zibotentan and Prostatic-Neoplasms--Castration-Resistant

Endothelin 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.. We 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.. Eight 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.. There 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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Atrasentan; Disease-Free Survival; Docetaxel; Endothelin A Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pyrrolidines; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Recently, novel endothelins like zibotentan and atrasentan and other novel taxanes have been introduced to treat prostate cancer. This study reviews zibotentan in the treatment of castration-resistant prostate cancer (CRPC) and derives a more precise estimate of their effect of treatment.. Two reviewers searched and extracted data of the published trials and review articles on zibotentan for prostate cancer using the Medline, Embase and Cochrane Controlled Trials Register database. We used hazard ratios (HRs) to assess the effects on overall survival (OS), progression-free survival (PFS), or time to PSA progression (TTP), and relative risk (RR) for the different types of toxicity. Four randomized controlled trials were identified.. The pooled HR showed that zibotentan did not improve OS and PFS (HR = 0.92, 95%CI = 0.82-1.03, p = 0.161, HR = 0.98, 95% CI = 0.89-1.08, p = 0.714). Zibotentan had modest benefits on TTP (HR = 0.94, 95% CI = 0.91-0.97, p = 0.001). In addition, zibotentan led to more peripheral edema, anemia, cardiac failure and pneumonia.. Our study concludes that zibotentan is not an attractive option for CRPC patients. However, additional studies on other novel therapies are needed to improve patient outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pyrrolidines; Randomized Controlled Trials as Topic; Survival Analysis

Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC).. This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS).. Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73-1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71-1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group.. This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Double-Blind Method; Drug Administration Schedule; Edema; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Pyrrolidines; Treatment Outcome

Assessment of skeletal metastases' response to therapy is a highly relevant but unresolved clinical problem. The main goal of this work was to compare pharmacodynamic responses to therapy assessed with positron emission tomography-computed tomography (PET/CT) using fluorine-18 sodium fluoride (NaF) and fluorine-18 fluorodeoxyglucose (FDG) as the tracers.. Patients with prostate cancer with known osseous metastases were treated with zibotentan (ZD4054) and imaged with combined dynamic NaF/FDG PET/CT before therapy (baseline), after 4 weeks of therapy (week 4), and after 2 weeks of treatment break (week 6). Kinetic analysis allowed comparison of the voxel-based tracer uptake rate parameter Ki, the vasculature parameters K1 (measuring perfusion/permeability) and Vb (measuring vasculature fraction in the tissue), and the standardized uptake values (SUVs).. Correlations were high for the NaF and FDG peak uptake parameters (Ki and SUV correlations ranged from 0.57 to 0.88) and for vasculature parameters (K1 and Vb correlations ranged from 0.61 to 0.81). Correlation was low between the NaF and FDG week 4 Ki responses (ρ = 0.35; P = .084) but was higher for NaF and FDG week 6 Ki responses (ρ = 0.72; P < .0001). Correlations for vasculature responses were always low (ρ < 0.35). NaF and FDG uptakes in the osseous metastases were spatially dislocated, with overlap in the range from 0% to 80%.. This study found that late NaF and FDG uptake responses are consistently correlated but that earlier uptake responses and all vasculature responses can be unrelated. This study also confirmed that FDG and NaF uptakes are spatially dislocated. Although treatment responses assessed with NaF and FDG may be correlated, using both tracers provides additional information.

Topics: Aged; Aged, 80 and over; Bone Neoplasms; Clinical Trials, Phase III as Topic; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Positron-Emission Tomography; Prostatic Neoplasms, Castration-Resistant; Pyrrolidines; Sodium Fluoride; Tomography, X-Ray Computed; Treatment Outcome