A more than doubling of progression-free survival (PFS) was achieved by adding everolimus to fulvestrant in women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer that was resistant to aromatase inhibitor (AI) therapy, reported Noah S. Kornblum, MD, Assistant Professor of Medicine at Albert Einstein College of Medicine, Bronx, NY, at the 2016 San Antonio Breast Cancer Symposium.
These findings come from the randomized, phase 2 PrECOG 0102 clinical trial. He stated that the results of the study provide “additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes.”
Although AI therapy is highly effective in the treatment of HR-positive metastatic breast cancer, resistance to AI therapy ultimately develops in most women. As a result, treating patients with AI-resistant disease remains a challenge.
One strategy for overcoming AI resistance is to target the PI3K/Akt/mTOR pathway, said Dr Kornblum. For example, combining the mTOR inhibitor everolimus with the AI exemestane significantly improved median PFS from 3.2 to 7.8 months compared with exemestane alone in the phase 3 BOLERO-2 trial, although overall survival (OS) was not improved. The addition of everolimus to tamoxifen in AI-resistant breast cancer also improved clinical outcomes in the randomized, phase 2 TAMRAD study.
Another strategy for overcoming AI resistance is by more completely blocking estrogen receptor signaling through the use of a selective estrogen receptor downregulator (SERD). For example, although fulvestrant at a dosage of 250 mg monthly was not more effective than exemestane in AI-resistant disease in the EFECT trial, the 500-mg monthly dosage proved more effective than the 250-mg dosage in the CONFIRM study, suggesting that the higher fulvestrant dosage may be a more effective antiestrogen therapy than exemestane in AI-resistant disease.
The investigators of the PrECOG 0102 trial therefore hypothesized that the combination of everolimus plus fulvestrant would be more effective than fulvestrant alone in AI-resistant disease.
They enrolled 130 postmenopausal women with HR-positive, HER2-negative metastatic breast cancer, all of whom were being treated with high-dose fulvestrant. These patients were randomly assigned to everolimus or placebo. Approximately 17% had received previous chemotherapy for metastatic disease, <10% had received fulvestrant prior to randomization, and only 2 patients—both in the placebo arm—had received previous cyclin-dependent kinase (CDK)4/6 inhibitor therapy.
In the induction phase, patients received their assigned treatments until evidence of disease progression orunacceptable toxicity, for a maximum of 12 cycles (48 weeks). Patients who did not experience progression or unacceptable toxicity were unblinded and allowed to proceed to the continuation phase of the study and remain on fulvestrant with or without everolimus.
Approximately 60% of patients in the everolimus arm discontinued therapy because of progression compared with 80% in the placebo arm. Twenty-two percent of patients in the everolimus arm discontinued protocol treatment due to an adverse event compared with 8% in the placebo arm.
Analysis after 101 patients experienced 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, 0.60; P = .02).
After a median follow-up of approximately 25 months, an estimated 23% of study participants had died. There was no difference in median OS; however, the trial was not designed to identify an impact of everolimus on OS, said Dr Kornblum.
Grade 3 or 4 adverse events occurred more frequently in the patients randomized to everolimus. Approximately half (48%) of those randomized to everolimus had a grade 3 adverse event compared with 14% of those assigned to placebo. The most common grade 3 adverse events, occurring in >5% of patients, included stomatitis (9%), pneumonitis (6%), fatigue (5%), and hyperglycemia (6%).
The improvement in PFS observed in this study is comparable to that observed in the PALOMA-3 trial with the CDK4/6 inhibitor palbociclib, noted Dr Kornblum. PrECOG 0102 was completed before the availability of CDK4/6 inhibitors. Because only 2 patients in PrECOG 0102 received previous CDK4/6 inhibitor therapy, further investigation is required to define whether previous CDK4/6 inhibitor treatment would have an impact on response to combination mTOR/SERD therapy.
“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 Dr Kornblum. “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 rates of grade 3 or 4 adverse events in PrECOG 0102 were similar to those observed in earlier studies evaluating combination therapies containing everolimus. “It is important for patients and clinicians to be aware of these potential complications, to try to identify them early, and to learn ways to manage them. For example, recently we have learned that the use of prophylactic corticosteroid mouthwash could significantly reduce the risk of oral mucositis for some patients taking everolimus,” Dr Kornblum concluded.