Researchers previously demonstrated improved efficacy of acalabrutinib (A) obinutuzumab (O) vs. O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months (mo) median follow-up in the ELEVATE-TN (NCT02475681) trial. The results of a 5-year update were now available. Pts were assigned to 1 of 3 groups: A+O, A, or O+Clb. Patients who improved on O+Clb could switch to A monotherapy. The progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety of investigator-assessed (INV) patients were investigated. The median age of the 535 points (A+O, n=179; A, n=179; O+Clb, n=177) was 70 years. At a median follow-up of 58.2 months (range 0.0–72.0; data cutoff October 1, 2021), median PFS for A+O and A (HR: 0.21) was not reached (NR) (hazard ratio [HR]: 0.11) vs. 27.8 months for O+Clb (both P<0.0001). About 60-month PFS rates were estimated to be 84% (A+O), 72% (A), and 21% (O+Clb). The A+O vs O+Clb arms had significantly longer median OS (HR: 0.55; P=0.0474); projected 60-mo OS rates were 90% (A+O), 84% (A), and 82% (O+Clb). A+O (96%; 95% CI 92–98) and A (90%; 85–94) had substantially higher ORRs than O+Clb (83%; 77–88; P<0.0001 [A+O], P=0.0499 [A]). Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were greater with A+O (29% /3%) than with O+Clb (13% /1%); 13%/1% had CR/CRi with A; CR rose from the interim study (previously 21% [A+O] and 7% [A]). In the table, adverse events (AEs) and treatment exposure were listed. AEs (17% [A+O], 16% [A], 14% [O+Clb]) and progressive disease were the most common reasons for treatment discontinuation in 65% (A+O) and 60% (A) of pts, respectively; the most common reasons for treatment discontinuation were AEs (17% [A+O], 16% [A], 14% [O+Clb]) (6%, 10%, 2%, respectively). Around 72 (41%) of patients switched from O+Clb to A, and 25% stopped taking A (10% due to AEs and 11% due to progressive disease). After a 5-year follow-up, the efficacy and safety of A+O and A monotherapy were maintained, with the A+O arm having a considerably longer OS than the O+Clb arm.