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There is limited evidence supporting the addition of everolimus to endocrine therapy in women with ER-positive/HER2-negative advanced breast cancer disease progression on CDK4/6 inhibitors. We aimed to assess the effectiveness and safety of everolimus in this setting.

EVERGREEN is a multicentre, international, retrospective quasi-experimental study of women with ER-positive/HER2-negative advanced breast cancer who started an immediate next line of endocrine therapy after progression on CDK4/6 inhibitors until 31/12/2022. We compared patients exposed to endocrine therapy plus everolimus in centres where this is the standard-of-care with those treated in centres where endocrine therapy alone is the standard-of-care. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints were time to everolimus failure, time to chemotherapy, and overall survival.

We included 207 women (everolimus n = 150, endocrine therapy alone n = 57), with a median follow-up of 31.8 months. Baseline characteristics were well balanced, except for a higher number of prior lines of therapy in the everolimus cohort. Median rwPFS was 5.0 for patients exposed to everolimus vs 4.3 months for endocrine therapy alone (adjusted hazard ratio 0.68, 95% confidence interval 0.47-0.99). Time to everolimus failure was 4.2 months. There were no statistically significant differences in time to chemotherapy or overall survival. The safety profile was consistent with previous reports.

The addition of everolimus to standard endocrine therapy resulted in a modest clinical benefit for patients with ER-positive/HER2-negative advanced breast cancer candidates for endocrine therapy after CDK4/6 inhibitors. This limited benefit and the toxicity profile warrants careful selection of patients with favourable risk-benefit profile.