A subgroup of patients participating in the randomized phase III NALA study of neratinib plus capecitabine (N+C) versus lapatinib plus capecitabine (L+C) in patients with third-line HER2+ metastatic breast cancer demonstrated improved central nervous system (CNS) outcomes with neratinib-based regimens in the treatment and prevention of CNS metastases from HER2+ breast cancer. The phase III NALA trial enrolled 621 patients who were randomized (1:1) to receive either N+C or L+C. The coprimary endpoints of the trial were independently adjudicated progression-free survival (PFS) and overall survival (OS). The NALA study met its primary endpoint, with the neratinib arm having significantly improved PFS versus the lapatinib arm (hazard ratio [HR], 0.76; mean PFS, 8.8 months vs. 6.6 months). The data showed no statistical difference in OS between treatment arms (HR 0.88). Time to intervention for symptomatic CNS disease was a predefined secondary endpoint of the trial. In the intent to treat population, significantly fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% vs. 29.2%).