Background: Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice., Methods: REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies., Findings: Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures., Interpretation: REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024., Funding: Bayer HealthCare., Competing Interests: All authors report support for the present manuscript from Bayer for medical writing funding to Open Health. Celestia S. Higano reports support for the present manuscript from Bayer for clinical trial funding to institution; grants or contracts from AbbVie (Contract to develop unbranded educational slide set), Vaccitech (Clinical trial consulting contract, no payments yet), and Verity; consulting fees from the Prostate Cancer Clinical Trials Consortium (Consulting PCCCTC medical monitor for trials sponsored by ESSA and Bayer), Prostate Cancer Supportive Care Program (Consulting Medical Director), and Astellas, AstraZeneca, Ferring, Genentech, Merck Sharp & Dohme, Myovant, Pfizer, Tolmar, and Vaccitech (all advisory boards); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tolmar (medical writing); payment for expert testimony from Ferring; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Exelixis, Advantagene/Candel, and Alliance Foundation (all DSMBs). Daniel J. George reports grants or contracts from Astellas, AstraZeneca, BMS, Calithera, Exelixis, J&J, Pfizer, Novartis, and Sanofi (all paid to his institution); royalties or licenses from Up-to-Date (paid to self); consulting fees from Bayer, Ideo Oncology, Merck, Michael J Hennessey, Myovant, Propella, RevHealth, Seattle Genetics, WebMD, and Xcures (all paid to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, Exelixis, and Sanofi (all paid to self); payment for expert testimony from Wilmer Hale (paid to self); support for attending meetings and/or travel from Bayer, Exelixis, and Sanofi (paid to self); participation on a Data Safety Monitoring Board or Advisory Board for Janssen and AstraZeneca (both paid to self); and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for AACR (senior editor), Millennium Med Pub, and CAHO (Co-Editor-in-Chief) (all paid to self). Neal D. Shore reports consulting fees from AbbVie, Alessa Therapeutics, Akido, Arquer, Asieris, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clarity, Cold Genesys, Dendreon, Exact Images, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Photocure, Pfizer, PlatformQ, Profound, Promaxo, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar, Vaxiion; payment for expert testimony from Ferring. Oliver Sartor reports grants or contracts from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio; consulting fees from Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien, Merck, Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., NorthStar, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien, Merck, Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., NorthStar, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics; patents planned, issued or pending: Koochekpour, Sartor AO, inventors. Saposin C and receptors as targets for treatment of benign and malignant disorders. US patent awarded January 23, 2007 (patent no. 7,166,691); participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Jannsen, Pfizer, and Myovant; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Louisiana Cancer Research Consortium – Board, LA. Cancer and Lung Trust; and stock or stock options in Clarity Pharmaceuticals, Noria Therapeutics, Inc., Lilly, Clovis, Glaxo Smith Kline, Abbvie, Cardinal Health, and United Health Group. Kurt Miller reports consulting fees from Accord, Janssen, Novartis, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Accord, Janssen, Novartis, Pfizer, and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Myovant. Peter S. Conti reports no other conflicts to declare. Cora N. Sternberg reports consulting fees from Pfizer, MSD, AZ, Astellas, Sanofi, Genzyme, Roche-Genentech, BMS, Bayer, Foundation Medicine, Gilead, Medscape, UroToday, CCN Clinical, Janssen, NCI (all ad boards over at least 5 years). Fred Saad reports grants or contracts from Astellas, AstraZeneca, Janssen, Myovant, Merck, Novartis, Sanofi, and Pfizer (payment to institution); consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Myovant, Merck, Novartis, Sanofi, Pfizer, Tolmar (payment to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Myovant, Merck, Novartis, Sanofi, Pfizer, Tolmar (payment to self). Juan Pablo Sade reports no other conflicts to declare. Joaquim Bellmunt reports royalties or licenses from UpToDate; consulting fees from Pfizer/MSD, Genentech, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer/MSD, Genentech, AstraZeneca, and Merck; support for attending meetings and/or travel from Pfizer; participation on a Data Safety Monitoring Board or Advisory Board from Pfizer/MSD, Genentech, AstraZeneca, and Merck. Matthew R. Smith reports grants or contracts from Bayer for the present study (paid to self and institution) and from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to institution); consulting fees from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to self); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bayer, Janssen, Lilly, and Pfizer (all paid to self); and participation on a Data Safety Monitoring Board or Advisory Board for Bayer, Janssen, and Lilly (all paid to self). Kumari Chandrawansa reports stock or stock options in Bayer; other financial or non-financial interests: employee of Bayer. Per Sandström reports other financial or non-financial interests: employee of Bayer. Frank Verholen reports other financial or non-financial interests: employee of Bayer. Bertrand Tombal reports support for the present manuscript from Bayer (support of study); grants or contracts from Bayer (grant for studies); consulting fees from Astellas, Bayer, Novartis, Janssen, Accor, and MSD (all payments to his company: UROADVISE); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer (paid to his company: UROADVISE) and Astellas., (© 2023 Published by Elsevier Ltd.)