A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer

Abstract

BackgroundEndothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC.MethodsWe systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC. Meta-analysis was conducted by STATA version 12.0 software.ResultsEight RCTs were identified, involving 6,065 patients. The results of direct comparison showed that compared with placebo, there was no statistically significant difference in the improvement of progression-free survival (PFS), overall survival (OS), time to disease progression (TTP), and total adverse events (AEs) with ET-A receptor antagonist treatment for CRPC. The results of ET-A receptor antagonists plus docetaxel versus docetaxel alone were similar. The indirect comparisons showed that there were no significant differences between zibotentan plus docetaxel versus atrasentan plus docetaxel when compared with docetaxel alone or zibotentan versus atrasenta compared with placebo in the improvement of PFS, OS, TTP, and total adverse events.ConclusionsThere were no significant benefits for ET-A receptor antagonists with or without docetaxel in the improvement of PFS, OS, TTP, and overall AEs. And there were no significant differences between zibotentan and atrasentan. Single-agent docetaxel should remain as one of the standard treatments.

Non‐Adrenergic, Tamsulosin‐Insensitive Smooth Muscle Contraction is Sufficient to Replace α1‐Adrenergic Tension in the Human Prostate

“…Although the role of endothelin-1 for smooth muscle tone in the lower urinary tract has been recognized, endothelin receptor antagonists did not proceed beyond the preclinical stage for LUTS treatment [48,49]. Meanwhile, they are tested for treatment of prostate cancer in clinical phase III studies [50].…”

Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia

“…The authors cite the following reason: “serious adverse events … due to the necessity of endothelin … to maintain the equilibrium of multiple physiological processes.” In our view, this rationale could also apply to the situation after ETA blockade in BPH/LUTS patients. Missing benefit of endothelin receptor blockers in prostatic cancer patients has been also documented in a recently published meta‐analysis . To overcome unconvincing patient benefit after ETA blockade among scleroderma patients, it was suggested that “therapies that specifically target autoantibodies against ETA could be a promising approach” .…”

Cancer and the metastatic substrate

“…These are divided into three categories: 1) epithelial cells, whose treatment is based on the use of cytotoxic agents such as docetaxel and cabazitaxel [75, 76]; 2) stroma cells which include endothelial, osteoblastic, and osteoclastic cells. The cytotoxics used are thalidomide which is an anti-angiogenic [77]; bevacizuman, a monoclonal antibody against VEGF-A [78]; antrasentan, an osteoblast proliferation inhibitor [79]; denosumab, a monoclonal antibody against RANKL; the activating receptor ligand for the nuclear factor ϰB [80]; zoledronic acid, belongs to the group of bisphonates which inhibit the action of the osteoclasts in the prostate carcinoma cells and encourage an increase in bone density [81, 82]; 3) block the androgen receptor activation or AR which is expressed both in the prostate carcinoma cells and the microenvironment cells. For this purpose abiraterone is used which suppresses testosterone production [83], and MDV3100 or enzalutamide, an androgen receptor antagonist or AR, which blocks signalling as it inhibits its translocation to the nucleus and prevents binding to the DNA [84].…”