Abstract Objective: Everolimus combined with endocrine therapy is one of the standard treatment options for patients who develop resistance to CDK4/6 inhibitors. However, prospective studies and real-world evidence regarding the efficacy of everolimus in patients previously treated with CDK4/6 inhibitors remain limited. This retrospective study evaluated the clinical outcomes of everolimus in such patients and aimed to identify factors associated with treatment response. Methods: We conducted a retrospective, registry-based analysis using data from the Advanced Breast Cancer Database (ABCD) Project, coordinated by the Japan Breast Cancer Research Group. Of 184 patients treated with everolimus plus endocrine therapy between January 2019 and March 2025, 169 ER+/HER2- cases with prior CDK4/6 inhibitor exposure and complete data were included. Collected variables included age, performance status, treatment line, reason for treatment discontinuation, best response, menopausal status, recurrence type, BRCA1/2 mutation status, histology, ER/PgR/HER2 expression, Ki-67 index, prior chemotherapy, antibody-drug conjugate (ADC) use, and type and duration of prior CDK4/6 inhibitor therapy. Sites and number of metastatic organs were also assessed. Time to treatment failure (TTF) and overall survival (OS) were measured from everolimus initiation. Prognostic factors for TTF were analyzed using univariate and multivariate Cox proportional hazards models. Kaplan-Meier methods and log-rank tests were used for survival comparisons. Results: The median age was 63 years, and 73% of patients had a performance status of 0. Treatment was discontinued due to disease progression in 64%. The objective response rate (CR + PR) was 9%. Most patients were postmenopausal (96%), with 30% presenting with de novo stage IV disease and 69% experiencing post-operative recurrence. Pathogenic BRCA1/2 variants were observed in 6%. Invasive ductal carcinoma accounted for 88% of cases. ER was ≥10% in 98%, PgR ≥10% in 62%, and HER2-low breast cancer (IHC score 1+ or 2+ with ISH-negative) was identified in 63%. The median Ki-67 index was 28%. Everolimus was administered within the third line in 62% of patients. CDK4/6 inhibitor therapy lasted less than one year in 51%; palbociclib only was used in 56%, abemaciclib only in 24%, and both agents in 20%. Prior chemotherapy and ADC therapy were given in 31% and 1%, respectively. Metastatic sites (not mutually exclusive) included bone (64%), liver (41%), lung (34%), and brain (2%), while distant lymph node and pleural involvement were observed in 28% and 17%, respectively. Bone-only metastasis was reported in 12%. The number of metastatic organs was one in 19%, two in 50%, and three or more in 30%. The median TTF was 4.1 months, and the median OS was 28.7 months. Univariate analysis identified several factors significantly associated with shorter TTF: non-ductal histology, PgR 10%, prior CDK4/6 TTF 1year, previous chemotherapy, prior ADC use, and ≥4 metastatic sites (all p 0.05). In multivariate analysis, non-ductal histology (HR 2.34), prior chemotherapy (HR 2.28), and ≥4 metastatic sites (HR 1.83) remained significant predictors of inferior TTF. A progressive decline in TTF was observed with increasing numbers of risk factors (log-rank p 0.05). Conclusion: This large-scale real-world study provides clinically meaningful insight into the effectiveness of everolimus following CDK4/6 inhibitors in ER+/HER2- metastatic breast cancer. Several clinicopathologic factors independently predicted reduced treatment durability, which may inform post-CDK4/6 treatment decision-making. Importantly, to our knowledge, this represents the largest real-world cohort reported to date in this setting, supporting the strength and generalizability of the findings. Citation Format: H. Kiyohara, T. Hanamura, Y. Sagara, M. Miyashita, S. Saji, N. Niikura. Real-world efficacy of everolimus in ER+/HER2- metastatic breast cancer following CDK4/6 inhibitors: a multicenter registry-based study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-04-20.
Kiyohara et al. (Tue,) studied this question.