Adding the mTOR inhibitor everolimus to conventional adjuvant endocrine therapy does not improve outcomes for patients with high-risk, hormone receptor (HR)–positive early breast cancer and it should not be used in this setting, researchers have concluded.
Previous positive results of everolimus in HR-positive metastatic breast cancer led to prospective trials in the adjuvant setting, but one of them was terminated early for futility, with many patient discontinuing treatment due to toxicity-related adverse events.
Results from the UNIRAD trial just published in the Journal of Clinical Oncology show that two years of adjuvant everolimus in combination with endocrine therapy did not improve three-year invasive disease-free survival over endocrine therapy alone (88% v 89%) in a comparison involving 1,278 patients with high-risk, early-stage ER-positive HER2-negative breast cancer.
In the phase 3 randomised controlled trial 30% of patients in the adjuvant everolimus arm reported Grade 3 or higher adverse events, compared to 6% of patients in the group treated with endocrine therapy alone.
More than half (53.4%) of the everolimus-treated patients stopped treatment early compared with 22.3% of the control group.
“Given the results of the UNIRAD trial, everolimus should not at present be recommended in the adjuvant treatment setting for patients with high-risk ER-positive HER2-negative early-stage breast cancer,” an accompanying editorial concluded.
The authors noted that everolimus was one of several novel adjuvant systemic therapy approaches being trialled to try reduce the chances of distant disease recurrence for patients with ER-positive breast cancer.
Currently optimal adjuvant systemic therapy, including five-ten years of adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor, would cure most patients and has contributed to a one-third decline in breast cancer mortality in recent decades, the article noted.
However, an unacceptably high rate of distant metastatic recurrence and mortality remains for some patients such as those with axillary lymph node involvement, grade 3 disease, or high genomic risk, the authors said.
Despite their efficacy in the metastatic setting, conflicting results studies of CDK 4/6 inhibitors in the adjuvant setting had provided conflicting results. But the negative results from the UNIRAD trial should not be seen as the ‘end of the story for adjuvant mTOR inhibitor, they asserted.
Another trial of everolimus in adjuvant treatment of high-risk, HR-positive breast cancer has just competed recruitment, and results would be available over the next few years, the authors said.
There are also unanswered questions about everolimus in the adjuvant setting such as everolimus whether it would be more effective if initiated concurrently with adjuvant endocrine therapy and its effects on risk of late disease recurrence.
“Although we would not recommend using adjuvant everolimus at present, we believe that there is more to learn before a definitive conclusion can be made,” they said.