Treatment with buparlisib in combination with endocrine therapy significantly improved PFS compared with placebo in patients with HR-positive advanced breast cancer that had progressed after treatment with everolimus plus exemestane.
Treatment with the PI3 kinase (PI3K) inhibitor buparlisib in combination with endocrine therapy significantly improved progression-free survival compared with placebo in patients with hormone receptor (HR)-positive advanced breast cancer that had progressed after treatment with everolimus plus exemestane, according to results of the phase III BELLE-3 trial presented at the 2016 San Antonio Breast Cancer Symposium, held December 6–10 in San Antonio, Texas.
“The BELLE-3 trial met its primary endpoint,” Ruth O’Regan, MD, of UniversitÃ¤tsklinikum Ulm, Ulm, Germany, said during a press conference. “Buparlisib plus fulvestrant prolonged progression-free survival compared with placebo plus fulvestrant in postmenopausal women with HR-positive/HER2-negative advanced breast cancer who had received prior aromatase inhibitor and mTOR inhibitor treatment.”
According to O’Regan, activation of the PI3K/mTOR pathway is a hallmark of HR-positive breast cancer resistant to endocrine therapy. However, preclinical studies of PI3K inhibitors suggest that adding the drugs to endocrine therapy may help overcome resistance.
The BELLE-3 study included 432 postmenopausal women with HR-positive/HER2-negative locally advanced or metastatic breast cancer. Patients were randomly assigned 2:1 to buparlisib 100 mg per day plus fulvestrant 500 mg (n = 289) or placebo plus fulvestrant (n = 143). All patients had progressed on or after treatment with an aromatase inhibitor. About 70% of patients had received two or more lines of endocrine therapy in the metastatic setting. The primary endpoint was progression-free survival.
Patients assigned to buparlisib plus fulvestrant had a median progression-free survival of 3.9 months compared with 1.8 months for patients assigned placebo (P < .001). The 6-month progression-free survival rate was 31% for the buparlisib arm compared with 20% in the placebo arm. Patients assigned buparlisib were 33% less likely to have their disease progress at the time of assessment (hazard ratio [HR], 0.67; 95% 0.53–0.84).
O’Regan pointed out that the overall response rate overall was low, but it was higher in the buparlisib arm compared with the placebo arm (7.6% vs 2.1%).
The researchers also looked at the efficacy of buparlisib based on PI3KCA gene status in the primary tumor tissue and in circulating tumor DNA (ctDNA) assessed using patients’ blood samples. Of the 349 patients for whom data from ctDNA on PIK3CA status was available, 147 had mutations in the gene; the rest were wild-type. Among patients with the mutation, the progression-free survival was 4.2 months for patients assigned buparlisib compared with 1.6 months for those in the placebo arm. These patients were 54% less likely to have their disease progress at the time of assessment (HR, 0.46; 95% CI, 0.29–0.73; P < .001). When assessed in the primary tumor tissue, those patients with PIK3CA mutations assigned to buparlisib had a median progression-free survival of 4.7 months compared with 1.4 months for patients assigned placebo (HR, 0.39; 95% CI, 0.23–0.65; P < .001).
Finally, the researchers also looked at progression-free survival by visceral disease status. Those patients with visceral disease assigned to buparlisib had significant improvements in progression-free survival compared with patients assigned placebo (3.1 vs 1.5 months; HR, 0.56; 95% CI, 0.43–0.74). There was no difference in progression-free survival for patients with non-visceral disease.
Overall, there was a higher rate of adverse events in patients assigned buparlisib compared with placebo. These patients had higher rates of transaminase elevations, and higher rates of depression and anxiety. O’Regan noted that a few patients on the buparlisib arm attempted suicide.
This study was funded by Novartis.