Purpose: Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL)., Methods: Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS)., Results: Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients., Conclusion: In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events., Competing Interests: John C. ByrdStock and Other Ownership Interests: Vincerx PharmaHonoraria: Pharmacyclics, AstraZeneca, Novartis, Syndax, Trillium TherapeuticsConsulting or Advisory Role: Acerta Pharma, Janssen, Kura Oncology, Novartis, Syndax, AstraZenecaResearch Funding: Acerta Pharma, Pharmacyclics, ZencorPatents, Royalties, Other Intellectual Property: OSU PatentsTravel, Accommodations, Expenses: Gilead Sciences, Janssen, Novartis, Pharmacyclics, TG Therapeutics Peter HillmenHonoraria: Janssen, AbbVie, RocheResearch Funding: Janssen, Pharmacyclics, Roche, Gilead Sciences, AbbVieTravel, Accommodations, Expenses: Janssen, AbbVie Paolo GhiaHonoraria: AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, Juno/Celgene/Bristol Myers Squibb, MSD, Lilly, RocheConsulting or Advisory Role: AbbVie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, MSD, Lilly, RocheResearch Funding: AbbVie, Janssen Oncology, Gilead Sciences, Sunesis Pharmaceuticals, Novartis, AstraZeneca Arnon P. KaterConsulting or Advisory Role: Janssen Oncology, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb/Celgene, Lava TherapeuticsResearch Funding: Janssen Oncology, Roche/Genentech, Bristol Myers Squibb/Celgene, AbbVie, AstraZenecaTravel, Accommodations, Expenses: Acerta Pharma/AstraZeneca, Roche/Genentech Asher Chanan-KhanStock and Other Ownership Interests: Matthew & Asher Inc, NanoDev Therapeutics, STARTON TherapeuticsHonoraria: BeiGene, Ascentage PharmaResearch Funding: Ascentage PharmaPatents, Royalties, Other Intellectual Property: Patent on PSMB9 biomarker Richard R. FurmanHonoraria: Janssen, AstraZenecaConsulting or Advisory Role: Pharmacyclics, Janssen Biotech, Genentech/Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, SanofiResearch Funding: Acerta Pharma, TG TherapeuticsExpert Testimony: AbbVie, Janssen OncologyTravel, Accommodations, Expenses: TG Therapeutics, Janssen OncologyOther Relationship: Incyte, Janssen Biotech Susan O'BrienEmployment: University of California, IrvineHonoraria: Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Eisai, TG Therapeutics, Nova Research CompanyConsulting or Advisory Role: Amgen, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis PharmaceuticalsResearch Funding: Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, TG Therapeutics, Pharmacyclics, Kite, a Gilead company, Sunesis PharmaceuticalsTravel, Accommodations, Expenses: Celgene, Janssen, Gilead Sciences, Regeneron, Janssen Oncology Mustafa Nuri YenerelConsulting or Advisory Role: Pfizer, Alexion PharmaceuticalsSpeakers' Bureau: Janssen OncologyTravel, Accommodations, Expenses: Pfizer Arpad IllésConsulting or Advisory Role: Janssen, Takeda, Novartis, Pfizer, Roche, CelgeneResearch Funding: Takeda, Seattle GeneticsTravel, Accommodations, Expenses: Novartis, Janssen, Pfizer, Roche Neil KayConsulting or Advisory Role: MorphoSys, Celgene, Agios, CytomX Therapeutics, AstraZeneca, Pharmacyclics, DAVA Pharmaceuticals, Juno Therapeutics, Rigel, Oncotracker, Bristol Myers Squibb, AbbVie, Targeted Oncology, Acerta Pharma/AstraZeneca, MEI Pharma, Sunesis Pharmaceuticals, TG Therapeutics, Tolero Pharmaceuticals, Janssen Biotech, Genentech/AbbVieResearch Funding: Pharmacyclics/Janssen, Tolero Pharmaceuticals, Acerta Pharma, MEI Pharma, Celgene, Genentech, Sunesis Pharmaceuticals, AbbVie, TG Therapeutics, Bristol Myers Squibb Jose A. Garcia-MarcoConsulting or Advisory Role: AbbVie, Janssen, AstraZeneca SpainSpeakers' Bureau: AbbVie, Janssen, AstraZeneca SpainResearch Funding: AbbVie, JanssenTravel, Accommodations, Expenses: AbbVie, Janssen Anthony MatoConsulting or Advisory Role: TG Therapeutics, AbbVie/Genentech, Celgene, Pharmacyclics, Adaptive Biotechnologies, Verastem, Johnson & Johnson, Acerta Pharma/AstraZeneca, DTRM, Loxo/Lilly, Curio/Vaniam Group, Merck, Bristol Myers Squibb/PfizerResearch Funding: Regeneron, TG Therapeutics, Sunesis Pharmaceuticals, LOXO, AbbVie/Genentech, Pharmacyclics, Adaptive Biotechnologies, Johnson & Johnson, Acerta Pharma/AstraZeneca, DTRM, Genmab, Nurix Javier Pinilla-IbarzHonoraria: Novartis, Pharmacyclics, Janssen, AbbVie, Takeda, AstraZenecaConsulting or Advisory Role: Novartis, Pharmacyclics, Janssen, AbbVieSpeakers' Bureau: Pharmacyclics/Janssen, AbbVie, Takeda, AstraZenecaPatents, Royalties, Other Intellectual Property: From a WT vaccine patent by Memorial Sloan Kettering Cancer Center John F. SeymourHonoraria: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals, TakedaConsulting or Advisory Role: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals, Takeda, AstraZeneca, BMS, Gilead Sciences, MEI Pharma, MorphoSysSpeakers' Bureau: AbbVie, RocheResearch Funding: AbbVie, Celgene, Janssen, RocheExpert Testimony: RocheTravel, Accommodations, Expenses: AbbVie, Roche Stephan StilgenbauerHonoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenConsulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenSpeakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenResearch Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenTravel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen Tadeusz RobakHonoraria: AbbVieConsulting or Advisory Role: AbbVieResearch Funding: AbbVie/Genentech Wayne RothbaumLeadership: Iovance BiotherapeuticsStock and Other Ownership Interests: Acerta Pharma/AstraZeneca, Telios, Kartos TherapeuticsPatents, Royalties, Other Intellectual Property: Telios Pharma and Kartos TherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics, Kartos TherapeuticsUncompensated Relationships: Kartos Therapeutics, Telios Raquel IzumiEmployment: Acerta Pharma, Vincerx PharmaStock and Other Ownership Interests: Acerta Pharma, Vincerx PharmaPatents, Royalties, Other Intellectual Property: Patents pending for Acerta PharmaExpert Testimony: Diablo Valley Oncology Ahmed HamdyEmployment: Acerta Pharma/AstraZenecaStock and Other Ownership Interests: Acerta PharmaPatents, Royalties, Other Intellectual Property: Acalabrutinib multiple patents Priti PatelEmployment: AstraZeneca, Neoleukin TherapeuticsLeadership: Neoleukin TherapeuticsStock and Other Ownership Interests: AstraZeneca, Neoleukin Therapeutics Kara HigginsEmployment: AstraZeneca, PROMETRIKA LLC Sophia SohoniEmployment: AstraZeneca, Portola PharmaceuticalsStock and Other Ownership Interests: Theravance Wojciech JurczakConsulting or Advisory Role: Janssen-Cilag, Roche, AstraZeneca, Debiopharm Group, EpizymeResearch Funding: Acerta Pharma, TG Therapeutics, Incyte, Bayer, Sandoz-Novartis, Roche, Takeda, Epizyme, Janssen-Cilag, BeiGene, Debiopharm Group, MorphoSys, MEI PharmaNo other potential conflicts of interest were reported.