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Prostate cancer is the most common non-dermatological cancer in men and has the second highest cancer-related death rates in men . Docetaxel and prednisone are currently the standard of therapy for patients with symptomatic metastatic castration-resistant prostate cancer (CRPC). Cabazitaxel and abiraterone are approved as second-line treatment options for patients with post-docetaxel progressive metastatic disease, but the duration of response is generally short-lived with a modest survival benefit; therefore, more effective therapeutic approaches are still needed, especially in the post-docetaxel setting.
Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, and its receptors have been shown to be important in promoting tumour angiogenesis, playing a critical role in prostate cancer development and progression [2-4]. In preclinical models, inhibition of angiogenesis has been shown to be an effective target in CRPC. VEGF expression is observed in prostate tumours and in plasma and urine from patients with metastatic disease, where increased expression is associated with disease progression [5, 6]. The fms-like tyrosine kinase/kinase insert domain receptor receptors are expressed in human prostate cancers and are correlated with higher grade lesions and outcome . While targeting angiogenesis appears to be a rational and therapeutic approach for CRPC , recent phase III trial results of VEGF pathway inhibitors bevacizumab  and sunitinib  have shown no clinical benefit, suggesting the need for predictive biomarkers to identify appropriate subgroups that may more likely benefit from this targeted therapy.
Cediranib (AZD2171) is a potent oral small molecule inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3 [11, 12] and also of c-kit, to a lesser extent . Cediranib has been investigated in clinical trials with multiple cancers including colorectal , lung [14, 15], ovarian  and renal  cancer, and glioblastoma [18, 19]. Cediranib has been reported to show activity in prostate cancer. Ryan et al.  reported a phase I trial that established a maximum tolerated dose of 20 mg with the dose-limiting toxicities of muscle weakness and hypertension. We conducted a phase II trial using cediranib 20 mg orally, once daily to assess the clinical efficacy and side-effect profile in patients with metastatic CRPC who have progressed after therapy with docetaxel. Previous studies have reported that serum PSA level has not been a dependable marker in assessing response using non-cytotoxic drugs [21, 22]. The present study used clinical and radiographical criteria to assess response. A second part of the study added prednisone in an attempt to limit the constitutional side effects that were associated with cediranib.
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A total of 59 patients were enrolled in the present study: 36 patients in the first cohort and 23 in the second cohort of the trial, between February 2007 and February 2010. The study demographics and baseline characteristics of all patients are shown in Table 1. Many patients had unfavourable prognostic factors, as evidenced by visceral disease, a high Gleason score at diagnosis, and previous treatment with two or more chemotherapy regimens. Eighteen patients (31%) had received previous treatment with at least one anti-angiogenic agent. The majority (n = 47) had an ECOG performance status of 1.
Table 1. Demographics and disease characteristics of enrolled patients (n = 59) patient demographics and clinical characteristics.
|Median (range) age, years||68.9 (51.4–79.8)|
|Race, n (%)|| |
|ECOG performance status, n (%)|| |
|Median (range) Gleason score at diagnosis||8 (4–10)|
|Gleason score at diagnosis, n (%)|| |
|PSA level during study, ng/mL|| |
|Median (range)||175.45 (4.94–1587)|
|Haemoglobin, g/dL|| |
|Median (range)||11.8 (6.7–14.9)|
|Lactate dehydrogenase, U/L|| |
|Median (range)||235.5 (124–3344)|
|Alkaline phosphatase, U/L|| |
|Median (range)||141 (46–1244)|
|Metastases, n (%)|| |
|Bone only||19 (33)|
|Soft tissue and bone||36 (62)|
|Pain at baseline, n (%)||40 (69)|
|Previous chemotherapy regimens, n (%)|| |
Of the 59 patients who were enrolled, 39 had measurable disease. One patient in the first cohort was not evaluable owing to the development of a cord compression on day 2 of therapy and was subsequently removed from the trial. Among those with measurable disease, six patients had confirmed partial responses and one had an unconfirmed partial response. The probability of PFS was 43.9% at 6 months. After a median potential follow-up of 33.5 months, nine patients of 58 evaluable patients remained alive as of the last follow-up. The median PFS was 3.6 months for the first cohort (n = 35) and 3.7 months for the second cohort (n = 23 [P = 0.79; data not shown]). The median PFS for all patients (n = 58) was 3.7 months (Fig. 1A). The median OS was 10.9 months for the first cohort and 9.6 months for the second cohort (P = 0.23; data not shown), and for the whole cohort of 58 patients it was 10.1 months (Fig. 1B).
Of the 59 patients enrolled in the study, 49 had DCE-MRI scans that were available for assessment: six patients were evaluated up to day 2, eight up to day 28, 16 up to day 56, 14 up to day 112, four up to day 224, and one up to day 448 (48 patients were evaluated on day 2, 43 on day 28, 33 on day 56, 18 on day 112, 5 on day 224, and one on days 336 and 448). A rapid reduction in the primary DCE-MRI variables Ktrans and iAUC60 was observed for the majority of patients within 24 h of the first dose (median reductions of 17.65 and 14.50%, respectively). The magnitude of change in either median Ktrans or iAUC60 observed after 28 days was greater overall than at 24 h (P = 0.001 and P = 0.015 respectively, Wilcoxon signed-rank test, n = 40). Based on previous studies with cediranib, we considered a >30% reduction in primary DCE-MRI variables to be representative of a positive pharmacodynamic response to anti-vascular therapy . After one cycle of therapy, 60% of patients experienced a vascular response with >30% reductions in Ktrans, where the mean reduction was 66%. Figure 2A shows the distribution of patients with minor to major reductions in DCE-MRI variables at day 28. Over 65% of patients experienced at least minor reductions from baseline in Ktrans and iAUC60, observed at the end of cycle 1. The proportion of patients with reductions in DCE-MRI variables began to decrease at 56 days after the initiation of therapy, for patients who remained on cediranib (data not shown).
Figure 2. A, The percent of patients, and reductions, (mean ± SD) in DCE-MRI variables after one cycle of therapy. B, The percent change in DCE-MRI variables during four cycles of cediranib therapy (median ± 95% CI). C, Maximum percent change in lesion volume through all cycles and maximum percent change during 1–2 cycles of cediranib therapy in 43 patients. Compound daily growth rate represents the maximum percent change normalized by 28 or 56 days on therapy.
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The change in vascular response to cediranib over the course of four cycles as percent reductions in DCE-MRI variables is shown in Fig. 2B. In the present study, the vascular response tended to reach a maximum at 28 days after initiation of treatment. The distribution of the largest percent change from baseline in lesion volume during 1–2 cycles of therapy is shown in Fig. 2C. Approximately 40% of patients had maximum lesion volume reductions of >25% (i.e. 28–84% decreases in lesion volume). The compound daily growth rate (%) is a more relative indicator for comparing patients who may have either fast or slow growth in lesion volume. For example, patients #1 and #4 in Fig. 3 had the same percent growth rate; however, patient #4 had a maximum reduction at 28 days compared with 56 days for patient #1. Also, the figure depicts only three patients who experienced maximum changes in lesion volume beyond two cycles (represented as spikes), for those patients who remained on therapy.
Figure 3. Kaplan–Meier estimates for PFS of patients with DCE-MRI variables. A, Ktrans (threshold defined as baseline Ktrans = 0.22). B, Kep (threshold defined as the post-therapy day 28 Kep = 0.35). Log rank P values shown have been adjusted for the effect of exploratory analyses used to determine the preferred quartile at which to divide the data for evaluation.
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The Ktrans, Kep and iAUC60 measurements at day 0 (baseline), day 28, and the difference between the day 28 and the day 0 measurements (day 28 – day 0), were evaluated for their association with tumour volume. There was no evidence of any association between change in tumour volume or relative change in volume and the DCE-MRI variables evaluated (data not shown). These same measurements were divided into quartiles and the relationship between these variables and PFS and OS was determined. When associations were identified, the data were re-divided at the quartile associated with a difference in the prognostic ability of the variables, and the association with outcome was re-determined. Only baseline Ktrans and Kep at day 28, divided as indicated, were found to be significantly associated with PFS in univariate analyses (Fig. 3), while none of the variables examined were significantly associated with OS. As shown in Table 2, using Cox hazards models for each variable individually, a baseline Ktrans > 0.22 was significantly associated with a lower probability of PFS than a Ktrans of <0.22 (P = 0.02), with a hazard ratio of 3.26 (95% CI: 1.22–8.76). A Kep at day 28 of >0.35 was associated with significantly lower probability of PFS than a Kep of <0.35 (P = 0.02), with a hazard ratio of 2.40 (95% CI: 1.14–5.03). When the two DCE-MRI variables were considered jointly, Kep at day 28 lost its significance in the presence of baseline Ktrans.
Table 2. Cox model analysis for the individual effects of baseline Ktrans < 0.22 vs >0.22, Kep at day 28 < 0.35 vs >0.35, and for the joint effects of these variables.
|Variable||DF||Parameter estimate||se||Chi-square||Pr > Chi-square||HR||95% HR CI|
|Ktrans at day 0||1||0.874||0.378||5.340||0.021||2.396||1.142–5.029|
|Kep at day 28||1||1.182||0.504||5.506||0.019||3.262||1.215–8.759|
|Joint effect of the parameters|| || || || || || || |
|Ktrans at day 0||1||1.389||0.695||3.990||0.046||4.011||1.026–15.672|
|Kep at day 28||1||0.348||0.432||0.648||0.42||1.417||0.607–3.306|
All patients who received treatment were analysed for toxicity. Patients received a median (range) of 3 (<1–16) cycles. Of the 58 patients, 30 (52%) discontinued therapy because of disease progression, 10 (17%) owing to toxicity, and 16 (28%) as a result of the physician's or the patient's own decision, but were not required by the protocol to discontinue. One patient discontinued therapy because of intercurrent illness not related to prostate cancer and one patient died during treatment from a cerebral haemorrhage complicated by disseminated intravascular coagulation. Protocol-required dose reductions for the management of cediranib toxicity were necessary for five patients.
Table 3AA shows the most common grade 2 toxicities that occurred in >10% of patients and all grade 3 and 4 toxicities. Significant grade 2 adverse events included hypertension (43%), fatigue (33%), anorexia (31%) and weight loss (27%). The intensity of these events was usually mild to moderate. Most side effects were of short duration and resolved without incident. Severe grade 3 toxicities included fatigue (10%), dehydration (10%), elevated alkaline phosphatase (9%) and muscle weakness (7%). There was a low overall incidence of Common Toxicity Criteria grade 4 toxicity that included thrombosis/embolism (n = 2) and CNS haemorrhage (n = 1). The addition of prednisone in the second stage of the study reduced the overall incidence of grade 2 constitutional toxicities of fatigue (43% in cohort 1 vs 17% in cohort 2), anorexia (34% in cohort 1 vs 26% in cohort 2), and weight loss (31% in cohort 1 vs 17% in cohort 2) as well as grade 2 dehydration, grade 2 prolonged QTc, and grade 3 elevated alkaline phosphatase (Table 3BB).
Table 3A. NCI Common Toxicity Criteria grade 2, 3 or 4 toxicities possibly, probably or definitely related to cediranib.
|Toxicity*||Grade 2 n (%)||Grade 3 n (%)||Grade 4 n (%)|
|Hypertension||25 (43)||0 (0)||0 (0)|
|Fatigue||19 (33)||6 (10)||0 (0)|
|Anorexia||18 (31)||2 (3)||0 (0)|
|Weight loss||15 (27)||2 (3)||0 (0)|
|Hypothyroidism||13 (22)||0 (0)||0 (0)|
|Dehydration||10 (17)||6 (10)||0 (0)|
|Prolonged QTc||10 (17)||2 (3)||0 (0)|
|Nausea||10 (17)||1 (2)||0 (0)|
|Diarrhoea||8 (14)||0 (0)||0 (0)|
|Hypoalbuminaemia||8 (14)||0 (0)||0 (0)|
|Proteinuria||8 (14)||0 (0)||0 (0)|
|Elevated alkaline phosphatase||6 (10)||5 (9)||0 (0)|
|AST||6 (10)||2 (3)||0 (0)|
|Vomiting||6 (10)||1 (2)||0 (0)|
|Hyperbilirubinemia||5 (9)||1 (2)||0 (0)|
|Muscle weakness||3 (5)||4 (7)||0 (0)|
|Haemoglobin, anaemia||3 (5)||1 (2)||0 (0)|
|Lymphopenia||2 (3)||3 (5)||0 (0)|
|Platelets||2 (3)||1 (2)||0 (0)|
|Alanine transaminase||2 (3)||1 (2)||0 (0)|
|Pain||1 (2)||2 (3)||0 (0)|
|Hypoxia||0 (0)||2 (3)||0 (0)|
|Thrombosis/embolism||0 (0)||1 (2)||2 (3)|
|Hyponatremia||0 (0)||1 (2)||0 (0)|
|Renal failure||0 (0)||1 (2)||0 (0)|
|Hypokalemia||0 (0)||1 (2)||0 (0)|
|Partial thromoboplastin time||0 (0)||1 (2)||0 (0)|
|CNS haemorrhage||0 (0)||0 (0)||1 (2)|
Table 3B. Number of toxicities in each cohort.
|Toxicity||Cohort 1 (n = 35)||Cohort 2 (n = 23)|
|Grade 2||Grade 3||Grade 2||Grade 3|
|Elevated alkaline phosphatase||4||5||2||0|
A total of 38 patients had echocardiograms. The median (range) ejection fraction on study entry was 65 (43–79)%. No patient had any clinical signs or symptoms of congestive heart failure and there were no clinically significant decreases in ejection fraction.
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Cediranib has been shown to inhibit the growth of bone and brain metastases in a preclinical model of advanced prostate cancer . A phase I study of cediranib was previously conducted in 83 patients with advanced solid tumours, with the primary objective of determining the maximum tolerated dose. The most common dose-limiting toxicity was hypertension (n = 7) occurring at doses of ≥20 mg . A separate phase I dose-escalation study was performed in patients with CRPC and showed good tolerability overall and an acceptable cediranib toxicity profile when given at therapeutic doses . Doses of 1, 2.5, 5, 10, 15, 20 and 30 mg were administered to 26 patients. Dose-limiting toxicities occurred at the 30 mg dose and the maximum tolerated dose was identified as 20 mg. Although safety, tolerability and DCE-MRI pharmacodynamic responses were the main objectives of the phase I study, an objective clinical response was observed in one patient whereas four patients experienced PSA level reductions after drug discontinuation.
In the current phase II study of patients with metastatic CRPC who have progressed after docetaxel therapy, cediranib, given at 20 mg daily, was generally well tolerated. The primary objective of the present study was met, as the probability of remaining progression-free at 6 months was 43.9%. The most common adverse events reported were hypertension, fatigue, anorexia and weight loss. Unlike Ryan et al. , we did not observe any grade 3 hypertension at the 20 mg dose in the present study. The most common grade 3 toxicities included fatigue, dehydration and elevated alkaline phosphatase. Grade 3/4 hromboembolism was observed in three patients and one patient experienced a grade 4 CNS haemorrhage that resulted in death. The addition of prednisone in the second cohort reduced the overall incidence of constitutional toxicities.
Until recently, life-prolonging therapies for patients with metastatic CRPC were limited to docetaxel-based regimens , which received US Food and Drug Administration (FDA) approval in 2004 as first-line chemotherapy for metastatic CRPC, whereas mitoxantrone had previously been approved based on improvements in quality of life . In 2010–2011, three more FDA-approved therapies were added to the CRPC treatment armamentarium: the autologous cellular immunotherapy product sipuleucel-T (indicated for men with minimal or no symptoms) , the chemotherapy agent cabazitaxel  and the targeted therapy abiraterone acetate (indicated for men with disease progression after docetaxel chemotherapy) . Although it appears that treatment options for patients with metastatic CRPC have increased and outcomes have improved, specifically for those in the post-docetaxel setting, the duration of PFS and OS still remains relatively short.
The median OS for the current study involving cediranib was 10.1 months and was shorter than that reported for phase III trials involving cabazitaxel (OS = 15.1 months)  or abiraterone (OS = 14.8 months) ; however, direct comparisons among the three studies should be tempered by the fact that patients in the present study were exposed to more previous chemotherapy regimens, thereby potentially affecting the benefit derived from cediranib. Although all three studies evaluated patients who had already had progressive disease after docetaxel, the majority of patients (67%) in present study of cederanib had undergone more than two previous chemotherapy regimens, including 31% who had undergone three or more. Patients in the abiraterone phase III trial were limited to only two previous chemotherapy regimens with only 30% of these patients having had more than one cytotoxic therapy . Similarly, only 15% of patients enrolled in the cabazitaxel phase III trial had had exposure to more than one previous chemotherapy regimen .
The present study used DCE-MRI to investigate the effect of once-daily 20 mg dosing on tumour vascular permeability. The primary DCE-MRI variables iAUC60 and Ktrans revealed rapid and sustained reductions from baseline up to two or more cycles in the majority of patients. The results support the hypothesis that cediranib has effects on tumour vasculature, as evidenced by statistically significant reductions in gadolinium uptake, by as much as 97%, and across large proportions of patients in the study. Moreover, vascular permeability and perfusion of gadolinium remained decreased up to day 112; however, no correlation was found between RECIST and changes in DCE-MRI primary or exploratory variables. High baseline Ktrans and post-therapy (day 28) Kep were found to be significantly associated with PFS, indicating that DCE-MRI variables may prove effective as pharmacodynamic predictive biomarkers of clinical outcome for cediranib, as previously shown for sorafenib [34, 35]. The clinical relevance of these findings and their predictive value remain to be determined and validated prospectively, especially given the recent studies showing higher morbidity in patients receiving anti-angiogenic therapy .
Although targeting angiogenesis appears to be a rational therapeutic approach for CRPC, there are still major obstacles to identifying the appropriate subgroups that may benefit more from these agents. Monotherapy with sunitinib, another small molecule tyrosine kinase inhibitor, despite supportive phase II data in patients with progressive metastatic CRPC after docetaxel treatment , recently failed in a phase III trial of the same patient population . It would be reasonable to expect that the use of angiogenesis inhibitors in combination with chemotherapy would prove to be more efficacious than monotherapy with anti-angiogenic agents; however, results from another recent phase III study showed that the addition of bevacizumab may add little clinical benefit in OS to docetaxel in chemotherapy-naïve patients with CRPC . The role that anti-angiogenic agents have in docetaxel-refractory mCRPC remains to be determined with the most promising candidate being cabozantinib, an oral small molecule inhibitor of multiple kinase signalling pathways including c-MET and VEGFR2. A phase II study investigating the use of cediranib in combination with or without dasatinib, an oral Src family kinase inhibitor, in patients with docetaxel-refractory metastatic CRPC is currently underway (clinicaltrials.gov identifier NCT01260688) as well as a phase II study of docetaxel with or without cediranib in chemotherapy-naïve patients with CRPC (NCT00527124). The challenge lies in how to best combine these agents and how to measure the responses seen with these treatments.
In conclusion, this phase II study showed that cediranib, 20 mg daily, in 58 patients with docetaxel-refractory metastatic CRPC, results in perturbations in tumour vasculature, >30% PFS at 6 months, and a median OS of 10.1 months. There remains a clear need to define the most appropriate treatment approach for patients with metastatic CRPC in light of new second-line treatment options becoming available, especially those who have progressive disease after docetaxel therapy. Future studies will need to focus on determining the optimum sequence and combination of new anti-angiogenics and other investigational agents with conventional chemotherapy. Further investigation into the potential predictive value of DCE-MRI parameters as biomarkers for anti-angiogenic therapy is warranted.
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We thank the nursing staff of the NCI and the fellows of the Medical Oncology Branch at the NCI for their care of our patients, Cynthia Graves for data management assistance, and the Cancer Therapy and Evaluation Program for sponsoring the trial. Most importantly, we appreciate the patients with cancer who enrol in investigational trials to advance the knowledge of this disease.
This project was funded in whole or in part with federal funds from the NCI, National Institutes of Health, under Contract No. HHSN261200800001E (SDS). This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. Trial Registration ID: NCT00436956 This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government.