Background: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials., Methods: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete., Findings: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups., Interpretation: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis., Funding: Melinta Therapeutics and Cidara Therapeutics., Competing Interests: Declaration of interests AFD reports consulting fees from Cidara. AS reports a grant from Gilead Sciences and, outside of the submitted work, grant from Pfizer; consulting fees and honoraria from Angelini, Gilead, Menarini, MSD, Pfizer, and Shionogi; and support for attending meetings from Pfizer. BJK reports independent data review committee membership for Cidara. GRT reports grants and consulting fees from Astellas, Cidara, F2G, Mayne, Mundipharma, and Scynexis. JAA reports being an employee of Melinta Therapeutics. JAV reports grants from Cidara and Scynexis; consulting fees from Cidara and F2G; and data safety monitoring board or advisory board participation for F2G and Scynexis, outside of the submitted work. JPH reports consulting fees from Angelini, Menarini, MSD, Pfizer, Tillots, and Zambon; honoraria from Angelini, Menarini, and Pfizer; support for attending meetings from MSD and Pfizer; and data safety monitoring board or advisory board participation for TFT Pharmaceuticals, outside of the submitted work. MB reports honoraria from, and data safety monitoring board or advisory board membership for, Angelini, Astellas, Bayer, Biomerieux, Cidara, Gilead, Menarini, MSD, Nabriva, and Shionogi, outside of the submitted work. MH reports grants from Cidara; and outside of the submitted work, honoraria from Gilead and Pfizer; support for attending meetings from Gilead, MSD, and Pfizer; and is President of the Belgian Society of Infectious Diseases. MK reports a grant from Barnes-Jewish Hospital Foundation, and data safety monitoring board or advisory board membership for Melinta Therapeutics, outside of the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, and Seres; honoraria from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); data safety monitoring board or advisory board participation for Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group; stocks from CoRe Consulting and EasyRadiology; and other interests with Wiley (Editor-in-Chief for Mycoses), outside of the submitted work. PGP reports grants from Cidara and Scynexis; consulting fees from Cidara; and data safety monitoring board or advisory board participation for Cidara, outside of the submitted work. PMH reports grants or contracts from Baxter, Cytosorbents, and Pfizer; consulting fees from Baxter, Cytosorbents, and Pfizer; honoraria from Baxter and Cytosorbents; and support for attending meetings from Mundipharma and Pfizer, outside of the submitted work. TS reports being an employee of Cidara Therapeutics; and, outside of the submitted work, reports being a shareholder in Cidara Therapeutics. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)