Abstract Background: The FDA approved neratinib (N), an irreversible pan-HER tyrosine kinase inhibitor, in combination with capecitabine (C) for patients with HER2+ advanced or metastatic breast cancer who have received ≥2 prior HER2-directed regimens in the metastatic setting based on the NALA clinical study, where N+C significantly improved PFS vs. lapatinib (L)+C. Characterizing HRQoL associated with this regimen can help inform treatment decision-making for these patients. The objective of this analysis was to characterize HRQoL among patients with HER2+ metastatic breast cancer from the NALA clinical study. Methods: NALA was a multinational, randomized, open-label, phase III clinical study of N+C vs. L+C in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens. From May 2013 to July 2017, patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid 14d/21d) with loperamide prophylaxis during the first cycle, or to L (1250 mg qd) + C (1000 mg/m2 bid 14d/21d). HRQoL, a prespecified secondary endpoint of the NALA study, was measured using the EORTC QLQ-C30 and the breast cancer-specific QLQ-BR23 at baseline and every 6 weeks (±3 days) until the end of treatment (data collection through treatment cycle 19, 12.5 months). The QLQ-C30 summary and global health status scores range from 0 (worst) to 100 (best) and the systemic therapy side-effects scores range from 0 (best) to 100 (worst). Patients were included in the analysis for a particular scale if they had a baseline assessment and at least 1 follow-up assessment. For these analyses, a change of ≥10 points was considered to be clinically meaningful. Descriptive statistics summarized observed scores and changes from baseline, Kaplan-Meier and log-rank tests were used for time-to-deterioration (TTD) of ≥10 points and mixed models estimated the change over time for 7 prespecified scales: QLQ-C30 summary score, global health status, physical functioning, fatigue, constipation and diarrhea, and the EORTC QLQ-BR23 systemic therapy side effects subscale. No adjustments for multiplicity were performed. Results: 621 patients from 28 countries were randomized (307 N+C; 314 L+C). The mean completion rate of the QLQ-C30 over the course of the study was 91% for both treatment arms. Discontinuation due to any treatment-emergent adverse event (TEAE) was lower in the N+C vs. L+C arm (14% vs. 18%). At baseline, the mean (SD) QLQ-C30 summary scores were 79.8 (14.1) for N+C and 79.9 (15.7) for L+C. After 19 treatment cycles, the mean (SD) QLQ-C30 summary scores were similar to baseline scores: 81.8 (16.7) for N+C and 81.3 (15.3) for L+C. There were no differences in TTD of ≥10 points for the QLQ-C30 summary score between treatment arms; the HR for N+C vs. L+C was 0.94 (95% CI 0.63-1.40). All prespecified HRQoL subscales had similar statistically non-significant results for TTD with the exception of diarrhea (HR=1.71; 95% CI 1.32-2.23). The mixed models analyzing change in HRQoL from baseline did not demonstrate persistent declines nor meaningful differences between the treatment arms. Conclusion: In these results from the NALA study, among patients with HER2+ metastatic breast cancer, at study end and throughout most of the study, there were no differences observed between the two treatment arms in HRQoL scores. HRQoL was sustained over the study period despite the early transient presence of diarrhea in some patients. Discontinuation due to any TEAE was lower in the N+C vs. the L+C arm. These results may help guide healthcare providers, patients and carers in selection of optimal treatment for HER2+ metastatic breast cancer. Citation Format: Beverly Moy, Mafalda Oliveira, Cristina Saura, William Gradishar, Sung-Bae Kim, Adam Brufsky, Sara Hurvitz, Larisa Ryvo, Daniele Fagnani, Nancy Chan, Sujith R Kalmadi, Paula Silverman, Suzette Delaloge, Richard Bryce, Kiana Keyvanjah, Judith Bebchuk, Bo Zhang, Nina Oestreicher, Ron Bose. Neratinib + capecitabine sustains health-related quality of life (HRQoL) while improving progression-free survival (PFS) in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-02.