Toxicities associated with buparlisib make it a poor option for the treatment of patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who progressed on or after mTOR inhibitor therapy, according to a new study. The efficacy of the agent, however, suggests that PI3K inhibitors along with endocrine therapy remain a reasonable approach in patients with PIK3CA mutations.
Previous research has suggested that PI3K inhibition may be clinically important in patients who progress on mTOR inhibitor treatment, wrote study authors led by Angelo Di Leo, MD, of Nuovo Ospedale di Prato Santo Stefano in Prato, Italy.
The BELLE-3 study was designed to test that idea; it was a randomized, double-blind, placebo-controlled phase III trial that included 432 patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer. All patients had relapsed on or after endocrine therapy and mTOR inhibitors; most patients (99% of each group) had received everolimus, while several had received ridaforolimus. They were randomized to receive either buparlisib (289 patients) or placebo (143 patients) along with fulvestrant. Results were published in Lancet Oncology.
The median progression-free survival (PFS) with buparlisib was 3.9 months, compared with 1.8 months with placebo, for a hazard ratio of 0.67 (95% CI, 0.53–0.84; P = .00030). The 6-month PFS rate was 31% with buparlisib and 20% with placebo. A multivariate analysis that adjusted for baseline variables confirmed these results, with a hazard ratio of 0.55 (95% CI, 0.42–0.72; P = .0001). PFS was better with the study drug for patients 65 years and older and for those younger than 65 years; though most did not reach significance, other subgroups also fared better with buparlisib.
Buparlisib was more effective in patients with a PIK3CA mutation. Median PFS in those patients with a mutation was 4.2 months with buparlisib and 1.6 months with placebo, for a hazard ratio of 0.46 (95% CI, 0.29–0.73; P = .00031). In PIK3CA wild-type patients, the hazard ratio was 0.73 (95% CI, 0.53–1.00; P = .026).
Grade 3/4 adverse events were reported in 61% of buparlisib patients and in 34% of placebo patients. Among the more frequent events in the buparlisib group were elevated alanine aminotransferase levels (22% vs 3%), elevated aspartate aminotransferase levels (18% vs 3%), hyperglycemia (12% vs 0%), and hypertension (6% vs 4%). Twenty-two percent of the buparlisib patients experienced a serious adverse event, compared with 16% of placebo patients. Dose interruptions due to adverse events were more frequent with the study drug, in 36% compared with 9% of placebo patients.
Suicidal ideation was reported in 2% of buparlisib patients and in 1% of placebo patients, and there were three suicide attempts in the buparlisib group.
“On the basis of the safety profile of buparlisib, we do not recommend its further exploration in this setting,” the authors wrote. “However, the present results set the stage for ongoing and future trials testing alpha-selective PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.”