic effects by binding this ligand before it can stimulate the EC surface VEGF receptor. Safety data from phase I studies have shown toxicities of hypertension, proteinuria and thrombosis [15], consistent with other antiangiogenic agents. Evidence of antitumor activity has been seen in a range of phase II studies

Drug Discovery Today: Therapeutic Strategies | Prostate cancer

[37] and a large phase III trial in metastatic CRPC patients comparing docetaxel plus prednisone with either VEGF-Trap or placebo has completed accrual and is awaiting final data analysis.

Indirect angiogenesis inhibitors: specific VEGF receptor tyrosine kinase inhibitor The three VEGF receptor isoforms are tyrosine kinases which, upon binding of the VEGF ligand, transduce pro-angiogenic intracellular signals via the PI3-K/AKT and RAF/MEK/ERK pathways [15]. There is a multitude of small-molecular inhibitors of these receptor tyrosine kinases that have been tested in prostate cancer patients Cediranib (Recentin1; AstraZeneca, London, UK) is an orally bioavailable indole-ether quinazoline small-molecule inhibitor of VEGF receptor tyrosine kinases Flt-1 (VEGFR-1) and KDR (VEGFR-2). Data from a phase II study of cediranib in postdocetaxel metastatic CRPC patients showed encouraging results. Of 34 patients with measurable soft tissue disease, 19 (56%) had evidence of tumor regression with six patients (18%) achieving a partial response (PR) by RECIST criteria [41]. PSA levels increased dramatically in some patients with tumor responses, indicating that PSA may not be a reliable marker for tumor activity with this therapy. Common toxicities included fatigue, dehydration, muscle weakness, hypertension and hyponatremia [41]. Cediranib appears to be a promising therapy for metastatic CRPC patients and is currently being evaluated in combination with docetaxel (NCT00527124) as well as dasatinib (NCT01260688).

Indirect angiogenesis inhibitors: multitargeted receptor tyrosine kinase inhibitors (TKIs) Sorafenib (Nexevar; Bayer HealthCare Pharmaceuticals Inc.; Wayne, NJ) is a bi-aryl urea TKI targeted to VEGFR-2, -3, PDGFR-beta and RAF kinase. Sorafenib has been tested in prostate cancer in several phase II studies. Although PSA response and median time to progression (often based on PSA evaluations) have been less than encouraging, it is important to note that, as with cediranib, discordance between rises in PSA and radiographic response had been observed. The National Cancer Institute conducted a phase II trial of single-agent sorafenib, 400 mg twice daily, in CRPC patients. This study was amended midway through the trial to re-define progression based solely on clinical or radiographic criteria. Of the 24 patients enrolled under this amendment, one had a confirmed PR by RECIST and 10 patients had stable disease. Median PFS was 3.7 months and median OS 18 months [37]. Additional trials of sorafenib in prostate cancer are ongoing, both as single agent and in combination with chemotherapy. Sunitinib malate (Sutent; Novartis, East Hanover, NJ) is an oral TKI targeted to all three VEGF receptor isoforms as well as www.drugdiscoverytoday.com

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PDGFRb and KIT. Multiple phase II studies of sunitinib have been undertaken in patients with metastatic CRPC, both in the chemotherapy-naı¨ve and in the postdocetaxel settings. Periman et al. reported on a trial of sunitinib in metastatic CRPC patients who had disease progression despite prior chemotherapy [42]. Of the 19 patients who enrolled, the median PFS was 2.8 months with 48% of patients achieving a 12-week PFS. PSA declines of >50% was seen in one patient. Anemia was the most commonly encountered grade 3 toxicity. Subsequently, a multicenter, randomized, double-blind phase 3 study of sunitinib plus prednisone versus prednisone alone (NCT00676650) in patients with postdocetaxel progressive metastatic CRPC was undertaken. This study was terminated prematurely as a scheduled interim analysis found that the combination of sunitinib with prednisone was unlikely to improve OS when compared to prednisone alone. No new or unexpected safety issues were identified. Additional non-selective receptor TKIs are in varying stages of early clinical development for CRPC; among these agents are vandetanib (Zactima; AstraZeneca, London, UK), pazopanib (Votrient; GlaxoSmithKline, London, UK) and enzastaurin (LY317615; Eli Lilly, Indianapolis, IN) (reviewed in [37]).

Indirect angiogenesis inhibitors: thalidomide, lenalidomide In 1994, D’Amato et al. hypothesized that the immunomodulatory drug thalidomide (Thalomid; Celgene Corporation, Summit, NJ) might have antiangiogenic (AA) properties based on the teratogenic effects observed in the 1950s when the drug was given to pregnant women as an antiemetic. This hypothesis was verified by finding that thalidomide inhibited angiogenesis in a rabbit cornea micropocket assay [43]. Despite multiple studies aimed at fully elucidating the antiangiogenic mechanism of thalidomide, this still remains poorly understood. Single-agent thalidomide was evaluated clinically in an open-label, randomized, phase II study; 200 mg daily was reasonably well tolerated and effective compared to higher doses [44]. Of the 50 patients in the 200 mg daily arm, 18% had a >50% decline in PSA. Weekly docetaxel (30 mg/m2 weekly for three out of every four weeks) with or without thalidomide (200 mg/day) has been evaluated in chemotherapy-naı¨ve metastatic CRPC [45]. The combination arm was favored in terms of PSA decline (53% versus 37% experiencing >50% decrease in PSA) and PFS (5.9 months versus 3.7 months). Toxicities included fatigue, peripheral neuropathy and constipation. The combination arm was notable for an increase in thromboembolic events requiring prophylactic anticoagulation. An updated analysis showed a statistically significant increase in median OS favoring the combination arm (25.9 months versus 14.7 months) [37]. 12

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Lenalidomide (Revlimid1, Celgene Corporation, Summit, NJ) is an analog of thalidomide currently being evaluated in CRPC patients in the hope of lessening the toxicities seen with thalidomide while improving on its antiangiogenic properties [46]. Single-agent lenalidomide had not been shown to have significant activity in prostate cancer (reviewed in [46]). However, a phase I study of 19 CRPC patients utilizing lenalidomide (20 mg daily on days 1–14 of each three-week cycle) in combination with docetaxel (75 mg/m2 every three weeks) and prednisone showed nine patients (47%) with PSA declines of >50% and five of 13 patients (38.5%) with measurable disease achieved a partial response (reviewed in [46]). There are ongoing clinical trials utilizing both thalidomide and its analog, lenalidomide, in combination with other antiangiogenic agents and chemotherapy that are discussed below.

Direct angiogenesis inhibitors: anti-CD105 monoclonal antibody TRC105 is a human/murine chimeric IgG1 monoclonal antibody to human CD105 (endoglin) that inhibits angiogenesis and tumor growth through the inhibition of EC proliferation, antibody-dependent cellular cytotoxicity and induction of apoptosis. A multi-institutional dose-finding phase 1 study of TRC105 in patients with advanced refractory cancer is currently underway (NCT00582985); doses up to 10 mg/kg TRC105 given every two weeks appears to be well tolerated, with grade two or three infusion reaction being the most commonly encountered toxicity [47]. Significant hypertension and proteinuria, seen with other antiangiogenic agents, have not been observed with TRC105. Of the 41 patients enrolled to date, eight have CRPC; one patient with chemotherapynaı¨ve CRPC and multiple bone metastases remains on study more than 29 months after the initiation of TRC105 with a complete PSA response and improvements in bone scan. The National Cancer Institute is currently enrolling patients in a combined phase I/II trial of TRC105 in metastatic CRPC (NCT01090765). Three cohorts of three to six patients receive TRC105 at doses of 1, 3 or 10 mg/kg IV every two weeks of a four-week cycle. To date, eight patients have been enrolled, with two patients at the highest dose level, 10 mg/kg (cohort 3). Dose-limiting toxicity has not yet been observed. PSA declines have been seen in both patients in cohort 3 (26 and 51% from baseline); each of these patients had progressed on docetaxel and at least one second-line agent [48]. Accrual is ongoing to evaluate higher doses and more frequent dosing.

Indirect angiogenesis inhibitors: dual antiangiogenic therapy Ning et al. recently reported on a phase II trial utilizing two antiangiogenic agents in combination with chemotherapy

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Drug Discovery Today: Therapeutic Strategies | Prostate cancer

for patients with metastatic CRPC. Sixty chemotherapy-naı¨ve CRPC patients received docetaxel (75 mg/m2 every three weeks) and prednisone (5 mg twice daily) combined with bevacizumab (15 mg/kg once every three weeks) and thalidomide (200 mg daily throughout the 21-day cycle). Of the 58 patients with PSA-active disease, 90% had PSA declines of 50% and 76% had PSA declines of 75%. Of the 33 patients with measurable disease, two had confirmed complete responses and 19 had partial responses for an overall response rate of 64%. Median PFS was 18.3 months and the estimated median OS time from study entry was 28.2 months, far exceeding the Halabi predicted survival of 14 months for this group of patients. Common grade three or higher toxicities included neutropenia, hypertension and syncope [49].

Summary The role of angiogenesis inhibitors in the treatment of CRPC remains an active area of clinical investigation. Despite the fact that the primary endpoint of OS in CALGB 90401 did not meet statistical significance, it is important to remember that almost half of the patients (47%) had a 30% chance of being alive at 24 month postrandomization, reflecting the increased proportion of low risk patients enrolled in this trial. This suggests a lead time bias, supported by the finding that the placebo arm

(those who had received docetaxel and prednisone) had a median OS of 21.5 months, exceeding the previously reported median OS of metastatic CRPC patients enrolled in the TAX 327 study treated with the same regimen [50]. Patients in the placebo arm of CALGB 90401 had fewer symptoms and longer survival from the time they enrolled, complicating interpretation of this trial. Results from CALGB 90401 highlight the need to identify appropriate subgroups of patients with metastatic CRPC who would most benefit from addition of antiangiogenic therapy to standard of care chemotherapy. Perhaps surrogate angiogenic biomarkers or prognostic models would be helpful to this end. Furthermore, the study by Ning et al. suggests that the optimal targeting of angiogenesis in prostate cancer may be through the use of at least two antiangiogenic agents simultaneously. This dual approach may limit the development of resistance which is likely to be occurring with a single-agent approach. Further elucidating the mechanisms that may underlie resistance to antiangiogenic agents would be beneficial in maximizing the clinical benefit of dual antiangiogenic therapy which has shown promising results in phase II evaluations. Toxicity with all the antiangiogenic agents remains a challenge, and hence there is a continued need to search out newer, less toxic agents that retain, or improve upon, the observed clinical efficacy.

Appendix A. Comparison summary table Strategy

Pros

Cons

Latest developments

Group, Institute, Company

Refs

Anti-VEGF mAba

Bevacizumab binds all isoforms of VEGF-A Dosing every three weeks

Limited activity as single agent Multiple toxicitiese

Phase II dual antiangiogenic therapy, Ning et al. [49] Phase III CALGB 90401, Kelly et al. [39]

NCIf

46 38

Anti-VEGF Fusion Protein

Fully humanized

Multiple toxicities, similar to mAb

VENICE phase III trial NCT00519285

VEGFR TKIb

Orally bioavailable

Cediranib

Active in postdocetaxel CRPC Targets multiple angiogenic pathways

PSA becomes unreliable marker of disease activity Fatigue Dehydration Hypertension PSA becomes unreliable marker of disease activity Sunitinib with minimal activity in CRPC Requires prophylactic anticoagulation for increased risk of thromboembolic events Dose reductions often required Frequent intravenous dosing, up to once per week

Phase II study of single-agent cediranib in postdocetaxel CRPC

Multi-institutional CALGB Sanofi-Aventis Regeneron Pharmaceuticals NCIf

Non-specific receptor TKI

IMIDc

Targets angiogenic pathways other than VEGF

Dual AAd Therapy

Highly active in CRPC

Anti-CD105 mAb

Directly attacks the tumor endothelial cell through

Phase III study of sunitinib in CRPC

14

40

AstraZeneca, Inc. Pfizer, Inc.

36

Phase I study of lenalidomide, docetaxel, prednisone NCT00988208

Celgene

45

Phase II study of bevacizumab thalidomide, docetaxel and prednisone NCT00089609 Phase 1 dose-finding study of TRC105 in patients with solid cancer NCT00582985

NCIf

46

Tracon Pharmaceuticals

47

NCT00676650

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Appendix A. (Continued ) Strategy

Pros

Cons

ADCCg and induction of apoptosis

Latest developments

Group, Institute, Company

Refs

A phase I/II study of TRC105 in mCRPCh NCT01090765

NCIf

48

a

mAb: monoclonal antibody. VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor. IMiD: immunomodulatory drug; includes thalidomide and lenalidomide. d AA: antiangiogenic. e Toxicities of bevacizumab include, but are not limited to, gastrointestinal perforation, wound healing complications, fistula, hemorrhage, arterial thromboembolic events, hypertension, proteinuria and reversible posterior leukoencephalopathy. f NCI: National Cancer Institute. g ADCC: Antibody-dependent cellular cytotoxicity. h mCRPC: metastatic castrate-resistant prostate cancer. b c

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