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SAN ANTONIO -- A second randomized trial failed to show a benefit of adding everolimus (Afinitor) to adjuvant endocrine therapy for high-risk hormone receptor (HR)-positive/HER2-negative breast cancer.

Patients who received the mTOR inhibitor plus endocrine therapy had a 5-year invasive disease-free survival (IDFS) of 74.9% versus 74.4% for endocrine therapy and placebo. Overall survival (OS) at 5 years, a secondary endpoint, also did not differ significantly between treatment groups. The results mirrored those of a European study that showed no effect of adjuvant everolimus on disease-free survival. Both trials had high rates of everolimus-related toxicity and discontinuation.

An exploratory analysis of the SWOG 1207 trial did show a significant benefit of adding everolimus in premenopausal patients, also suggested by heterogeneity in a subgroup analysis of the European study, reported Mariana Chavez-MacGregor, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the San Antonio Breast Cancer Symposium (SABCS).

"This observation [in premenopausal patients] is thought-provoking and hypothesis generating," she said. "We're planning translational studies that will evaluate the potential predictors of everolimus treatment drug toxicity, and that hopefully will clarify important issues related to endocrine therapy resistance."

Though intriguing, the observed benefit in premenopausal patients raises a number of questions, said SABCS invited discussant Polly Niravath, MD, of Houston Methodist Hospital. Were premenopausal patients more compliant? Is the biology of premenopausal HR-positive breast cancer inherently different from premenopausal disease? Did the choice of endocrine therapy influence outcomes with everolimus?

"Even if this were proven to have an effect in premenopausal women in the future, how would this fit into our current landscape, with so many options that we have for many premenopausal breast cancer patients?" Niravath asked.

Discussion of the results has to include the "elephant in the room" for most trials of adjuvant endocrine therapy, which is compliance, she continued. Fewer than half the patients in the everolimus arm of SWOG 1207 completed the trial, and most discontinuations involved adverse events. High rates of treatment-related discontinuation also have been reported from adjuvant trials of CDK4/6 inhibitors.

"This trend for low compliance due to increased side effects is very troubling for several reasons," said Niravath. "One is that obviously we may bend up with falsely negative trials where promising agents appear to not confer benefit only because patients are unable to tolerate the medications."

"Perhaps even more importantly, when these drugs are found to be effective, and then used in standard clinical care, we are unfortunately sentencing many of our patients to a very significantly decreased quality of life."

Future trials should focus more on compliance and tolerability, she added.

Interest in moving everolimus into the adjuvant setting emerged almost immediately after the BOLERO-2 trial showed that the combination of the aromatase inhibitor exemestane (Aromasin) and everolimus more than doubled median progression-free survival in postmenopausal women with metastatic HR-positive breast cancer.

SWOG 1207 evaluated physician's choice of endocrine therapy plus everolimus or placebo in patients with early high-risk HR-positive/HER2-negative breast cancer. Adjuvant therapy continued for a year. All patients also received chemotherapy. High risk was defined by tumor size, risk score, nodal status, and/or outcome after neoadjuvant chemotherapy. Data analysis included 1,939 randomized patients.

The primary outcome was IDFS, and OS was a key secondary endpoint. Prespecified subgroup analyses included evaluation of outcomes by risk group. Outcome by menopausal status was an exploratory analysis. Median follow-up on patients still alive was 55.2 months.

The study population had a median age of 54. Most patients had a high risk of recurrence because of nodal outcomes after adjuvant or neoadjuvant therapy (40% each). A third of the patients were premenopausal.

As Niravath noted, only 48% of patients assigned to everolimus completed planned treatment (vs 73% in the placebo group) and most patients who discontinued in the everolimus arm did so because of adverse events or side effects (37% vs 10% in the placebo group).

The negligible absolute difference in 5-year IDFS translated into a hazard ratio of 0.94 (95% CI 0.77-1.14). The estimated 5-year OS also did not differ between the everolimus (88.1%) and placebo (85.8%) groups (HR 0.97, 95% CI 0.75-1.26). Subgroup analyses failed to identify a group of patients who clearly benefited more from everolimus.

The exploratory analysis of outcomes by menopausal status showed a 5-year IDFS of 81.0% with everolimus in premenopausal patients versus 74.7% with placebo, representing a 36% reduction in the hazard ratio (95% CI 0.44-0.94). Premenopausal patients had a 5-year median OS of 95.7% with everolimus versus 86.0% with placebo, a 51% reduction in the hazard (95% CI 0.28-0.86). Hazard ratios for IDFS and OS trended in favor of the placebo arm among postmenopausal patients.

Grade ≥3 toxicity occurred five times as often with everolimus (35%) versus placebo (7%). The most common grade ≥3 toxicity in the everolimus group was oral mucositis (7%), followed by lymphopenia, hypertriglyceridemia, and hyperglycemia (4% each).

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