Phase II clinical trial of cediranib in patients with metastatic castration‐resistant prostate cancer
Authors: Dahut William L. , Madan Ravi A. , Karakunnel Joyson J. , Adelberg David , Gulley James L. , Turkbey Ismail B. , Chau Cindy H. , Spencer Shawn D. , Mulquin Marcia , Wright John , Parnes Howard L. , Steinberg Seth M. , Choyke Peter L. , Figg William D. 
Published: February 2013

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 (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.