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The addition of everolimus to fulvestrant improves outcomes for postmenopausal patients with HR-positive, HER2-negative metastatic breast cancer

Data from the PrECOG0102 phase II clinical trial revealed that progression-free survival (PFS) was more than doubled for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer resistant to aromatase inhibitor therapy by adding everolimus to treatment with the endocrine therapeutic fulvestrant. Endocrine therapy, often with an aromatase inhibitor, is the standard of care for most patients with HR-positive advanced breast cancer. However, over time, resistance to aromatase inhibitors develops and treating patients with aromatase inhibitor–resistant disease remains a challenge. Recent studies have shown that adding the mTOR inhibitor everolimus to the aromatase inhibitor exemestane and adding a CDK4/6 inhibitor to fulvestrant improves outcomes for patients.

130 postmenopausal women with HR-positive, HER2-negative metastatic breast cancer (MBC) enrolled in the PrECOG0102 trial all received fulvestrant (500 mg IM q2 weeks for 3 doses, then q4 weeks) and then were randomly assigned (1:1) to either oral everolimus (10mg; N=64) or placebo (N=66). Tumor assessment was performed at baseline and every 12 weeks. Treatment continued until progressive disease (PD) by RECIST 1.1 criteria. Patients who discontinued everolimus/placebo due to toxicity continued fulvestrant until PD. The primary endpoint was progression-free survival (PFS), defined as time from start of treatment until progression or death. Analysis conducted after 98 patients who had disease progression showed that median PFS was 10.4 months among patients assigned to everolimus, compared with 5.1 months among those assigned to placebo (hazard ratio: 0.61, 95% CI :0.40–0.92; stratified log rank p= 0.02).

Grade 3/4 adverse events were more commonly experienced by those assigned to everolimus: 53% of those assigned to everolimus had a grade 3 adverse event compared with 23% of those assigned to placebo. The most common grade 3/4 adverse events were hyperglycemia (16%/2% versus 0%) stomatitis (11%/0% versus 0%), hypertriglyceridemia (9%/2% versus 0%), lymphopenia (9%/0% versus 0%), and pneumonitis (6%/2% versus 0%). The rates of grade 3/4 adverse events in this trial were very similar to those found in earlier studies evaluating combination therapies containing everolimus. Everolimus/placebo was discontinued for adverse events, patient withdrawal, or at physicians’ discretion in 39% of the patients in the everolimus-arm and in 21% of the patients in the placebo-arm.

To summarize, the addition of everolimus to fulvestrant significantly improved PFS in post-menopausal women with MBC resistant to aromatase inhibitor therapy. However, large studies are required to confirm this result. The main limitation of the study is that it was designed and conceived prior to the FDA approval of the CDK4/6 inhibitor palbociclib as a treatment for metastatic HR-positive breast cancer. There were only two patients enrolled in this trial who had been treated with a CDK4/6 inhibitor. In future it will be important to determine whether combination treatments that include everolimus are active in that category of patients.


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 (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy. San Antonio Breast Cancer Symposium 2016, abstract S1-02.

Speaker Noah Kornblum


Noah S. Kornblum, MD, PhD,
Montefiore Einstein Center for Cancer Care, New York, USA


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