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Objective To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy. Patients and Methods The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months. We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily. In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib. Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity. Results A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens. Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response. At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively. We found that the DCE-MRI variables baseline transport constant (Ktrans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly. The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities. Conclusion This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy. Keywords: castration-resistant prostate cancer, angiogenesis inhibitors, cediranib, AZD2171 Introduction Prostate cancer is the most common non-dermatological cancer in men and has the second highest cancer-related death rates in men [1]. 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 [7]. While targeting angiogenesis appears to be a rational and therapeutic approach for CRPC [8), recent phase III trial results of VEGF pathway inhibitors bevacizumab [9] and sunitinib [10] 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 [12]. Cediranib has been investigated in clinical trials with multiple cancers including colorectal [13], lung [14, 15], ovarian [16] and renal [17] cancer, and glioblastoma [18, 19]. Cediranib has been reported to show activity in prostate cancer. Ryan et al. [20] 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.

To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy.The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months. We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily. In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib. Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity.A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens. Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response. At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively. We found that the DCE-MRI variables baseline transport constant (Ktrans ) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly. The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities.This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy.