Everolimus/Fulvestrant Combo Improves PFS in HR+ Breast Cancer

Adding everolimus to fulvestrant reduced the risk of progression or death by 40% compared with fulvestrant alone for postmenopausal patients with metastatic HR-positive, HER2-negative breast cancer who are resistant to aromatase inhibitor therapy.


In the study, the median progression-free survival with the combination was 10.4 months compared with 5.1 months for fulvestrant (HR, 0.60; 95% CI, 0.40-0.92;P= .02). The safety profile of the everolimus/fulvestrant combination was consistent with that of the everolimus/exemestane combination in the BOLERO-2 trial.

“We have to resist temptation to immediately adopt a positive result of a novel combination from a small study into a new standard of care,” said Noah S. Kornblum, MD, assistant professor of medicine, Albert Einstein College of Medicine, and attending physician of medicine, Montefiore-Einstein Center for Cancer Care. “It may one day be the case that everolimus and fulvestrant becomes a new approved therapy for metastatic HR-positive breast cancer, but caution is prudent until larger studies confirm our results.”

The authors had hypothesized that the combination of everolimus and fulvestrant could be used to treat AI-resistant disease, which usually develops in most patients with HR-positive breast cancer treated with AI therapy. Researchers have shown that AI resistance can be overcome by targeting the PI3K-AKT-mTOR pathway,2as seen in the phase III BOLERO-2 trial of everolimus and exemestane in patients with HR-positive advanced breast cancer and resistance to AI therapy.3

In the BOLERO-2 trial, the addition of the mTOR inhibitor to exemestane improved PFS rates from 3.2 months on exemestane alone to 7.8 months with the combination (P<.0001). The combination was approved in 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer, largely based on results from the BOLERO-2 trial.

The patient population in the PrECOG trial were similar to those in the BOLERO-2 study, yet Kornblum believes that patients in the PrECOG placebo arm may have had longer PFS rates than those in the BOLERO-2 placebo arm due to the superiority of high-dose fulvestrant over exemestane.

“There are some potential advantages of fulvestrant in some people’s minds over steroidal AIs, such as exemestane,” Kornblum said. We don’t really have a direct comparison of these 2 combinations, but I think [fulvestrant and everolimus] does offer some [additional] options and it’s nice to have great options.”

Patients in the PrECOG trial were eligible if they had relapsed while on adjuvant AI therapy or had progressed after an AI therapy for metastatic disease, had an ECOG performance status score of 0 or 1, and had previously received no more than 1 chemotherapy regimen.

The 130 patients were randomized 1:1 in the induction phase to receive either high-dose fulvestrant in addition to 10 mg of everolimus or fulvestrant with matching placebo. Patients continued treatment until progression or unacceptable toxicity for a maximum of 48 weeks. After 48 weeks, patients moved on to the continuation phase and could continue treatment of fulvestrant with or without everolimus.

The combination was associated with additional toxicity compared with the fulvestrant-alone arm with grade 3 adverse events (AEs) occurring in 48% of patients in the combination arm versus 14% in the fulvestrant group. The most common grade 3 AEs in the combination arm included stomatitis in 9% of patients, pneumonitis in 6%, fatigue in 5%, and hyperglycemia in 6%.

"[Physicians] are learning on the fly, somewhat, how to manage the safety and toxicity profiles for these combinations,” said Kornblum. For instance, he noted that in the trial supportive care with prophylactic corticosteroid mouthwash was not used, which could have possibly prevented the frequency of cases of stomatitis as recent data has shown that the use of corticosteroid mouthwash reduces the risk of low-grade stomatitis. “That information was not known at the inception and conduction of this study,” he said.


Kornblum NS, Manola J, Klein P, et al. PrECOG 0102: A randomized, double-blind phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone-receptor positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S1-02.

Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261-275.

Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.Adv Ther.2013;30(10):870-874.