Background: Early results from ELEVATE-TN (NCT02475681) at a median follow-up of 28.3 mo demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) (Sharman et al. Lancet 2020;395:1278-91). Results from a 4-year update are reported here. Methods: Pts received A±O or O+Clb. Crossover to A monotherapy was permitted in pts who progressed on O+Clb. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) were randomized with a median age of 70 y; 63% had unmutated IGHV and 9% del(17p). At a median follow-up of 46.9 mo (range, 0.0–59.4; data cutoff: Sept 11, 2020), the median PFS was not reached (NR) for A+O and A pts vs 27.8 mo for O+Clb pts (both P<0.0001). In pts with unmutated IGHV, the median PFS was NR (A+O and A) vs 22.2 mo among O+Clb pts (both P<0.0001). In pts with del(17p), the median PFS was NR (A+O and A) vs 17.7 mo for O+Clb (P<0.005). Estimated 48-mo PFS rates were 87% for A+O, 78% for A, and 25% for O+Clb. Median OS was NR in any treatment arm with a trend towards significance in the A+O group (A+O vs O+Clb, P=0.0604); estimated 48-mo OS rates were 93% (A+O), 88% (A), and 88% (O+Clb). ORR was significantly higher with A+O (96.1%; 95% CI 92.1–98.1) vs O+Clb (82.5%; 95% CI 76.2–87.4; P<0.0001); ORR with A was 89.9% (95% CI 84.7–93.5; P=0.035 vs O+Clb). Complete response/complete response with incomplete hematologic recovery (CR/CRi) rates were higher with A+O (26.8%/3.9%) vs O+Clb (12.4%/0.6%); 10.6%/0.6% had CR/CRi with A. Common adverse events (AEs) and AEs of interest are shown in the Table. Overall treatment discontinuation rates were 25.1% (A+O), 30.7% (A), and 22.6% (O+Clb); the most common reasons were AEs (12.8%, 12.3%, 14.7%, respectively) and progressive disease (4.5%, 7.8%, 1.7%). Most pts (77.4%) completed O+Clb treatment. Conclusions: With a median follow-up of 46.9 mo (̃4y), the efficacy and safety of A+O and A monotherapy was maintained, with an increase in CR since the interim analysis (from 21% to 27% [A+O] and from 7% to 11% [A]) and low rates of discontinuation.