Di Leo A, et al. - Herein, the efficacy and safety of buparlisib plus fulvestrant were comprehensively examined in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors. The results revealed that the safety profile of buparlisib plus fulvestrant did not support its further development in this setting. The efficacy of buparlisib, however, supported the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.

Methods

• The design of BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
• Researchers enrolled postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, from 200 trial centres in 22 countries.
• Enrollees were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles.
• Randomisation was stratified by visceral disease status.
• The progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat) was included as the primary endpoint.
• Safety analysis was carried out in all patients who received at least one dose of treatment and at least one post-baseline safety assessment.

Results

• A total of 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups, between Jan 15, 2013, and March 31, 2016.
• Findings reported substantially longer median progression-free survival in the buparlisib vs placebo group (3.9 months [95% CI 2.8-4.2] vs 1·8 months [1.5-2.8]; hazard ratio [HR] 0·67, 95% CI 0.53-0.84, one-sided p=0.00030).
• As per the findings, most frequent grade 3-4 adverse events in the buparlisib vs placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]).
• The data displayed serious adverse events in 64 (22%) of 288 patients in the buparlisib group vs 23 (16%) of 140 in the placebo group.
• Elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none) were discovered to be the most frequent serious adverse events (affecting ≥2% of patients).
• The occurrence of on-treatment deaths was found in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group.
• Maximum deaths were the result of metastatic breast cancer, and two were treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group).