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Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL., Methods: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m 2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m 2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m 2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment., Findings: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B)., Interpretation: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL., Funding: BeiGene., Competing Interests: Declaration of interests CST reports receiving funding from AbbVie and Janssen; and honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, outside the submitted work. JRB reports receiving funding from Gilead, Lilly–LOXO, TG Therapeutics, Verastem–SecuraBio, and Sun; consulting fees from AbbVie, Acerta–AstraZeneca, BeiGene, Bristol Myers Squibb–Juno–Celgene, Catapult Therapeutics, Dynamo Therapeutics, Eli Lilly, Genentech/Roche, Gilead, Janssen, Kite, LOXO, MEI Pharma, MorphoSys, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Rigel, Sunesis, TG Therapeutics, and Verastem; honoraria from Janssen; and participation on an advisory board for Invectys and MorphoSys, outside of the submitted work. BSK reports receiving funding from BeiGene paid to Washington University School of Medicine (St Louis, MO, USA), and receiving consulting fees from AbbVie, AstraZeneca, BeiGene, Janssen, and Pharmacyclics, outside the submitted work. PG reports receiving funding from BeiGene with regards to the submitted work; funding from AbbVie, AstraZeneca, Janssen, Gilead, Novartis, and Sunesis; consulting fees from and participating on an advisory board for AbbVie, AstraZeneca, ArQule–MSD, Celgene–Juno–Bristol Myers Squibb, Janssen, Lilly–LOXO, and Roche; and receiving honoraria from AbbVie, AstraZeneca, Janssen, and MSD, outside the submitted work. KG reports receiving consulting fees and honoraria from BeiGene, with regards to the submitted work; funding from AbbVie, Amgen, AstraZeneca, Janssen, Novartis, Roche, Sanofi-Genzyme, and Takeda and paid to the Next Generation Hematology Association; receiving consulting fees from GSK and Sandoz; receiving honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Gilead, GSK, Janssen, Karyopharm, Novartis, Pfizer, Roche, Sandoz, Takeda, and Teva; receiving financial support for attending meetings or travel, or both, from Janssen, Roche, and Sanofi-Genzyme; participating on an advisory board for AbbVie, Amgen, AstraZeneca, Gilead, GSK, Janssen, Novartis, Roche, Sandoz, and Takeda; and a leadership role at the Next Generation Hematology Association, outside the submitted work. WJ reports receiving funding from BeiGene and Janssen, with regards to the submitted work, and funding from AstraZeneca and TG Therapeutics, outside the submitted work. MŠ reports receiving consulting fees from AbbVie and AstraZeneca; receiving honoraria from AbbVie and Janssen-Cilag; participating on an advisory board for AbbVie, AstraZeneca, and Janssen-Cilag; and stock or stock options, or both, from AbbVie, AstraZeneca, Eli Lilly, Johnson & Johnson, and Merck, outside the submitted work. MS reports receiving funding from BeiGene paid to Fred Hutchinson Cancer Research Center and the University of Washington (Seattle, WA, USA), with regards to the submitted work; funding from AbbVie, AstraZeneca, Atara Biotherapeutics, BeiGene, GenMab, Genentech, Gilead, Mustang Bio, Bristol Myers Squibb, Celgene, Pharmacyclics, Sunesis, and TG Therapeutics; and receiving consulting fees from AbbVie, Adaptimmune, Adaptive Biotechnologies, AstraZeneca, Atara Biotherapeutics, BeiGene, Bristol Myers Squibb, Eli Lilly, Epizyme, Genentech, InnatePharma, Kite Pharma, MorphoSys, Mustang Bio, Pharmacyclics, Sound Biologics, and TG Therapeutics, outside the submitted work. PW reports receiving consulting fees from Acerta and BeiGene, outside the submitted work. SO reports receiving funding from BeiGene paid to Monash University (Clayton, VIC, Australia), with regards to the submitted work; and honoraria and participating on an advisory board for BeiGene, outside the submitted work. HCh reports receiving financial support for attending meetings or travel, or both, from Celgene and Janssen, and participating on an advisory board for AbbVie, Eusa, and Janssen, outside the submitted work. RG reports receiving consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, and Takeda; honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Merck, MSD, Novartis, Roche, Takeda, and Sandoz; financial support for attending meetings or travel, or both, from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, MSD, Novartis, and Roche; and participating on an advisory board for AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, and Takeda, outside the submitted work. MTr reports receiving consulting fees from AbbVie, Amgen, Janssen, Bristol Myers Squibb, Gilead Sciences, Incyte, MorphoSys, Novartis, Roche, Takeda; receiving honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Roche, MorphoSys, Novartis, Portolla, and Takeda; receiving financial support for attending meetings or travel, or both, from AbbVie, Bristol Myers Squibb, Gilead, Janssen, Roche, and Takeda; participating on an advisory board for AbbVie, Bristol Myers Squibb, Incyte, Janssen, MorphoSys, Novartis, Portolla, Roche, and Takeda; and employment at Charles University General Hospital in Prague, outside the submitted work. DMB reports receiving funding from AbbVie, ArQule, Ascentage, AstraZeneca, BeiGene, DTRM, Genetech, Juno–Celgene–Bristol Myers Squibb, LOXO, MEI Pharma, Novaris, Pharmacyclics, and TG Therapeutics; receiving consulting fees from AbbVie, Genentech, Pharmacyclics, Pfizer, TG Therapeutics, and Verastem; participating on an advisory board for AbbVie, Genentech, Novartis, Pharmacyclics, Pfizer, TG Therapeutics, and Verastem; and a leadership role with NCCN (panel member), informCLL registry (steering committee; AbbVie), and Biosimilars outcomes research panel (Pfizer), outside the submitted work. IWF reports receiving funding from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, LOXO, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development, Unum Therapeutics, and Verastem, paid to the Sarah Cannon Research Institute; and consulting fees from AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, and Yingli Pharmaceuticals, paid to the Sarah Cannon Research Institute, outside the submitted work. AT reports receiving consulting fees from AbbVie, AstraZeneca, BeiGene, and Janssen; and honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen, outside the submitted work. TT, LZ, CM, JCP, and AC are employees of BeiGene, with regards to the submitted work, and report stocks or stock options, or both, from BeiGene, outside the submitted work. JH is an employee of BeiGene, with regards to the submitted work; reports receiving royalties from BeiGene; receiving financial support for attending meetings or travel, or both, from BeiGene and Protara; patents with BeiGene; a leadership role with BeiGene and Protara; and stock or stock options, or both, from BeiGene and Protara, outside the submitted work. TR reports receiving funding from BeiGene, with regards to the submitted work; receiving funding from AbbVie, AstraZeneca, Janssen, and Roche; and participating on an advisory board for AbbVie, AstraZeneca, BeiGene, Janssen, and Roche. PH reports receiving funding from AbbVie, Gilead, Janssen, Pharmacyclics, and Roche; honoraria from AbbVie, AstraZeneca, BeiGene, Janssen, Pharmacyclics, and SOBI; and financial support for attending meetings or travel, or both, from AbbVie and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)