Background: PACE is a multicenter randomized phase II trial investigating palbociclib (P) in combination with fulvestrant (F) after progression on any CDK4/6 inhibitor (CDK4/6i), with or without the PD-L1 inhibitor avelumab (A), in HR+/HER2- MBC. CTCs are rare cells in the blood stream whose detection is associated with worse outcome and treatment resistance. Methods: Eligible patients (pts) had HR+/HER2- MBC with prior progression after ≥ 6 months (mo) of AI and CDK4/6i for MBC, or during/within 12 mo in the adjuvant setting, with ≤ 1 prior chemotherapy for MBC. Pts were randomized 1:2:1 to F, F+P, or F+P+A. CTC detection and enumeration were performed utilizing CellSearch (Menarini Silicon Biosystems) at baseline (BL), at time of first tumor assessment (TTA1), and at progression. Results were dichotomized using the standard CTC threshold (≥ 5 CTCs/7.5 ml) into a novel prognostic classification: StageIV_indolent and StageIV_aggressive (Cristofanilli et al 2019). Concurrent ctDNA Sequencing was performed using Guardant360 (Guardant Health). Results: Of the 220 randomized pts, 203 (92%) had sample available for BL CTC enumeration, 155 had detectable CTCs (70.5%), and 99 (48.8%) were StageIV_aggressive. De novo disease at initial diagnosis was associated with StageIV_aggressive (47.5% vs 30.8% StageIV_indolent), and distribution of visceral versus non-visceral disease was similar across the two CTCs groups. StageIV_aggressive represented 38.3%, 54.8%, and 46.2% of the F, F+P and F+P+A treatment groups, respectively. BL CTCs were prognostic in the overall cohort; median PFS was 5.7mo vs 3.5mo for StageIV_indolent vs StageIV_aggressive (HR: 1.69, 90%CI 1.27,2.24, P<0.001). Median PFS for the F, F+P and F+P+A arms was 1.9mo, 4.6mo and 5.4mo in StageIV_aggressive compared to 8.2mo, 5.3mo and 8.3mo in StageIV_indolent. Among patients in the StageIV_aggressive subgroup, the F+P and F+P+A arms demonstrated improved outcomes compared to F alone. (F+P vs F HR 0.43, 90% CI 0.25-0.71, and F+P+A vs F HR 0.26, 90% CI 0.14-0.49). No benefit of F+P or F+P+A over F was observed in the StageIV_indolent subgroup (F+P vs F HR 1.45, 90% CI 0.87 - 2.40 and F+P+A vs F HR 1.06, 90% CI 0.61 - 1.84, each p(interaction)<0.01). Changes in StageIV CTC characterization (indolent vs aggressive) between BL and TTA1 among the subset of 175/203 pts with both timepoints available are reported. Conclusions: Baseline CTC enumeration is prognostic in patients receiving F with or without CDK4/6i. The StageIV_aggressive subgroup may derive preferential benefit with combinations of F+P or F+P+A over F alone. Findings should be confirmed in other studies. ctDNA analyses are ongoing. Clinical trial information: NCT03147287.