Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents – post hoc analyses of the ASCEND-ND and ASCEND-D trials


 
 
 The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305).
 
 
 
 ASCEND-ND randomized 3 872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2 964 patients to daprodustat or conventional ESAs. In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date (LDD) +1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at LDD, LDD + dosing intervals, or end of study).
 
 
 
 In ASCEND-ND, the safety of daprodustat vs. darbepoetin on cancer-related AEs depended on the duration of follow-up after LDD: hazard ratio (HR) 1.04 (95%CI 0.77, 1.40) at end of study; HR 1.12 (95%CI 0.81, 1.56) for LDD + dosing interval; HR 1.50 (95%CI 1.04, 2.15) for LDD + 1 day. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.
 
 
 
 Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat.
