EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study.

Diogo Martins-Branco, Soraia Lobo-Martins, Philippe Aftimos, Bernardo Pereira, Leonor Vasconcelos de Matos, Leonor Fernandes, Elsa Campôa, Guilherme Nader-Marta, Michel Moreau, Donatienne Taylor, Francois P Duhoux, Pedro Simões, Ana Rita Garcia, Vanessa Patel, Caterina Confente, Diogo Alpuim Costa, José Pereira, Catarina Santos, Marianne Paesmans, Frederico Sarmento, Teresa Gantes Padrão, Diana Simão, Daniel Bandarra, Berta Sousa, Margarida Brito, Andrea Gombos, Lieveke Ameye, Evandro de Azambuja

Journal: Breast cancer research and treatment 2026;218(1):

PMID: 42429895

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Abstract

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Address: Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Bruxelles, Belgium.; Medical Oncology Department, Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Bruxelles, Belgium.; Medical Oncology Department, Portuguese Oncology Institute Lisbon (IPOLFG), Lisbon, Portugal.; Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal.; Medical Oncology, Hospital Santo António dos Capuchos (HSAC), Unidade Local de Saúde São José (ULS São José), Centro Clínico Académico de Lisboa (CCAL), Lisbon, Portugal.; Medical Oncology, Unidade Local de Saúde do Algarve, Faro, Portugal.; Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Unité de Gestion de l'Information - UGI, Bruxelles, Belgium.; Oncology, CHU UCL Namur, Site Sainte-Elisabeth, Namur, Belgium.; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, and Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.; Medical Oncology Department, Hospital Beatriz Ângelo, Unidade Local de Saúde Loures Odivelas, Loures, Portugal.; Medical Oncology, Portuguese Oncology Institute of Coimbra, Coimbra, Portugal.; Oncology Department, Unidade Local de Saúde Santa Maria, Lisbon, Portugal.; Medical Oncology Unit, CHU Hélora site Jolimont, La Louvière, Belgium.; Haematology and Oncology Department, CUF Oncologia, Lisbon, Portugal.; Unidade Funcional De Oncologia, Hospital de Cascais, Cascais, Portugal.; Oncology, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.; Unidade Funcional De Oncologia, Hospital de Cascais, Cascais, Portugal.; Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Bruxelles, Belgium. [email protected].; Medical Oncology Department, Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Bruxelles, Belgium. [email protected].

DOI: 10.1007/s10549-026-08012-5

MeSH Terms: Humans, Female, Everolimus, Breast Neoplasms, Erb-b2 Receptor Tyrosine Kinases, Middle Aged, Antineoplastic Combined Chemotherapy Protocols, Receptors, Estrogen, Cyclin-Dependent Kinase 4, Aged, Retrospective Studies, Cyclin-Dependent Kinase 6, Protein Kinase Inhibitors, Adult, Disease Progression, Antineoplastic Agents, Hormonal, Treatment Outcome