Everolimus Effective for Overcoming Endocrine Resistance in Breast Cancer

Everolimus proved to be effective tool for overcoming endocrine resistance in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer that have become resistant to aromatase inhibitor therapy.

Noah S. Kornblum, MD

Everolimus proved to be effective tool for overcoming endocrine resistance in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer that have become resistant to aromatase inhibitor (AI) therapy.

Published in theJournal of Clinical Oncology, findings from the PrE0102 trial demonstrated the addition of the mTOR inhibitor to fulvestrant (Faslodex) resulted in a median progression-free survival (PFS) of 10.3 months versus 5.1 months for fulvestrant plus placebo in this patient population (HR, 0.61; 95% CI, 0.40-0.92; stratified log-rankP= .02). PFS results were shared at the 2016 San Antonio Breast Cancer Symposium before an additional follow-up was conducted.

“Our findings provide additional evidence that everolimus plus antiestrogen therapy is more efficacious than is antiestrogen therapy alone in patients with metastatic, hormone receptor—positive, HER2-negative breast cancer resistant to AI therapy, and that the fulvestrant/everolimus combination represents a new therapeutic option for AI-resistant disease,” first author Noah Kornblum, MD, Department of Oncology, Montefiore Medical Center, and colleagues wrote.

The data cutoff was March 2017 for the additional follow-up. It was determined that everolimus did not improve median overall survival (28.3 vs 31.4 months; HR, 1.31; 95% CI, 0.72-2.38; stratified log-rankP= .37), but investigators added that the study was not designed to find improvement in survival.

From May 2013 to November 2015, 131 postmenopausal women enrolled PrE0102. The randomized, double-blind, placebo-controlled, phase II trial was set up in 23 institutions. Patients had histologically- or cytologically-confirmed, unresectable, locally advanced or metastatic, ER-positive, HER2-negative breast cancer, and AI-resistant disease.

Study authorsd defined AI resistance as “either as relapse while receiving adjuvant AI therapy or disease progression while receiving an AI for metastatic disease.’’ One prior chemotherapy regimen for metastatic disease was permitted to be included in this trial.

Overall, 66 women were randomized to 10 mg of daily everolimus plus fulvestrant while another 65 women were to receive to fulvestrant plus placebo. Fulvestrant was given to all patients at a dose of 500 mg on days 1 and 15 of cycle 1, then on day 1 of each subsequent 28-day cycle.

There was a maximum of 12 cycles (48 weeks) of treatment or until progression, unacceptable toxicity, or withdrawal of consent. Patients who did not progress by week 48 underwent unblinding of the treatment arm, followed by continuation on open-label evermolimus for all patients originally assigned to everolimus.

The efficacy analysis included all women from the trial, while all women in the placebo arm and 64 women in the everolimus arm were included in the updated safety results. Only 1 patient withdrew consent. One was deemed ineligible due to performance status deterioration. Neither of these 2 women received the protocol treatment.

In the experimental arm, 12 patients (18.2%; 95% CI, 9.8-29.6) had an objective response versus 8 (12.3%; 95% CI, 5.5-22.8) in the placebo arm. However, the difference was not significant (P= .47). Investigators observed a significant difference (P= .01) in clinical benefit rate which favored the experimental arm (63.6% vs 41.5%).

Median duration of treatment in the experimental arm was 5.1 months (range, 0-28.6) for everolimus and 6.9 months (range, 1.4-29.8) for fulvestrant. Median duration was 4.6 months for both fulvestrant and placebo in the control arm.

Women were more likely to require a dose modification in the experimental arm (66% vs 37%), dose held (45% vs 22%), or dose reduced (23% vs 3%), and more likely to miss a dose due to noncompliance (14% vs 9%).

Progression was the most common reason for treatment discontinuation, with 37 (58%) patients in the everolimus arm and 49 (75%) in the placebo arm discontinuing due to progression.

Adverse events (AEs) caused 13 (20%) of patients in the experimental arm to discontinue, compared to 5 (8%) in the placebo arm.

An increased toxicity was associated with everolimus. The most common (≥5%) grade ≥3 or higher treatment-related AEs in the everolimus arm compared with the placebo arm were oral mucositis (11% vs 0%), fatigue (6% vs 5%), and pneumonitis (6% vs 0%). Investigators noted that 1 patient in the placebo arm experienced grade 4 elevated AST. No grade 4 AEs were recorded in the experimental arm.

Three deaths occurred during the study or within 30 days of completing protocol therapy, 2 in the everolimus arm (sepsis and cardiac arrest) and 1 cardiac arrest in the placebo arm. No deaths were attributed to the study treatment.

Study authors addressed the emergence of CDK4/6 inhibitors as an effective treatment option for overcoming endocrine resistance in their conclusion.

“This study was completed before the availability of the CDK4/6 inhibitors, which are effective when added to both first-line AI therapy and second-line fulvestrant in AI-resistant disease,” wrote Kornblum et al. “Given the activity of the CDK4/6 inhibitors such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), in combination with AIs as first-line endocrine therapy, the use of everolimus may represent an option for combination with fulvestrant as second-line therapy in AI-resistant disease.


Kornblum N, Zhao F, Manola J, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor—positive, human epidermal growth factor receptor 2–negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102 [published online April 17, 2018].J Clin Oncol. doi: 10.1200/JCO.2017.76.9331.