Article Published in the Author Account of

Eun-mi Yu

Angiogenesis Inhibitors in Prostate Cancer Therapy

Abstract: Limited treatment options exist for metastatic castrate-resistant prostate cancer (mCRPC). The concept of targeting tumors via anti-angiogenic mechanisms has been studied over the last decade, giving rise to a new class of anti-cancer drugs. Currently, the use of angiogenesis inhibition in prostate cancer is the focus of many ongoing clinical trials, with tumor progression and overall survival established as outcome measures. Several anti-angiogenic agents are currently under investigation with varying mechanisms by which they exert activity against prostate tumors. We describe the significant findings and outcomes of clinical trials involving the use of these drugs in mCRPC patients, along with how these results will translate to their use in the clinical setting. Open interventional trials that are currently recruiting participants are also mentioned. While the use of angiogenesis inhibition holds promise in the treatment of prostate cancer, several challenges still exist. The foreseeable clinical implications and limitations of anti-angiogenic therapy and the potential use of biomarkers are hereby discussed.



Introduction

Angiogenesis inhibition as an anti-cancer therapeutic strategy is one of the most rapidly evolving fields in oncology. Since the landmark discovery that blood vessels are needed in order for tumors to proliferate and grow (Folkman, 1971), thousands of studies from pre-clinical work to clinical studies have been published, demonstrating angiogenesis inhibition’s firm role in cancer therapeutics. The utility of angiogenesis inhibition in prostate cancer has garnered wide interest among various groups of investigators and with reason. Prostate cancer remains to be the most common non-cutaneous malignancy in the United States. In 2010 alone, it is estimated that 217,730 new cases of prostate cancer will be diagnosed and about 32,050 men are expected to die from prostate cancer (Jemal et al., 2010). However, more work remains to be done as several important questions remain to be answered. Among them is the utility of angiogenesis inhibition. While the prototype drug targeting the vascular endothelial growth factor (VEGF) ligand bevacizumab is approved by the Food and Drug Administration (FDA) for varying tumor types as standard treatment in combination with chemotherapy, there are other tumor types in which the use of bevacizumab remains controversial. The benefit of angiogenesis inhibition in prostate cancer has been shown in various studies. However, a recently concluded phase III trial using bevacizumab in addition to the current standard of docetaxel and prednisone was disappointingly negative (Kelly et al., 2010). Nevertheless, several theories abound regarding the reasons behind the findings.

A corollary question is how best to measure the responses in those who receive anti-angiogenic therapies. Certainly, the traditional method of measuring tumors via computed tomography scans using Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse et al., 2000) and technetium scintigraphy or bone scan has been widely employed; but increasingly, we are recognizing that limitations exist when relying solely on these traditional methods of gauging response. In addition, the use of the prostate-specific antigen (PSA) has its own limitations. As such, the Prostate Cancer Clinical Trials Working Group published guidelines that caution the use of PSA alone in determining response or being the sole basis of switching therapy especially with the use of these targeted agents (Scher et al., 2008).

Mechanisms of Angiogenesis

The significance of angiogenesis in the biology of tumor growth, thereby the concept of using angiogenesis as a target for cancer therapy, was described by Dr. Judah Folkman almost three decades ago (Folkman, 1971). He observed that the growth of tumors was severely limited in the absence of neo-vascularization. This was further studied and observed in melanoma, where neovascularization directly correlated with thickness and risk of recurrence (Srivastava et al., 1988). Not surprisingly, it was later found that increased microvessel density, a measure of angiogenesis, was associated with increased metastases and poorer prognosis in prostate carcinoma (Weidner et al., 1993).

Tumors rely on blood supply to persist and grow. An “angiogenic switch” has been described as a rate-limiting step in tumor progression, where tumors lacking blood vessels acquire the ability to vascularize (Bergers and Benjamin, 2003). Angiogenesis is a complex process involving multiple pathways of key regulatory proteins, pro- and anti-angiogenic stimuli, and endothelial cell activation. Endothelial cells that make up existing blood vessels are activated to multiply and migrate as surrounding basement membrane and extracellular matrix is degraded to make way for new capillaries. Capillary tubes are formed by endothelial cell precursors that migrate in response to angiogenic stimuli and re-adhere to one another while recruiting surrounding peri-endothelial and smooth muscle cells for support.

The hypoxic state is thought to stimulate the production of angiogenic cytokines such as VEGF, fibroblast growth factor 2 (FGF-2), and tumor necrosis factor-alpha (TNF-α), among others. There are also naturally-occurring anti-angiogenic factors, such as endostatin and angiostatin, which, together with the pro-angiogenic factors, determine the overall tumor microenvironment and angiogenic potential.

The VEGF family is the most extensively-studied group of angiogenic growth factors. This includes VEGF-A, the prototypical VEGF ligand which activates VEGF receptor 1 (VEGFR1) and VEGFR2. When these receptors are bound by VEGF-A, they are activated via dimerization and phosphorylation of receptor tyrosine residues, resulting in downstream signals that propagate angiogenesis. More specifically, the binding of VEGF-A to VEGFR2 induces vasodilation, increased vessel permeability, endothelial cell mitosis, and migration.

The expression of VEGF-A is induced by hypoxic conditions via the modulation of hypoxia-inducible factors (HIFs) (Semenza, 2003). HIF-1 is a transcription factor consistent of alpha and beta subunits (HIF-1α and HIF-1β). Under normoxic conditions, HIF-1α is hydroxylated and targeted for degradation. In contrast, HIF-1α is allowed to accumulate under hypoxic conditions due to the limited availability of oxygen that is needed for hydroxylation. Intact HIF-1α dimerizes with HIF-1β and together they induce the transcription of hypoxia-survival genes, including VEGF. The induction of VEGF therefore allows tissues to survive under hypoxia by means of neovascularization. It has been shown that prostate tumor cells express VEGF-A and use similar mechanisms to spread into non-vascularized tissue. Therefore, the concept of targeting tumor cells by the neutralization of the VEGF-A ligand gave way to bevacizumab, a humanized IgG1 monoclonal antibody that targets the major isoforms of VEGF-A (Ferrara et al., 2004). Bevacizumab is the first of its class that has been approved by the FDA for cancer therapy. There are other anti-angiogenic targets that are being studied, including tyrosine kinase and extracellular matrix inhibitors which will also be discussed.

Clinical Drug Targets

Targeting VEGF

Bevacizumab

Bevacizumab is a monoclonal antibody that targets the human VEGF ligand, specifically the major isoforms of VEGF-A. Although it showed activity against multiple human cancer cells lines in vitro, further testing involving its use as a single agent in prostate cancer was disappointing (Reese et al., 2001). This phase II trial used bevacizumab at 10mg/kg given every two weeks for a total of 6 doses in 15 metastatic castrate-resistant prostate cancer (mCRPC) patients without significant measurable responses or PSA declines of more than 50% by day 70. However, the results of the phase II CALGB trial involving 79 mCRPC patients using bevacizumab combined with chemotherapeutic agents docetaxel and estramustine were more promising (Picus et al., 2010), with 75% of patients exhibiting a PSA decline of at least 50% while 59% of patients who had measurable disease showed partial radiographic response. The primary endpoint of progression free survival in this study was not met but encouraging antitumor activity and overall survival were observed in this study, although somewhat limited by the increased toxicity, partly due also to the use of estramustine.

More recently, a randomized phase III trial (CALGB 90401) has been conducted comparing the combined use of docetaxel, prednisone (DP), and bevacizumab (Bev) with docetaxel and prednisone alone (Kelly et al., 2010). This study randomized 1050 chemotherapy-naïve mCRPC patients into each treatment group using overall survival as a primary endpoint. Preliminary results suggest that statistically-significant overall survival benefit was not observed in the bevacizumab group (22.6 months DP + Bev versus 21.5 months for the DP alone arm, HR=0.91, p=0.181). There was a higher rate and severity of treatment-related toxicity and mortality in the bevacizumab arm (3.8% grade 5 events in the DP + Bev arm vs. 1.1% in the DP alone arm), with the majority of treatment-related deaths being secondary to infection. Further exploratory subset analysis to determine the patients who may have a clinical benefit are under way. Additionally, the bevacizumab group exhibited superiority in other relevant outcome measures such as progression-free survival (9.9 months in DP + Bev vs. 7.5 months DP arm), PSA response rate (69.5% on the DP + Bev arm vs. 57.9% DP arm), and objective response rate (53.2% in the DP + Bev arm vs. 42.1% in the DP alone arm).

The results of another trial involving the use of bevacizumab in combination with standard chemotherapy with docetaxel and prednisone as well as the immunomodulatory agent thalidomide was recently published (Ning et al., 2010). This was a phase II trial enrolling 60 chemotherapy-naïve mCRPC patients which showed a remarkable PSA decline rate of greater than 50% occurring in 90% of the patients. Progression free survival was estimated to be 18.2 months, with median overall survival reported as 28.2 months. Given these favorable results, the National Cancer Institute is sponsoring a phase II study evaluating the combination of bevacizumab with docetaxel, prednisone, and the presumably less toxic lenalidomide, a thalidomide derivative (see Table 1).

Aflibercept

Aflibercept, also known as VEGF-trap, is a decoy receptor fusion protein comprised of the Fc portion of human IgG1 and the VEGFR-1 and VEGFR-2 ligand binding domains. It binds and neutralizes the major VEGF isoforms, including VEGF-A and VEGF-B. A phase I dose escalation study has been completed using aflibercept in combination with docetaxel (Isambert et al., 2008). A phase III study (VENICE, NCT00519285, see Table 2) is currently investigating aflibercept used in combination with docetaxel plus prednisone or prednisolone in mCRPC, with overall survival being the primary outcome measure.

Tyrosine kinase inhibitors

Tyrosine kinase inhibition is another mechanism by which tumors can be targeted. Tyrosine kinases are enzymes involved in various cell processes key to the growth and survival of tumors. The development of agents that bind the ATP-binding domain of VEGF tyrosine kinases, thereby inhibiting angiogenesis, has led to another class of anti-cancer drugs. Sorafenib and sunitinib are VEGF tyrosine kinase inhibitors that have been studied in the treatment of prostate cancer.

Sorafenib

Sorafenib functions as a multi-tyrosine kinase inhibitor that targets tumor cell proliferation by inhibiting Raf kinase. It also targets angiogenesis by inhibiting VEGFR-2, VEGFR-3, and platelet derived growth factor receptor (PDGFR) kinases. Several phase II trials have been done using sorafenib as single agent therapy, including one that treated 22 mCRPC patients with sorafenib 400 mg twice daily (Dahut et al., 2008) with later completion of the trial at 46 patients (Aragon-Ching et al., 2009). This and other trials using sorafenib shows that the use of sorafenib as monotherapy shows minimal activity in CRPC patients with or without metastases, based on the lack of significant PSA declines and radiographic response. However, whether this is inherent of a class effect with tyrosine kinase inhibitors or limitations in measurement of response is unclear at this time (Aragon-Ching and Dahut, 2010). New trials studying the use of sorafenib in early disease and in combination with chemotherapy or hormone therapy are underway at this time.

Sunitinib

Sunitinib is another tyrosine kinase inhibitor that targets VEGF and PDGF receptors. A phase II study on 34 predominantly mCRPC patients (Dror Michaelson et al., 2009), half of whom were docetaxel-resistant and the other half chemotherapy-naïve, showed that only 2 patients had a PSA decline of >50% and 1 patient had an objective radiographic response. Stable disease at twelve weeks based on RECIST criteria was seen in 18 patients, however.

Again, the results of both sorafenib and sunitinib have shed light on the possibility that PSA levels may not be the best measure of response, given the equivocal results of most of these trials and the observation that, at times, radiographic response was observed in patients with rising PSA levels.

Dasatinib

Dasatinib is a tyrosine kinase inhibitor with activity against the Src family kinases (SFKs) and BCR-ABL and is now primarily used in the treatment of chronic myelogenous leukemia and acute lymphoblastic leukemia. Src is a nonreceptor tyrosine kinase belonging to the Src family kinase group (SFK). Src is predominantly expressed in platelets, neuronal tissue, and bone and was the first proto-oncogene identified. It has a role in multiple pathways involved in tumor survival, proliferation, and metastasis. Src inhibition is thought to target tumors primarily by preventing the activation of osteoclasts. Osteoclasts play an important role in the bone remodeling process, whereby a delicate balance exists between bone formation and resorption, alteration of which could lead to increased osteolytic metastasis and potential colonization of tumor in the bone. However, Src signaling may also have a role in angiogenesis given the observation that cell lines with greater expression of c-Src produced more VEGF under hypoxic conditions (Mukhopadhyay et al., 1995). Furthermore, the inhibition of c-SRC in a human colon cancer cell line appeared to proportionally decrease the expression of VEGF (Ellis et al., 1998). These observations led to the concept that combination therapy with Src and VEGF inhibitors would be feasible to explore in solid tumors.

Dasatinib may have a role in the treatment of metastatic prostate cancer given the reduction of bony biomarkers and achievement of stable disease in patients with bony metastases. These benefits were seen in a phase II study of dasatinib as monotherapy in 47 patients with mCRPC (Yu et al., 2009). Combination therapy with dasatinib and docetaxel for mCRPC was also studied (Araujo et al., 2009), with results showing partial response documented in 12 out of 21 RECIST-evaluable patients. Of 32 patients evaluable for PSA response, 13 (41%) had a PSA decline. Declines in bone marker urinary N-telopeptide and alkaline phosphatase were observed in 46% and 71% of patients, respectively, as well as reduction in size and number of lesions on bone scans seen in 28% of patients, all demonstrating favorable effects on bony lesions. A phase III study is now underway based on these promising results, comparing dasatinib plus docetaxel with docetaxel plus placebo with the primary endpoint being overall survival.

There are three other phase II trials studying the use of dasatinib in prostate cancer. One study (CA180-097) is investigating dasatinib as monotherapy in patients previously treated with chemotherapy. Another study is testing dasatinib in combination with leuprolide acetate (a luteinizing hormone-releasing hormone agonist) for patients with high-risk localized prostate cancer. A third study is looking into dasatinib therapy in patients with CRPC and low level androgen-receptor activity, based on genomic testing of metastatic tissue.

Cediranib

Cediranib (AZD2171) is another receptor tyrosine kinase inhibitor directed against VEGFR1/2 and PDGFR. Preclinical studies have shown that cediranib may inhibit the growth of bone and brain metastases in prostate cancer. Also, increased survival was seen in tumor-bearing mice treated with cediranib (Yin et al., 2010). A phase I study using cediranib in 26 castration-resistant prostate cancer patients showed overall good tolerability and acceptable toxicity of cediranib when given at therapeutic doses (Ryan et al., 2007). Nineteen of these patients completed 28 days of therapy and were further observed for response analysis. Four patients had PSA reductions between 10 and 50%; none had a PSA decline greater than 50% during the study period. One patient achieved a 58% reduction in PSA 30 days after discontinuing therapy. This patient received 15 days (incomplete therapy, discontinued secondary to muscle weakness) of 30 mg daily of cediranib. Another patient who completed 28 days on 20mg daily dosing had a 93% reduction in PSA 30 days after discontinuing of therapy. Interestingly, one patient had an increase in PSA during therapy and had a decline in PSA over 80% associated with resolution of retroperitoneal adenopathy. This response was sustained for over 17 months.

A phase II study of cediranib therapy enrolled 59 patients with mCRPC (NCT00436956) with a 6-month progression-free survival as the primary outcome measure. Preliminary results reported encouraging responses with 13 of 23 evaluable patients exhibiting tumor shrinkage and 4 patients meeting criteria for partial response (Karakunnel et al., 2009). As in the sorafenib and sunitinib trials, discrepancy between PSA and standard imaging changes were seen and further correlation with the use of digital contrast enhanced-magnetic resonance imaging (DCE-MRI) was utilized to determine alternative imaging to measure tumor response. Another phase II study that investigates the use of cediranib in combination with docetaxel and prednisone in patients with metastatic prostate cancer that have not responded to hormone therapy is underway. It would be reasonable to expect that the use of angiogenesis inhibitors in combination with chemotherapy will prove to be more efficacious than monotherapy with anti-angiogenic agents. However, it may be worth investigating the use of less-toxic anti-angiogenic agents with reduced doses of chemotherapeutic drugs in hopes of maintaining efficacy while avoiding the toxicities of standard-dose chemotherapy.

Pazopanib

Pazopanib is one of the newer multitargeted tyrosine kinase inhibitors, just FDA-approved for use in the treatment of advanced renal cell carcinoma in October 2009 (LaPlant and Louzon, 2010). It potently inhibits several receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, PDGFRα, and PDGFRβ which are involved in tumor angiogenesis. This new agent has shown activity against many tumors, from renal cell carcinoma to multiple myeloma. Results of a phase II study (NCT00454571) investigating pazopanib therapy in relapsed prostate cancer patients who have undergone gonadotropin-releasing hormone (GnRH) agonist therapy are still pending. Two other phase II trials are currently recruiting patients to study pazopanib use in patients with prostate cancer. One will focus on patients refractory to total androgen blockage with bicalutamide, with pazopanib given as second-line therapy (NCT00945477). The other study will compare the use of pazopanib with and without bicalutamide in prostate cancer patients who have not responded to prior hormone therapy, including those who have received luteinizing hormone-releasing hormone agonist agents or have undergone surgical orchiectomy (NCT00486642).

Extracellular matrix inhibitors

The invasiveness and metastatic potential of a tumor has been felt to be dependent on other processes in the microenvironment, such as the degradation of extracellular components comprised of stromal connective tissue and basement membrane. Thalidomide is a drug that was initially marketed as an oral sedative and anti-emetic, which later gained notoriety for its teratogenic effects. Subsequent studies led to the discovery of thalidomide’s potential anti-angiogenic properties which may have led to its teratogenic potential (D’Amato et al., 1994). The exact mechanism by which thalidomide inhibits angiogenesis is still not fully understood, but studies have suggested that it may inhibit the secretion of VEGF and FGF from tumor and stromal cells. Thalidomide may also modulate the tumor microenvironment via the reduction of sonic hedgehog signaling, down regulation of integrins, and control of several matrix metalloproteinases, which together, inhibit endothelial cell migration and adhesion.

Many studies have been done using thalidomide as mono- and combination-therapy in CRPC. Overall, the use of thalidomide in combination with other chemotherapeutic agents has yielded favorable results, including significant PSA declines and prolonged overall survival. Nevertheless, additional phase III studies are needed to be done to clarify its role in prostate cancer therapy. Lenalidomide, a less-toxic thalidomide analog is also under investigation. As mentioned earlier, lenalidomide in combination with bevacizumab, docetaxel, and prednisone is currently under phase II study (NCT00942587). Another phase III trial will compare the use of lenalidomide plus docetaxel with the use of docetaxel alone in prostate cancer (NCT00988208).

Integrins are heterodimer transmembrane receptors involved in the maintenance of basement membranes. Certain integrin heterodimers can be targeted to inhibit tumor angiogenesis. Cilengitide, a synthetic peptide that inhibits integrin-ligand interaction has undergone phase II trials in chemotherapy-naïve mCRPC patients. Stable disease was noted as the best objective response in 27% to 36% of patients who received cilengitide (Bradley et al., 2010). Another phase II study investigated cilengitide monotherapy in patients with non-metastatic, castration-resistant prostate cancer with PSA progression (Alva et al., 2010). Unfortunately, cilengitide did not show detectable clinical activity in this study that used circulating tumor cells (CTCs) as a biomarker for disease activity. Furthermore, there were no PSA responses in all 13 of the patients included in outcome analyses; at best, two patients had stable disease at 12 weeks while the other 11 had PSA progression.

Matrix metalloproteinases (MMPs) are a family of proteinases involved in the degradation of basement membrane proteins. Activated MMPs catalyze the destruction of extracellular matrix and transmembrane proteins, and most isoforms have been associated with tumor progression. Many studies over the last decade have shown that the over-expression of MMPs correlates with prostate cancer progression. Therefore, MMP-inhibiting agents are potential therapies for prostate cancer. Several naturally-existing agents that modulate angiogenesis partly via MMP inhibition include endostatin, TNP-470 (a synthetic analog of fumagillin), and 2-methoxyestradiol (an estrogen derivative).

Endostatin is a C-terminal fragment derived from type XVIII collagen with anti-angiogenic properties, possibly via MMP-2 inhibition (Kim et al., 2000). One preclinical study done showed that endostatin and angiostatin therapy may be effective for early, non-metastatic disease (Isayeva et al., 2007). Angiogenesis-related gene expression analysis was done in a follow-up study which revealed increased sensitivity of cells with higher androgen receptor expression to endostatin. Endostatin was found to down-regulate the expression of growth factors, receptor tyrosine kinases, and proteases in androgen-sensitive cells, which resulted in inhibition of cell migration (Isayeva et al., 2009). These preclinical results are promising and they suggest that endostatin may have a role in preventing metastases in early-stage, androgen-sensitive prostate cancers. TNP-470 and 2-methoxyestradiol have also been investigated in prostate cancer. However, phase I studies of these agents have yielded disappointing results (Dahut et al., 2006; Logothetis et al., 2001).

Role of Biomarkers in Response Assessment

The encouraging results seen thus far with the use of angiogenesis inhibitors have been tempered with mixed results as well as limitations in the measurement of response as evidenced by the discordant PSA responses and radiographic assessments. Since the advent of PSA testing several decades ago, no other potential biomarker has improved upon the results gleaned from the PSA test. The PSA is a 34 kD glycoprotein that is found almost exclusively in normal and neoplastic prostate cells and seminal fluid (Wang et al., 1981) and measurable declines in serum PSA certainly has been a useful indicator of outcome in mCRPC and, as such, has been used as part of the response criteria in evaluating effects of drug treatment. However, there is still a question regarding true surrogacy for the use of PSA in predicting for survival especially in patients with mCRPC. In addition, the use of PSA as a biomarker for response in patients treated with targeted agents has also been discordant with radiographic response. Therefore, the use of alternative biomarkers, such as CTCs, is heavily incorporated in some of the recently accruing contemporary clinical trials.

The measurement of CTCs was based upon the concept that tumor cells circulate in the peripheral blood of patients who have known carcinoma and not typically found in healthy or normal subjects (Allard et al., 2004). In a study looking at the relationship between post-treatment CTCs in patients treated with chemotherapy, CTC counts predicted overall survival (OS) better than PSA decrement algorithms at all time points (de Bono et al., 2008). Patients who had unfavorable CTCs, defined as more than or equal to 5 CTCs per 7.5 ml of blood sample, and converted to favorable CTCs, defined as less than 5 CTCs per 7.5 ml, had better prognostic improvement in OS from 6.8 to 21.3 months. Other biomarkers such as serum or tissue markers, including TMPRSS2-ETS gene rearrangement, in varying stages of prostate cancer has been studied (Makarov et al., 2009). This is but one step in establishing the role of alternative biomarkers in predicting for survival in patients with mCRPC, and would be useful to include them in such trials using angiogenesis inhibitors.

Clinical Implications

While encouraging responses have been seen in various studies outlined above, there remain some perplexing discrepancies in the results of clinical trials using anti-angiogenic therapy compared to what has been seen in preclinical data. One hypothesis is that this may be due to intrinsic or adaptive mechanisms of resistance. Since the target tumors for anti-angiogenic therapy are metastatic cancers in tissues with high vessel densities, tumors may have the ability to progress independently of neo-vascularization (Roodink and Leenders, 2010).

In addition, the benefits of the use of angiogenesis inhibitors clinically in varying tumor types have also been mixed. While several approvals have resulted in landmark changes in standard of care with addition of angiogenesis inhibitors to chemotherapy, increasing data has also been emerging questioning its true benefits especially in the absence of overall survival, as seen for instance, in metastatic breast cancer. To date, some of the agents that have been approved by the FDA are bevacizumab (approved for use in combination with chemotherapy in metastatic colorectal cancer, non-small-cell lung cancer, and advanced renal cell cancer in combination with interferon, and as 2nd line treatment for glioblastoma multiforme), sorafenib (used in metastatic renal cancer and hepatocellular carcinoma), and sunitinib (used in advanced renal cancer and gastrointestinal stromal tumors). Although none of these agents have been approved for prostate cancer, there are many ongoing trials investigating their potential use in patients with this cancer.

One of the long-awaited trials that sought to answer the question of the value of angiogenesis inhibition in prostate cancer was the randomized phase III trial (CALGB 90401) comparing the combined use of docetaxel, prednisone (DP), and bevacizumab (Bev) with docetaxel and prednisone alone (Kelly et al., 2010) as mentioned earlier. Whether the results signify the lack of efficacy of angiogenesis inhibitors in prostate cancer, given the equivalent survival outcomes, is up for debate. Several observations explaining these results include a possible stage migration effect, whereby an overall healthier population may have been enrolled, as evidenced by the observation that the control arm in this trial also notably fared better than the same docetaxel arm from the TAX327 trial, essentially rendering this an underpowered study. Perhaps the better overall prognostic factors of patients enrolled this trial also negated the beneficial effects since earlier treatment of asymptomatic patients with a regimen that is potentially more toxic also resulted in more adverse effects, leading to morbidity and mortality. Premature discontinuation of treatment due to PSA progression may have blunted the positive outcomes of bevacizumab, as adequate dosing and duration of therapy may be needed until efficacy can be fully appreciated. In addition, the use of the bevacizumab combination may be more beneficial in patients who have worse overall prognosis, as indicated by the forest plot of overall survival in select subgroups of patients which showed that the patients with worse prognostic indicators such as less hemoglobin (< or = to 12.8 g/dl), higher alkaline phosphatase, higher lactic dehydrogenase, and lower testosterone all had hazard ratios < 1 that favored the use of combination bevacizumab with docetaxel and prednisone.

Conclusions and Future Directions

Angiogenesis inhibitors have the potential to enhance therapeutic options for patients with prostate cancer. Increasing results of different clinical trials lend insight to how we may use these agents. Better selection of the right patient population, improvement in tools for assessing tumor response, and rational use in combination with other agents such as cytotoxic chemotherapy or alternative drug targets are key to the success of the use of angiogenesis inhibitors. Future studies could focus on the use of anti-angiogenic agents given in conjunction with a synergistic cytotoxic chemotherapy that would allow reduced dosing of chemotherapy in the hopes of delivering effective, yet less-toxic, regimens.

With the success seen in various other tumor types using anti-angiogenesis, similar results may still be achieved in prostate cancer.

Disclosure

The authors report no conflicts of interest.

Acknowledgments

This research is supported by an Institutional Research Grant (IRG-08-091-01) from the American Cancer Society to The George Washington University Cancer Institute.

(Corresponding author: Jeanny B. Aragon-Ching, M.D., Assistant Professor of Medicine, Division of Hematology and Oncology, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA.)

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(55):521-530, December 2010.]

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