Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Primary Breast Cancer

Abstract

PURPOSE Everolimus, an oral inhibitor of the mammalian target of rapamycin, improves progression-free survival in combination with endocrine therapy (ET) in postmenopausal women with aromatase inhibitor–resistant metastatic breast cancer. However, the benefit of adding everolimus to ET in the adjuvant setting in early breast cancer is unknown. PATIENTS AND METHODS In this randomized double-blind phase III study, women with high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer were randomly assigned to everolimus or placebo for 2 years combined with standard ET. Stratification factors included ET agent, receipt of neoadjuvant versus adjuvant chemotherapy, progesterone receptor status, duration of ET before random assignment, and lymph node involvement. The primary end point was disease-free survival (DFS). The trial is registered with ClinicalTrials.gov identifier: NCT01805271 . RESULTS Between June 2013 and March 2020, 1,278 patients were randomly allocated to receive everolimus or placebo. At the first interim analysis, the trial was stopped for futility and a full analysis undertaken once data snapshot complete. One hundred forty-seven patients have had a DFS event reported and at 3 years, DFS did not differ between patients who received ET plus everolimus (88% [95% CI, 85 to 91]) or ET plus placebo (89% [95% CI, 86 to 91; hazard ratio = 0.95, 95% CI, 0.69 to 1.32, P = .77]). Grade ≥ 3 adverse events were reported in 22.9% of patients (29.9% with everolimus v 15.9% with placebo, P < .001). 53.4% everolimus-treated patients permanently discontinued experimental treatment early compared with placebo-treated 22.3%. CONCLUSION Among high-risk patients, everolimus added to adjuvant ET did not improve DFS. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting.

Exploring neurotransmitters and their receptors for breast cancer prevention and treatment

“…A large number of novel targeted therapeutics have recently entered clinical application or are being evaluated in clinical trials [9][10][11][12]. For example, the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, as well as abeamciclib, and the allosteric inhibitor of mTOR complex 1 (mTORC1) everolimus are now available for the treatment of ER-positive HER2-negative advanced BCs [9][10][11][12].…”

“…A large number of novel targeted therapeutics have recently entered clinical application or are being evaluated in clinical trials [9][10][11][12]. For example, the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, as well as abeamciclib, and the allosteric inhibitor of mTOR complex 1 (mTORC1) everolimus are now available for the treatment of ER-positive HER2-negative advanced BCs [9][10][11][12]. Similarly, the selective estrogen receptor degrader (SERD) elacestrant is being investigated in clinical trials for the treatment of ER-positive HER2-negative advanced BCs [ClinicalTrials.gov Identifier: NCT03778931], and the humanized monoclonal antibody against trophoblast cell-surface antigen 2 (TROP2), for the treatment of triple-negative BCs (TNBCs) [ClinicalTrials.gov Identifier: NCT04230109; NCT04927884; NCT02574455].…”

CDK4/6 Inhibitors—Overcoming Endocrine Resistance Is the Standard in Patients with Hormone Receptor-Positive Breast Cancer

“…Furthermore, Alpelisib was the second therapy to show that endocrine resistance could be overcome in patients with PIK3CA -mutated hormone receptor-positive, HER2-negative aBC [ 10 ]. However, everolimus did not achieve an improvement in outcomes in the early therapy setting [ 11 ]. Figure 1 shows the diverse pathways within the cell cycle that are potential contributors to ET resistance.…”

Recent Advances in Adjuvant Endocrine Therapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

“…The positive results of everolimus in HR-positive metastatic breast cancer led to prospective adjuvant trials, and one of these, the UNIRAD study, is the focus of the report by Bachelot et al 25 recently published in the Journal of Clinical Oncology. In this trial, 2 years of adjuvant everolimus in combination with ET did not improve 3-year IDFS over ET alone (88% v 89%) in a population of patients with high-risk, early-stage ER-positive HER2-negative breast cancer.…”

“…In the article that accompanies this editorial, Bachelot et al 25 report findings from a phase III randomized double-blind placebo-controlled trial of everolimus added to adjuvant endocrine therapy in patients with high-risk hormone receptor–positive breast cancer (the UNIRAD study), indicating no improvement in 3-year invasive disease-free survival with the addition of everolimus to adjuvant endocrine therapy. Therefore, this treatment strategy should not be used in current clinical practice and further research is imperative to improve clinical outcomes in this population.…”