Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line ibrutinib (I) + venetoclax (V) in CLL/SLL. Follow-up results from the fixed duration (FD) cohort showed 3-y PFS rate of 88% overall and rates ≥80% in patients (pts) with high-risk features (Wierda, ASCO 2022). Here we present updated results from the FD cohort with 4-y follow-up. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; <10^‒4) was assessed by 8-color flow cytometry. Results: 159 pts were enrolled, including pts with high-risk features of unmutated IGHV (uIGHV) (56%) or del(17p) and/or TP53 mutation (17%). Median time on study was 50 mo (range 1‒53). At 4 y of follow-up, the best CR rate was 58% and ORR was unchanged at 96%. At 4 y, PFS rate was 79% (95% CI 71‒84) and OS rate was 98% (95% CI 94–99). 4 y PFS rates were numerically lower in pts with uIGHV (73%) or del(17p) and/or TP53 mutation (63%), while OS rates remained consistently high (Table). 4 y PFS rates by MRD status 3 mo after stopping treatment (EOT+3) were significantly higher overall in pts with uMRD vs detectable MRD (dMRD) in PB (90% vs. 66%, Table); this difference was minimal at 24 mo (100% vs 91%). Median TTNT was not reached overall (range 1–53 mo); the 4 y rate of freedom from next treatment was 84% (95% CI 77–89). Second malignancies continue to be collected off treatment; 1 AE of prostate cancer occurred during this y of follow-up. To date, 19 pts with PD after completing fixed duration I+V in either the FD cohort or MRD cohort placebo arm initiated retreatment with I. Responses in 17 pts with available data were 1 CR, 13 PR, and 1 each PR with lymphocytosis, SD, and PD. Median time on retreatment was 11 mo (range 0–39). The most common AEs (≥10%) with retreatment were diarrhea (n=3), COVID-19 (n=3), and anemia (n=2). In addition, 4 pts have started I+V retreatment to date. Conclusions: Results of the CAPTIVATE study support I+V as an all-oral, once-daily fixed-duration regimen for previously untreated pts with CLL/SLL. With 4 y follow-up, fixed-duration I+V continues to provide deep, durable remissions with clinically meaningful PFS and time off treatment, including in pts with high-risk disease features. New safety findings off-treatment were expectedly negligible, highlighting the benefits of a fixed duration regimen. Promising responses were observed upon retreatment with I in progressing pts. Clinical trial information: NCT02910583.