Research in context
Evidence before this study
We searched PubMed to identify clinical studies published between March 30, 2012, and March 30, 2017, using the terms “PI3K”, “endocrine therapy”, “mTOR”, “advanced”, and “breast cancer”. Several phase 1 and 2 studies were identified that had investigated PI3K inhibitors combined with endocrine therapy in advanced breast cancer, but none focused on this combination of agents in patients with advanced breast cancer who were previously treated with endocrine therapy plus mTOR inhibitors.
Added value of this study
This is, to our knowledge, the first phase 3 study to evaluate the efficacy and safety of buparlisib, a pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, δ, and γ), combined with fulvestrant, an endocrine therapy, in patients with advanced breast cancer relapsing on or after endocrine therapy and mTOR inhibition. Our results show that buparlisib plus fulvestrant prolonged progression-free survival compared with fulvestrant alone, particularly in patients with tumours harbouring PIK3CA mutations detected in circulating tumour DNA or those with visceral disease. This combination also offered improvements in overall response and clinical benefit when compared with fulvestrant alone. However, the safety profile of buparlisib plus fulvestrant was consistent with that of previous reports; unfavourable adverse events included mood disorders, liver toxicities, and hyperglycaemia.
Implications of all the available evidence
On the basis of the safety profile of buparlisib plus fulvestrant, we recommend discontinuation of further research of this combination therapy within the setting of advanced breast cancer. However, the positive efficacy outcomes associated with buparlisib plus fulvestrant support continued investigation of endocrine therapy combined with more selective PI3K inhibitors. Further studies are warranted to validate the predictive value of PIK3CA mutations as biomarkers for PI3K inhibitor activity.