Publication
In the UNIRAD phase III trial, evening intake of tamoxifen was previously associated with improved disease‐free survival (DFS), while no timing effect was observed for aromatase inhibitors. This sub‐study evaluated whether the timing of everolimus intake affects DFS in patients receiving adjuvant endocrine therapy (ET). A total of 1278 patients with high‐risk HR+/HER2− early breast cancer were randomized to receive adjuvant ET with either placebo or everolimus. Patients prospectively recorded the timing of both ET and everolimus intake using four time slots: morning (06:00–11:59), afternoon (12:00–17:59), evening (18:00–23:59), and night (00:00–05:59). The relationship between intake timing and DFS was a pre‐specified secondary endpoint. Timing data were available for 513 of 632 patients (81.2%) in the everolimus arm. After a median follow‐up of 60.6 months, 15 local relapses, 55 metastases, and 36 deaths were reported. Overall, everolimus timing had no significant association with DFS (HR = 0.84, 95% CI 0.53–1.35, P = 0.4). However, a significant interaction was found between everolimus timing and ET type (P = 0.001). Among tamoxifen users, evening/night intake of everolimus significantly improved DFS compared to morning/afternoon intake (HR = 0.17, 95% CI 0.05–0.59, P = 0.005), independently of tamoxifen timing. No timing effect was observed in patients on aromatase inhibitors (HR = 1.56, P = 0.1). In multivariate analysis, evening/night everolimus with tamoxifen remained an independent predictor of improved DFS (HR = 0.13, P = 0.002). Evening or nighttime intake of everolimus may enhance the efficacy of tamoxifen‐based adjuvant therapy in high‐risk HR+/HER2− early breast cancer.