April 2015, Vol 4, No 2
Cabozantinib in Prostate Cancer Patients with Bone MetastasisProstate Cancer
Prostate cancer is the most common nondermatologic cancer diagnosed among males in the United States with approximately 233,000 new cases annually. In addition, prostate cancer is the second leading cause of cancer death in men with over 29,000 estimated deaths in 2014.1 Once prostate cancer has metastasized and progressed to a castration-resistant state, it is considered a lethal disease. Most patients with advanced castration-resistant prostate cancer (CRPC) develop bone metastases, which frequently become a major source of disease-related morbidity and mortality.2 The bones with higher vascularization such as the vertebral column, ribs, skull, and proximal ends of long bones are the predilected sites for prostate cancer cells.3 Bone metastases are often symptomatic and frequently affect the quality of life of patients, causing debilitating pain, pathologic fractures, bone marrow suppression, nerve compression syndromes, or spinal cord compression.4 Recent advances in the understanding of the biology of prostate cancer have led to the approval of multiple drugs for CRPC, including the chemotherapeutics docetaxel and cabazitaxel, the immunotherapeutic sipuleucel-T, and the androgen signaling pathway inhibitors abiraterone and enzalutamide.5 Although these agents can prolong survival, the prognosis for CRPC remains poor, and the morbidity related to bone metastases remains a major clinical problem. New therapeutic options are needed for treating patients with castration-resistant disease, particularly in the presence of bone metastasis. Cabozantinib (XL184) is an oral inhibitor of multiple receptor tyrosine kinases (RTKs), including MET and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). Cabozantinib is a promising agent for the treatment of patients with prostate cancer. This review will focus on the rationale for targeting the MET and VEGF signaling pathway with cabozantinib in prostate cancer patients with bone metastasis.
MET and VEGF Signaling in CRPC and Bone Metastases
Data from preclinical models and clinical biomarker studies suggest that the RTK MET and the VEGF signaling pathway are implicated in development and progression of CRPC.6,7 Expression of VEGF is upregulated in metastatic prostate cancer compared with normal prostate tissues,8 and elevated levels of VEGF in plasma or urine correlate with advanced stage, progression, and poor patient outcomes in prostate cancer.9-11 Despite promising results in early-phase clinical trials, multiple VEGF-only targeting agents failed to demonstrate an improvement in overall survival in patients with CRPC.12,13 The lack of survival benefit may reflect the development of adaptive mechanisms of resistance such as upregulation of alternative proangiogenic signaling pathways.14 Upregulation of the MET signaling pathway has emerged as a potential mechanism for the development of resistance for VEGF-targeting therapies.15 MET is an RTK and the only known receptor for hepatocyte growth factor (HGF). MET signaling plays important roles in embryogenesis, cell proliferation, angiogenesis, survival, and tumor cell invasion.6 In cancer cells, inappropriate activation of MET occurs through overexpression of wild-type MET or its ligand HGF, or as a result of activating mutations in the gene encoding MET. Both HGF and MET levels are increased by hypoxia triggered by angiogenesis inhibitors contributing to resistance to VEGF-targeting therapies.16,17 MET signaling plays a role in the biology of CRPC independently of VEGF. Preclinical models suggest that HGF and MET expression is higher in CRPC cell lines and CRPC xenograft tumors growing in vivo.18-20 Furthermore, clinical data suggest that MET expression is significantly higher in tumors from CRPC patients compared with androgen-sensitive tumors.21 A potential explanation of this difference originates from molecular studies showing that the androgen receptor directly represses expression of the gene encoding MET via inhibition of its promoter.19 Interestingly, MET expression is higher in bone metastases than in primary tumors or lymph node metastases.22,23 Overall, robust preclinical data indicate that increased MET expression and signaling contribute to the emergence of castration-resistant disease.
The development of bone metastasis in prostate cancer involves an intricate process of dynamic interactions between cancer cells and the bone microenvironment, mainly osteoblasts, osteoclasts, and endothelial cells.24 Invading cancer cells cause local disruption of normal bone remodeling, with lesions exhibiting osteoblastic (bone-forming) and osteolytic (bone-resorbing) activity.5 Osteoblastic lesions are typically visualized by bone scan, which detects the rapid incorporation of a radiotracer into newly forming or remodeling bone. VEGF and MET signaling pathways are implicated in bone formation, remodeling, and development of metastases. Osteoblasts and osteoclasts express VEGF, VEGF receptors, HGF, and MET, which mediate cell proliferation, migration, differentiation, and survival.25-31 VEGF signaling is involved in potential autocrine and/or paracrine feedback mechanisms regulating osteoblast and osteoclast cellular function.32,33 Secretion of HGF by osteoblasts promotes the development of bone metastases by tumor cells that express MET.30 This body of evidence suggests that simultaneous inhibition of MET and VEGF signaling may offer significant benefit over targeting either pathway alone.
Cabozantinib in Prostate Cancer
Cabozantinib (XL184) is a potent inhibitor of RTKs, including MET and VEGFR2. Other targets inhibited by cabozantinib include AXL, FLT3, KIT, and RET. Preclinical studies in multiple cancers, including glioma, breast, lung, and pancreatic cancers, show that cabozantinib exhibits a potent and reversible inhibition of its targets, affecting angiogenesis and tumorigenesis.15,34 Cabozantinib potently inhibits both wild-type MET and MET with activating mutations. In vitro studies demonstrated that cabozantinib strongly inhibits HGF-induced migration and proliferation in cell lines known to be dependent on MET. Likewise, the in vivo studies showed that cabozantinib inhibits phosphorylation of MET and VEGFR2 in a reversible manner and significantly increases tumor hypoxia and cell death not only in tumor cells but also in endothelial cells of tumor vasculature.34 These studies suggest that antitumor efficacy of cabozantinib is the result of mechanisms affecting tumor angiogenesis and the blockade of invasive tumor growth as well as direct cytotoxicity in sensitive cells. Therefore, this drug has the potential to affect the malignant tumor cells and the tumor microenvironment. Furthermore, the simultaneous inhibition of MET and VEGFR2 by cabozantinib may enhance the antitumor effect suppressing the development of resistance through MET-driven escape pathways seen with agents targeting the VEGF pathway alone.14,15,35,36
More recent preclinical investigations reinforce the potential effects of cabozantinib on bone metastasis. Nguyen and colleagues37 found upregulated levels of MET, P-MET, and VEGFR2 in prostate cancer bone and soft tissue metastases compared with primary tumors. Because VEGFR2 and MET signaling are important in bone biology, cabozantinib treatment not only affects metastatic bones but potentially normal bone as well. In vivo studies with LuCaP 23.1 and castration-resistant C4-2B prostate cancer xenografts showed that cabozantinib treatment attenuates the bone response to the tumor and increases bone volume in intact as well as castrated animals.37 Interestingly, in vitro studies in a bone organ culture model show that cabozantinib inhibits bone resorption, blocking the effects of parathyroid hormone–related protein (PTHrP).38 PTHrP stimulates VEGF expression and bone resorption by cancer metastases.39 PTHrP is produced by tumor cells and binds to receptors on osteoblasts stimulating the production of the membrane-bound cytokine RANKL, which then promotes the fusion activity and survival of osteoclasts.40 In this in vitro study, cabozantinib inhibited the expression of RANKL by osteoblastic cells, affected TRAP in osteoclastic cells, alkaline phosphatase in osteoblastic cells, and decreased cell viability in both cell types. The activity profile of cabozantinib on bone differs from that of the standard antiresorptive agents, which largely target osteoclasts.40 In summary, accumulating evidence suggests an effect of cabozantinib on both tumor and tumor-induced bone matrix remodeling important in treating patients with prostate cancer and bone metastases.
Clinical Trials of Cabozantinib in Prostate Cancer
The phase 1 dose-escalation trial of oral cabozantinib enrolled patients with multiple advanced solid tumors with an expansion cohort for patients with medullary thyroid cancer (MTC) added to the trial.41 Eighty-five patients were enrolled, including 37 with MTC. There were no patients with prostate cancer included in this trial. The maximum tolerated dose with an acceptable side effect profile was 175 mg daily. A total of 77 patients (90%) reported at least 1 treatment-related adverse event (AE), 43% of which were reported as grade 1 or 2. The most frequent AEs related to treatment were diarrhea, fatigue, anorexia, nausea, rash, increased AST level, vomiting, and mucosal inflammation. One patient had a pulmonary embolism, a grade 4 event that was assessed as related to cabozantinib. Dose-limiting toxicities were hand-foot syndrome and liver enzyme elevations. Peak plasma concentrations were reached 5 hours following oral administration. The half-life was shown to be 91 ± 33 hours. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response, and 18 patients had tumor shrinkage of 30% or more. Forty-one percent of patients with MTC had stable disease for at least 6 months.41 Interestingly, 3 patients with a confirmed response had previously been treated with vandetanib or sorafenib that also target RET and VEGFR, supporting the hypothesis of MET being an escape mechanism to VEGFR inhibition.42
On the basis of the broad activity and responses seen in the phase 1 study, a phase 2 randomized discontinuation trial (RDT) was conducted in 9 selected tumor types, including CRPC.43 The results of cabozantinib treatment in the subset of patients with CRPC were encouraging. A total of 171 patients with metastatic CRPC were enrolled, of whom 87% had bone metastases. The patients received open-label treatment with cabozantinib 100 mg daily during a 12-week lead-in stage. The original design of the study stated that patients with stable disease at 12 weeks were randomly assigned to cabozantinib or placebo. At progression, patients were taken off study if they were receiving cabozantinib or were allowed to restart cabozantinib if on placebo. After enrollment of 122 patients, the random assignment to placebo was suspended because of unexpected changes on bone scan and decrease in pain observed during the lead-in stage; at that time, 31 patients had been randomly assigned to receive either cabozantinib or placebo.
Substantial improvements in bone scans were observed in 79 (68%) of the 116 evaluable patients, including complete resolution of lesions in 12% of these patients. Furthermore, 72% exhibited regression in soft tissue lesions, and 67% reported an improvement in pain control.43 In the 31 patients with stable disease who were randomized to placebo or cabozantinib before suspension of random assignment, cabozantinib treatment resulted in a median progression-free survival (PFS) of 23.9 weeks (95% CI, 10.7-62.4 weeks) compared with 5.9 weeks (95% CI, 5.4-6.6 weeks; hazard ratio, 0.12; P <.001) with placebo. Nine patients (5%) had a confirmed partial response within the first 12 weeks, 127 (75%) had stable disease, and 18 (11%) had disease progression. Prostate-specific antigen (PSA) levels of the patients did not correlate with the clinical responses to cabozantinib.43 Despite the relatively low response rate by RECIST, the results were promising, with cabozantinib-treated patients showing consistent effects on markers of bone formation and resorption, improvement in bone pain, narcotic use on retrospective analysis, and better PFS compared with the placebo group. More than 60% of patients required dose reductions related to AEs, similar to what has been observed with other tyrosine kinase inhibitors (TKIs) that target VEGFR. A subsequent single-institution dose-ranging study of men with metastatic CRPC reported bone scan improvements in most patients treated with cabozantinib at a lower starting dose of 40 mg daily, with more modest effects at the lowest dose of 20 mg daily.44
As an attempt to confirm the results of the phase 2 RDT and to test lower doses of cabozantinib, a multicenter phase 2 nonrandomized expansion study of men with CRPC and bone metastases was recently conducted.45 This study used a prespecified bone scan response as the primary study outcome. Patients with CRPC and bone metastases were sequentially enrolled into 100-mg (n = 93) and 40-mg cohorts (n = 51). All patients had received a docetaxel-containing regimen, and some had also received abiraterone or cabazitaxel. The primary end point was bone scan response, defined as at least a 30% improvement in bone scan lesion area (BSLA). BSLA is a quantitative biomarker of osseous disease obtained with validated software that assesses prostate cancer treatment response on a technetium-99 bone scan.46 In this study, 63% of patients had significant bone scan response, 19% had stable disease, and 10% had progressive disease. The bone scan response rate in the 100-mg cohort was 73% compared with 45% in the 40-mg cohort. The bone scan improvements were mostly observed at the first 6-week evaluation. In patients with measurable soft tissue disease, 80% had a reduction in measurable disease that was similar for both cohorts (80% vs 79%). Furthermore, 68% of the patients reported a pain decrease of at least 30%, and 55% of patients had a reduction in the use of narcotics. The AE profile was similar to that previously reported in the phase 2 RDT. Compared with patients treated at a starting dose of 100 mg, those who received 40 mg had lower rates of dose reduction or drug discontinuation because of AEs. It is important to note that the study was not randomized; therefore, the outcomes for the 100-mg and 40-mg cohorts are not directly comparable.45
Both phase 2 studies support the beneficial effects of cabozantinib on a variety of disease-related outcomes in patients with metastatic CRPC, including improvement in bone scans, patient-reported pain and analgesic use, measurable disease, and bone biomarkers.43,45 Moreover, in the most recent phase 2 study, the benefits of cabozantinib were seen in patients heavily pretreated with drugs including docetaxel, abiraterone, and cabazitaxel, suggesting that cabozantinib does not share mechanism(s) of resistance with other prostate cancer treatments. The apparent nonoverlapping resistance between cabozantinib and other agents may reflect targeting of tumor, stroma, and tumor-stroma interactions by cabozantinib.45
Phase 3 studies (Cabozantinib MET Inhibition CRPC Efficacy Trial [COMET] 1 and 2) have been initiated to evaluate the effect of cabozantinib on morbidity and mortality in patients with CRPC with bone metastases. These studies are using cabozantinib at 60 mg daily as the starting dose. The main clinical trials determinants for the potential use of cabozantinib in prostate cancer are summarized in the Table.
Biomarkers of Response to Cabozantinib in CRPC
Serum PSA is the most widely used marker to assess disease response and progression in patients with prostate cancer. Serum PSA is easily measured, and decreased PSA in prostate cancer patients correlates with better overall survival during treatment with androgen deprivation and chemotherapy.47-49 Nevertheless, multiple clinical trials with antiangiogenic TKIs have demonstrated conflicting changes in serum PSA levels. In the cabozantinib phase 2 trials reviewed above, PSA changes did not correlate with other efficacy parameters. Other trials with antiangiogenic TKIs such as cediranib, sorafenib, and sunitinib showed a similar pattern, with few patients having a decline in PSA levels despite reductions in pain and lymph node, lung, liver, and/or bone lesions.50-54 Interestingly, in vitro experiments have shown that PSA secretion from prostate cancer cells can increase during incubation with sorafenib,50 and PSA expression in prostate cancer cells can decrease in the presence of osteoblasts.55 These results suggest that during treatment of CRPC patients with angiogenesis inhibitors, changes in serum PSA may reflect a pharmacodynamic effect of tyrosine kinase inhibition in tumor cells or changes in osteoblast-tumor cell interactions in bone lesions, rather than changes in tumor growth.5 These observations emphasize the importance of radiographic or symptomatic progression over PSA progression, especially in trials of antiangiogenic agents.
Changes in bone scan measurements also have been correlated with survival.56,57 New techniques are being validated for computer-assisted detection and assessment of bone lesions to standardize the measure of treatment effects.46 The significant improvement in bone scans seen with cabozantinib in the phase 2 studies is promising; however, its significance in terms of survival needs evaluation in a phase 3 clinical trial.
Circulating tumor cells (CTCs) are another promising measure of angiogenesis inhibitor effects in prostate cancer. CTCs have been shown to have prognostic value for patients treated with cytotoxic chemotherapy or targeted therapies.58-60 In the phase 2 nonrandomized expansion study of cabozantinib in chemotherapy-pretreated CRPC, posttreatment changes in CTC counts were assessed in 103 patients with baseline unfavorable CTC counts (?5 per 7.5-mL blood) and at least 1 follow-up assessment at week 6 or 12. In this study, 82% of patients had a decrease of at least 30% in CTCs at week 6 and/or 12.45 Additional clinical trials are needed to validate the use of CTCs as a surrogate end point, and more robust technologies are needed to improve the detection of CTCs.
Extensive preclinical and early clinical data suggest that cabozantinib is biologically active in metastatic CRPC especially in patients with bone metastases. The therapeutic effects of cabozantinib are mediated by the simultaneous inhibition of VEGFR2, MET, and other RTKs that are important in prostate cancer progression, metastasis, and development of drug resistance. Furthermore, cabozantinib not only has effects on cancer cells but also on the tumor microenvironment and normal bone. This broad anticancer effect provides a biologic explanation for the significant clinical benefits in a variety of disease-related outcomes observed in the phase 2 clinical trials. The effect of cabozantinib on overall survival of patients with CRPC is under investigation in 2 phase 3 randomized clinical trials.
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- Michaelson MD, Oudard S, Ou Y, et al. Randomized placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2011;29(suppl). Abstract 4515.
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- Pfeiffer MJ, Smit FP, Sedelaar JP, et al. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer. Mol Med. 2011;17:657-664.
- Knudsen BS, Gmyrek GA, Inra J, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60:1113-1117.
- Zhang S, Zhau HE, Osunkoya AO, et al. Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. Mol Cancer. 2010;9:9.
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J Clin Oncol. 2011;29(suppl). Abstract LBA4517.
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Dr Hernandez-Aya is a Hematology/Oncology Fellow at the University of Michigan Comprehensive Cancer Center.
Dr Smith is Professor of Medicine and Urology and Associate Chief for Clinical Services in the Division of Hematology/Oncology at the University of Michigan Comprehensive Cancer Center.
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