In a phase II trial, the mTOR inhibitor everolimus, combined with the endocrine therapy fulvestrant, improved progression-free survival in postmenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer who had become resistant to aromatase inhibitors.

Adding the mTOR inhibitor everolimus (Afinitor; Novartis) to the endocrine therapy fulvestrant (Faslodex; AstraZeneca) improved progression-free survival (PFS) for women with advanced breast cancer, according to results presented December 7 at the 2016 San Antonio Breast Cancer Symposium in Texas.

Endocrine therapy with aromatase inhibitors (AI) or other antiestrogens is the treatment of choice for postmenopausal women with hormone receptor (HR)–positive advanced breast cancer, but drug resistance usually develops. An emerging strategy to overcome resistance involves inhibiting accessory pathways, such as the PI3K/AKT/mTOR pathway, that contribute to treatment failure. Previously, everolimus proved effective at increasing PFS in women treated with the AI exemestane (Aromasin, Pfizer). Combining the CDK4/6 inhibitor palbociclib (Ibrance; Pfizer) with fulvestrant has also been shown to prolong PFS.

In the new study, Noah Kornblum, MD, of the Albert Einstein College of Medicine in New York, NY, and colleagues enrolled 130 postmenopausal women with HR-positive, HER2-negative metastatic breast cancer resistant to AIs. All received high-dose fulvestrant, an antiestrogen that acts by accelerating proteasomal degradation of the estrogen receptor, with either everolimus or placebo. Patients were treated until their disease advanced or unacceptable toxicity developed, for a maximum of 48 weeks. A minimum of 98 events—either death or disease progression—was required to trigger data analysis. An analysis of 101 events showed that the addition of everolimus to fulvestrant doubled median PFS from 5.1 months to 10.4 months.

“The results provide additional evidence that adding everolimus to antiestrogen therapy in AI-resistant disease improves clinical outcomes,” said Kornblum, who presented data from the double-blind phase II trial called PrECOG 0102.

However, the combination treatment was associated with additional toxicity, with 48% of participants in the fulvestrant/everolimus arm reporting grade 3 adverse events, versus 14% in the fulvestrant/placebo group. The most common grade 3 adverse events included stomatitis (9%), pneumonitis (6%), hyperglycemia (6%), and fatigue (5%). The rate of adverse events was consistent with an earlier trial of everolimus plus exemestane, said Kornblum.

One limitation of the study, said Kornblum, is that it was designed and conceived prior to the FDA approval of palbociclib to treat metastatic HR-positive breast cancer in combination with AIs or fulvestrant. He said he is eager to learn whether combination treatments that include everolimus will be active in patients who have already received palbociclib and developed resistance to it.

“This clinical trial tells us that we can use fulvestrant with everolimus clinically,” said Virginia Kaklamani, MD, of the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio. “When we don't want to use another AI, having the freedom to use fulvestrant with everolimus is extremely important. And, it seems that for CDK4/6 inhibitors and everolimus, the sort of endocrine therapy we pair them with may not be as important as the fact that we use [these new drugs].” –Pat McCaffrey