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Adding mTOR inhibitor everolimus (Afinitor) to adjuvant endocrine therapy failed to improve disease-free survival (DFS) in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-), a large randomized trial showed.

Three-year DFS was 88% with everolimus plus endocrine therapy and 89% with placebo plus endocrine therapy. Tolerability figured prominently in the results, as more than half the patients in the everolimus arm discontinued treatment prematurely, almost 30% because of toxicity.

"Added toxicity was significant, and early treatment discontinuation may be in part responsible for the lack of observed benefit," reported Thomas Bachelot, MD, PhD, of the Leon Berard Center in Lyon, France, and co-authors, in the . "Follow-up will continue to evaluate long-term outcomes. At the present time, everolimus cannot be recommended in the adjuvant setting."

The failed to duplicate the success of the BOLERO-2 trial, which showed significant improvement in progression-free survival with the addition of everolimus to an aromatase inhibitor after progression on front-line endocrine therapy. However, BOLERO-2 also had a high discontinuation rate, including 29% because of adverse events.

During an for the European Society for Medical Oncology (ESMO) virtual plenary series, moderator Rebecca Dent, MD, of the National Cancer Center Singapore, asked Bachelot whether everolimus "is not effective or just not tolerable."

"When you give an adjuvant treatment, it has to be deliverable," said Bachelot. "If patients don't get it, it won't be effective ... you just won't see any benefits. The fact that we were not able to give it to more than 50% of the patients was an answer to me. Because they cannot give it, the results were bad."

Dent noted that UNIRAD began at a time when oncologists were still learning how to manage everolimus toxicity.

"I think we've become much better at treating the side effects of everolimus," she said. "I think many of us would agree now that we actually find it quite a lot easier than it used to be because we're quite familiar and we have the dexamethasone steroid wash."

ESMO-invited discussant Peter Schmid, MD, of the Barts Center in London, England, said the trial did not answer the question of whether everolimus plus endocrine therapy can be an effective adjuvant regimen for patients with high-risk HR+/HER2- breast cancer.

"I'm not sure whether we can really evaluate, by this trial, whether everolimus did work," he noted.

Schmid also referred to a "psychological effect" that might have contributed to the high discontinuation rate. All the patients had received prior single-agent endocrine therapy, some for as long as 4 years.

"The feedback I have received is that it's more difficult to be on single-agent hormone therapy for some time and then restart it," said Schmid. "It's like a more intensive therapy, even if biologically, it's a great concept. [Patients] may have had chemotherapy and they're relatively well and then the acceptance to have additional side effects 3 or 4 years later on can be much lower than it is in the immediate phase after diagnosis."

Schmid and Dent both pointed out that "high risk" was defined by clinical criteria alone, not genomic testing. The degree to which that might have influenced patient selection was unclear.

Investigators in the multicenter UNIRAD trial enrolled women who had high-risk early HR+/HER2- breast cancer, defined as four or more positive lymph nodes or one or more positive nodes if surgery occurred after neoadjuvant chemotherapy or neoadjuvant endocrine therapy or up to three positive nodes at surgery and an EndoPredict score ≥3.3. Despite availability of effective treatment, as many as 20% of such patients will relapse within 5 years.

The protocol initially limited enrollment to patients who had received 2.5 to 3.5 years of adjuvant endocrine therapy. That was amended to allow enrollment of patients who had received at least 1 year and as many as 4 years of hormonal therapy.

The trial accrued 1,278 patients, who were randomized to receive everolimus or placebo in addition to standard endocrine therapy for 2 years. The primary endpoint was DFS.

Enrollment began in 2013, and the trial was stopped for futility after the first interim analysis in early 2020. The analysis yielded a 3-year DFS hazard ratio of 1.08 for everolimus versus placebo, which exceeded the predefined threshold for futility (95% CI 0.76-1.54). Analysis of secondary endpoints, including overall survival, also showed no significant differences between treatment groups.

Grade ≥3 adverse events (AEs) occurred almost twice as often with everolimus (29.5% vs 15.9%, P<0.001). Rates were significantly higher in patients who started treatment with everolimus 10 mg/day (38.2% vs 15.5%, P<0.001) or everolimus 5 mg/day (25.4% vs 16.1%, P<0.001). Grade ≥3 AEs led to permanent withdrawal rates of 29.6% in the everolimus arm versus 9.1% in the placebo group (P<0.001). Everolimus was associated with one treatment-related death (septic shock).

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