Background: Investigators reporting treatment-emergent adverse events (TEAEs) in the 3^rdline or greater abemaciclib MONARCH1 Phase 2 study observed Grade 1-3 diarrhea, fatigue, and abdominal pain in 90, 65, and 39% of the patients (n = 132). Unknown is the extent that diarrhea and overall pain add to fatigue in this setting. Using patient-reported outcome (PRO) measures, we conducted cross-sectional and longitudinal multivariate analyses to estimate these effects. Methods: Data came from a single-arm, open-label study of previously-treated patients with mBC. Throughout the study, the Brief Pain Inventory and the EORTC QLQ-C30 v3 were co-administered. All constructs and items from these two questionnaires –except EORTC Items 25 and 28 (memory and financial difficulties) - were used to estimate the Structural Equation Model (SEM) and the direct and indirect effects of pain and diarrhea on fatigue. Extended pattern mixture modeling (ePMM) – a latent variable modeling method that allows the explicit analysis of missing data and identifies subgroups with differential changes over time – was used to explore these relationships from screening through cycle 8. Results: SEM results showed that at cycle 2 of treatment, pain was a significant predictor of fatigue (b = 0.68; P < 0.001; CI 0.48 – 0.90); diarrhea was not a significant predictor of fatigue (b = 0.06; P = 0.12; CI -0.04 – 0.17). ePMM results across eight 30-day cycles found three fatigue subgroups: no change, improvement, worsening then improvement. Belonging to a similar pain subgroup predicted belonging to the corresponding fatigue subgroup (ref class was no change; improving b = 5.03, P = 0.004; worsening b = 22.01, P < 0.001); the same was not true for diarrhea and fatigue (ref class was no change; improving b = 0.213, P = 0.75; worsening b = 0.04, P = 0.97). Conclusions: These results suggest that for patients undergoing 3^rd line or greater mBC treatment, pain is a significant predictor of fatigue early and over the course of the trial. However, diarrhea is not a significant predictor of fatigue. Clinical trial information: NCT02102490