{"doi":"10.1093/ndt/gfac342","title":"Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents—<i>post hoc</i> analyses of the ASCEND-ND and ASCEND-D trials","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).","journal":"Nephrology Dialysis Transplantation","year":2022,"id":273501,"datarank":0.7673320850136759,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.39459608754547576,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.39459608754547576,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":9,"citers_with_citation_signal":9,"citers_with_endowment":9,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9338,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02876835","NCT02879305"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":463302,"name":"Finnian R. 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McMurray","orcid":"0000-0002-6317-3975","position":8,"is_corresponding":false},{"id":266928,"name":"Janet Wittes","orcid":"0000-0002-6625-835X","position":9,"is_corresponding":false},{"id":29452,"name":"Steven Snapinn","orcid":"0000-0002-2961-8774","position":10,"is_corresponding":false},{"id":941530,"name":"Allison Blackorby","orcid":null,"position":11,"is_corresponding":false},{"id":940981,"name":"Amy M. Meadowcroft","orcid":"0000-0002-5934-0136","position":12,"is_corresponding":false},{"id":941531,"name":"Tara Barker","orcid":null,"position":13,"is_corresponding":false},{"id":941532,"name":"Tara DiMino","orcid":null,"position":14,"is_corresponding":false},{"id":940982,"name":"Stephen Mallett","orcid":"0000-0003-1053-958X","position":15,"is_corresponding":false},{"id":941533,"name":"Alexander R. Cobitz","orcid":null,"position":16,"is_corresponding":false},{"id":27970,"name":"Scott D. 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