Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer

What's known on the subject? and What does the study add? Recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC) have resulted in improved outcomes; however, the effects have not proved to be long term, highlighting the need for new therapies, particularly in patients with docetaxel-refractory metastatic CRPC. Angiogenesis has been shown to play an important role in the development and progression of prostate cancer. Although targeting angiogenesis appears to be a rational and therapeutic approach for metastatic CRPC, identifying the appropriate subgroups that may benefit from anti-angiogenic therapy remains a challenge. The study demonstrates the potential use of dynamic contrast-enhanced (DCE)-MRI variables as pharmacodynamic endpoints in predicting the clinical outcomes associated with anti-angiogenic agents such as cediranib. Further investigation into the potential predictive value of DCE-MRI variables as biomarkers for antiangiogenic therapy is warranted. 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 (K_trans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline K_trans 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.