Abstract C9: Utility of serological apoptosis biomarkers: Assessment in a phase II study of zibotentan (ZD4054) in patients with hormone-resistant prostate cancer

Abstract

Abstract Serological apoptosis biomarkers, cytokeratin-18 (M65), cleaved cytokeratin 18 (M30) and nucleosomal DNA (nDNA) are frequently elevated above normal levels in patients with various cancers and are considered to reflect tumor burden.1 Moreover, these biomarkers appear to be dynamically modulated by cytotoxic therapy capable of inducing tumor response.2–4 We retrospectively investigated whether a non-cytotoxic agent, zibotentan, had any impact on serological levels of these apoptosis biomarkers. Zibotentan has shown survival benefit in hormone-resistant prostate cancer (HRPC) patients despite the lack of RECIST based responses.5 Serological samples were obtained from consented patients before the start and at 12 weeks after the assigned randomized treatment (placebo, zibotentan 10 or 15 mg daily oral doses) and were processed for M30, M65 and nDNA concentrations. Approximately 59% (N=184) and 42% (N=82) of the study intent to treat population (N=312 and N=195) had M30 values at baseline and at week 12, respectively. Similar numbers of M65 and nDNA values were available for analysis. No consistent dose-related trends in mean percentage change from baseline or at 12 weeks were observed for any of the biomarkers. However, there were trends towards reductions for M30 in patients receiving zibotentan 10 mg (−11%, 95% confidence interval [CI] −24%, +6%) and for nDNA in patients receiving zibotentan 15 mg (−15%, 95% CI −44%, +30%). Applying a Cox proportional hazards regression model for overall survival (OS) and including a treatment factor and baseline covariates, stratifying the apoptosis biomarkers on the basis of ‘high’ or ‘low’ concentrations (based on median baseline values) revealed a statistically significant difference for OS ± M65 (P value = <0.001). M30 and nDNA were without significant relationship. The M65 data suggest a potential utility for this marker in prognosis. Further evaluation of the clinical relevance of these findings is warranted with access to a larger patient dataset. The ongoing phase III clinical trials for zibotentan in HRPC patients will provide this opportunity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C9.