Fulvestrant Plus Everolimus: New Second-Line Option for Postmenopausal Metastatic Breast Cancer

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The addition of everolimus (Afinitor) to fulvestrant (Faslodex) doubled progression-free survival in postmenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy compared with fulvestrant plus placebo, according to the randomized, controlled phase II PrECOG 0102 trial. These results were presented at the 2016 San Antonio Breast Cancer Symposium.1

Median progression-free survival was 5.1 months with fulvestrant alone vs 10.4 months for the combination of fulvestrant and everolimus, representing a 40% improvement that was statistically significant (P = .02). The combination did lead to more toxicity, but it appears to be another option for second-line therapy in this setting after endocrine resistance develops.

We are learning on the fly how to manage the toxicities of the combination [fulvestrant and everolimus]. In my experience, the benefit outweighs the risk.
— Noah S. Kornblum, MD

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“Our results are encouraging. I think this benefit is real and consistent with other findings in studies of fulvestrant and everolimus. My personal opinion is that this combination is likely to become a good treatment option for women with metastatic endocrine-resistant breast cancer, but I don’t know if the pharmaceutical companies will apply for the U.S. Food and Drug Administration (FDA) approval for this indication,” said lead author Noah S. Kornblum, MD, of Montefiore-Einstein Center for Cancer Care, Bronx, New York. “I am not aware of any phase III trial.”

Emerging strategies for the treatment of aromatase inhibitor resistance include targeting the mechanistic target of rapamycin (mTOR) pathway as well as use of more complete blockade of the estrogen receptor with a selective estrogen receptor downregulator. Everolimus, an mTOR inhibitor, improved progression-free survival when added to exemestane in the phase III BOLERO-2 trial, Dr. Kornblum said.

Study Details

PrECOG 0102 sought to evaluate the combination of everolimus with fulvestrant vs fulvestrant plus placebo in 131 postmenopausal women with hormone receptor–positive HER2-negative inoperable breast cancer (locally advanced or metastatic) previously treated with an aromatase inhibitor for metastatic disease or relapsing on adjuvant aromatase inhibitor. One prior chemotherapy regimen for metastatic disease was allowed.

New Option for Breast Cancer Resistant to Hormonal Therapy

  • The combination of the selective estrogen receptor downregulator fulvestrant plus the mTOR inhibitor everolimus doubled progression-free survival compared with fulvestrant alone in women with postmenopausal hormone receptor–positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy.
  • The combination had more toxicity, and managing adverse events is a learning curve.
  • Fulvestrant plus everolimus represents a new option for postmenopausal hormone receptor–positive breast cancer that becomes resistant to hormonal therapy.

Patients were randomized in a 1:1 ratio in a blinded manner to fulvestrant (500 mg/d on days 1 and 15 of cycle 1, then day 1 of cycles 2–12 given every 28 days) plus oral everolimus (10 mg/d) or the same dose of fulvestrant plus placebo during the induction phase. Treatment continued until disease progression or unacceptable toxicity, for a maximum of 12 cycles (48 weeks). If patients did not progress or could tolerate treatment without unacceptable toxicity, they moved on to an unblinded continuation phase. No corticosteroid mouthwash was used in the study.

Key Findings

The study met the primary endpoint for progression-free survival. However, the combination was associated with more toxicity, including more frequent grade 3 adverse events (48% for the combination vs 14% for fulvestrant plus placebo). The most common adverse events occurring in more than 5% of patients on the combination arm were stomatitis (9%), pneumonitis (6%), fatigue (5%), and hyperglycemia (6%). The safety profile of both drugs was consistent with that seen in other studies.

Dr. Kornblum noted that prophylactic corticosteroid mouthwash has been shown to reduce the risk of grades 1 and 2 stomatitis from about 65% to 20%, but this was not known when the trial was started.

“Patients have combined toxicities. We are learning on the fly how to manage the toxicities of the combination. Early recognition and vigilance, as well as better physician and patient education, are needed to manage side effects. In my experience, the benefit outweighs the risk,” he said. ■

Disclosure: Dr. Kornblum reported no potential conflicts of interest.


1. 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. 2016 San Antonio Breast Cancer Symposium. Abstract S1-02. Presented December 7, 2016.

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Expert Point of View: Virginia Kaklamani, MD

Everolimus and fulvestrant is another standard-of-care option, and with the evidence from this trial, I won’t have to fight insurance companies for reimbursement.
— Virginia Kaklamani, MD

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