No Benefit Found for Everolimus Plus Adjuvant Hormone Therapy in High-Risk Early-Stage Breast Cancer

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Everolimus plus hormone therapy improves outcomes in the advanced disease setting but apparently not in the adjuvant setting, according to the results of the UNIRAD trial, presented as a part of the European Society for Medical Oncology (ESMO) Virtual Plenary program.1

“In the UNIRAD study, after 3 years of median follow-up of 1,278 patients with high-risk early-stage breast cancer, everolimus given in combination with adjuvant hormone therapy did not improve disease-free survival compared with hormone therapy alone,” said Thomas Bachelot, MD, of the Centre Léon Bérard, Lyon, France. “Acceptability was also a concern, with 50% of patients stopping everolimus before study completion for toxicities or by personal decision.”

“Acceptability was also a concern, with 50% of patients stopping everolimus before study completion for toxicities or by personal decision.”
— Thomas Bachelot, MD

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The combination of everolimus and hormone therapy has been shown to improve progression-free survival in advanced hormone receptor–positive, HER2-negative breast cancer. The double-blind randomized French UNIRAD trial investigated the benefit of this approach in a similar population with early-stage breast cancer, but it failed to meet its primary endpoint.


UNIRAD enrolled 1,278 women from 72 largely French centers. Patients had high-risk hormone receptor–positive, HER2-negative early breast cancer with at least four positive nodes (approximately half the enrolled population); at least one positive node after neoadjuvant chemotherapy or hormone therapy; or at least one positive node and an EndoPredict score of at least 3.3 (indicating a high risk of relapse).

All patients had completed their initial treatment and could have received up to 4 years of adjuvant hormone therapy (patients were initially selected after up to 3 years of hormone therapy). A study amendment allowed patients to start everolimus at 5 mg and to titrate as tolerated up to 10 mg; another amendment allowed them to initiate study treatment concurrently with hormone therapy.


  • The multicenter French UNIRAD trial evaluated everolimus plus hormone therapy in patients with high-risk, early-stage breast cancer.
  • The study did not meet its primary endpoint of invasive disease–free survival.
  • More than half the experimental arm discontinued treatment early due to toxicity.

Between June 2013 and March 2020, patients were randomly assigned to hormone therapy (by investigator’s choice) plus everolimus or placebo for 2 years. The primary endpoint was invasive disease–free survival from randomization. The hypothesis was that the doublet would lead to a gain of 3% in 2-year invasive disease–free survival (90% vs 93%, hazard ratio [HR] = 0.7). The current analysis was conducted after the decision to stop the study for futility at the first preplanned interim analysis in March 2020.

Primary Endpoint Not Met

The endocrine backbone was an aromatase inhibitor for 60% of patients and tamoxifen for 40%. Prior to the study, 43% of
patients had received 0 or 1 year of hormonal therapy, and 42% had received it for 2 to 3 years. Adjuvant chemotherapy was received by 74% and neoadjuvant chemotherapy, by 26%.

After a median follow-up of 35.7 months, 147 events had occurred. An interim analysis showed no outcome to be favorable for the everolimus arm. For everolimus/hormone therapy vs hormone therapy alone, here are the key clinical outcomes:

  • Median 3-year invasive disease–free survival: 88% vs 89% (HR = 0.95; P = .7764)
  • Median metastasis-free survival: 91% vs 90% (HR = 0.88; 95% confidence interval [CI] = 0.62–1.25)
  • Median overall survival: 96% vs 96% (HR = 1.09; 95% CI = 0.62–1.92).

In the preplanned subgroup analysis, there was not much difference between the arms except for endocrine therapy backbone. Patients treated with tamoxifen seemed to derive more benefit from everolimus and hormone therapy, as compared with patients treated with an aromatase inhibitor. Hazard ratios for patients receiving tamoxifen vs an aromatase inhibitor were 0.63 (95% CI = 0.36–1.05) and 1.25 (95% CI = 0.82–1.90), respectively, which reflected a significant treatment interaction (P = .04).

Toxicity Leads to Treatment Discontinuations

Treatment with everolimus plus hormone therapy resulted in more adverse events, dose reductions, and treatment discontinuations than hormone therapy alone, as shown, respectively, here:

  • Median treatment duration: 9 vs 22 months
  • Treatment discontinuation: 53% vs 22%
  • Dose reduction: 34% vs 12%
  • Grade ≥ 3 adverse events: 30% vs 16% (one toxic death related to everolimus)
  • Mucositis, any grade: 66% vs 32%
  • Rash, any grade: 29% vs 11%.

The study was conducted before the protective effect of dexamethasone mouthwash was known; thus, mucositis rates were particularly high. Because of this and other side effects, full doses of the drug could not be given to most patients. “This could be part of the problem, but it’s one of many,” Dr. Bachelot said. 

DISCLOSURE: Dr. Bachelot has served as a consultant or advisor to AstraZeneca, MSD Oncology, Novartis, Pfizer, Roche, and Seattle Genetics; has received institutional research funding from AstraZeneca, Novartis, Pfizer, Roche, and Seagen; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Pfizer, and Roche.


1. Bachelot T, Dalenc F, Chabaud S, et al: Efficacy of everolimus in patients with HER+/HER2– high-risk early-stage breast cancer. ESMO Virtual Plenary. Presented February 19, 2021.

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