PMID- 36565721 OWN - NLM STAT- MEDLINE DCOM- 20230801 LR - 20231225 IS - 1460-2385 (Electronic) IS - 0931-0509 (Print) IS - 0931-0509 (Linking) VI - 38 IP - 8 DP - 2023 Jul 31 TI - 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. PG - 1890-1897 LID - 10.1093/ndt/gfac342 [doi] AB - 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). CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the ERA. FAU - Singh, Ajay K AU - Singh AK AD - Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. AD - Harvard Medical School, Boston, MA, USA. FAU - McCausland, Finnian R AU - McCausland FR AUID- ORCID: 0000-0002-0299-0533 AD - Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. AD - Harvard Medical School, Boston, MA, USA. FAU - Claggett, Brian L AU - Claggett BL AD - Harvard Medical School, Boston, MA, USA. AD - Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Wanner, Christoph AU - Wanner C AUID- ORCID: 0000-0001-9507-5301 AD - University Hospital of Wurzburg, Wurzburg, Germany. FAU - Wiecek, Andrzej AU - Wiecek A AD - Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland. FAU - Atkins, Michael B AU - Atkins MB AD - Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA. FAU - Carroll, Kevin AU - Carroll K AD - KJC Statistics, Cheshire, UK. FAU - Perkovic, Vlado AU - Perkovic V AD - Faculty of Medicine and Health, University of New South Wales, Sydney, Australia. FAU - McMurray, John J V AU - McMurray JJV AD - Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, Glasgow, University of Glasgow, UK. FAU - Wittes, Janet AU - Wittes J AUID- ORCID: 0000-0002-6625-835X AD - Wittes LLC, Washington DC, USA. FAU - Snapinn, Steven AU - Snapinn S AD - Seattle-Quilcene Biostatistics LLC, Seattle, WA, USA. FAU - Blackorby, Allison AU - Blackorby A AD - GlaxoSmithKline, Collegeville, PA, USA. FAU - Meadowcroft, Amy AU - Meadowcroft A AD - GlaxoSmithKline, Collegeville, PA, USA. FAU - Barker, Tara AU - Barker T AD - GlaxoSmithKline, Collegeville, PA, USA. FAU - DiMino, Tara AU - DiMino T AD - GlaxoSmithKline, Collegeville, PA, USA. FAU - Mallett, Stephen AU - Mallett S AD - GlaxoSmithKline, Brentford, London, UK. FAU - Cobitz, Alexander R AU - Cobitz AR AD - GlaxoSmithKline, Collegeville, PA, USA. FAU - Solomon, Scott D AU - Solomon SD AD - Harvard Medical School, Boston, MA, USA. AD - Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. LA - eng SI - ClinicalTrials.gov/NCT02876835 SI - ClinicalTrials.gov/NCT02879305 GR - R01 DK129749/DK/NIDDK NIH HHS/United States GR - R03 DK122240/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 RN - 0 (Hematinics) RN - 11096-26-7 (Erythropoietin) RN - 0 (GSK1278863) RN - 15UQ94PT4P (Darbepoetin alfa) RN - 0 (Hemoglobins) SB - IM MH - Humans MH - *Hematinics/adverse effects MH - *Erythropoietin/adverse effects MH - Erythropoiesis MH - Renal Dialysis MH - Darbepoetin alfa/adverse effects MH - *Neoplasms/complications/epidemiology/chemically induced MH - *Renal Insufficiency, Chronic/drug therapy MH - Hemoglobins PMC - PMC10387380 OTO - NOTNLM OT - anaemia OT - cancer OT - chronic kidney disease OT - prolyl-hydroxylase inhibitor OT - safety COIS- The results presented in this paper have not been published previously in whole or part, except in abstract format. A.K.S. reports consulting income from GSK, Bayer, Zydus and Nephrology Times. F.R.M.C. reports grant funding NIDDK (R03DK122240 and R01DK129749), research grants from Advanced Medical and Fifth Eye that are paid directly to his institution, and consulting fees from GSK, Advanced Medical and Zydus Therapeutics. B.L.C. reports consulting fees from AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia and Novartis. A.W. reports serving on the steering committee for the ASCEND program. M.B.A. has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pneuma, Leads, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Exelixis, Iovance, COTA, Idera, Agenus, Apexigen, Asher Bio, Neoleukin, AstraZeneca, Calithera, SeaGen, Sanofi and GSK. He reports research support to his institution from Bristol-Myers Squibb, Merck and Pfizer. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. K.C. reports consultancy fees from GlaxoSmithKline. V.P. reports consultancy agreements with AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen and Pfizer; Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier and Vitae. Research funding from Pfizer (supplied drug and seed funding for TESTING trial) and GlaxoSmithKline. Honoraria from AbbVie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Pfizer; Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Chinook, Durect, Eli Lilly, Gilead, Janssen, Merck, Mitsubishi, Tanabe, Mundipharma, Novartis, Novo Nordisk, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, and Vitae. A Scientific Advisor or Membership: serving/served on Steering Committees for trials funded by AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Retrophin. Other Interests/Relationships reported include: Board Director: George Clinical, George Institute, Garvan Institute, Mindgardens Network, Childrens Cancer Institute, Victor Chang Cardiac Research Institute. J.J.V.M. reports personal fees from Abbott, Hickma, Sun Pharmaceuticals and Servier, and that his employer received fees from Alnylam Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, Novartis, Pfizer and Theracos. J.W. reports that WCG, the company for which she worked at the time of preparing this manuscript, had contracts with many pharmaceutical companies. She receives consultancy fees from GlaxoSmithKline. She owns no stock in pharmaceutical companies. S.S. reports consultancy fees from Allogene, Equillium, GlaxoSmithKline and Nesos. A.B. is employed by and holds stock in GlaxoSmithKline. A.M. is employed by and holds stock in GlaxoSmithKline. T.B. is employed by and holds stock in GlaxoSmithKline. T.D. is employed by and holds stock in GlaxoSmithKline. S.M. is employed by and holds stock in GlaxoSmithKline. A.R.C. is employed by and holds stock in GlaxoSmithKline. S.D.S. reports research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos and US2.AI, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros and Puretech Health. EDAT- 2022/12/25 06:00 MHDA- 2023/08/01 06:45 PMCR- 2023/12/24 CRDT- 2022/12/24 19:06 PHST- 2022/08/12 00:00 [received] PHST- 2023/08/01 06:45 [medline] PHST- 2022/12/25 06:00 [pubmed] PHST- 2022/12/24 19:06 [entrez] PHST- 2023/12/24 00:00 [pmc-release] AID - 6960682 [pii] AID - gfac342 [pii] AID - 10.1093/ndt/gfac342 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2023 Jul 31;38(8):1890-1897. doi: 10.1093/ndt/gfac342.