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

Nephrol Dial Transplant. 2023 Jul 31;38(8):1890-1897. doi: 10.1093/ndt/gfac342.

Abstract

Background: 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).

Methods: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (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 + 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 last dose date, last dose date + dosing intervals, or end of study).

Results: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.

Conclusions: 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.

Trial registration: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Keywords: anaemia; cancer; chronic kidney disease; prolyl-hydroxylase inhibitor; safety.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Darbepoetin alfa / adverse effects
  • Erythropoiesis
  • Erythropoietin* / adverse effects
  • Hematinics* / adverse effects
  • Hemoglobins
  • Humans
  • Neoplasms* / chemically induced
  • Neoplasms* / complications
  • Neoplasms* / epidemiology
  • Renal Dialysis
  • Renal Insufficiency, Chronic* / drug therapy

Substances

  • Hematinics
  • Erythropoietin
  • GSK1278863
  • Darbepoetin alfa
  • Hemoglobins

Associated data

  • ClinicalTrials.gov/NCT02876835
  • ClinicalTrials.gov/NCT02879305