Research in context
Evidence before this study
We searched PubMed between date of inception and June 15, 2020 for clinical trials or studies published in public medical databases assessing targeted therapies used for the treatment of advanced breast cancer after progression on treatments including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Terms used in this search included “CDK4/6 inhibitor” and “targeted therapies for advanced breast cancer”. We did not identify any trials evaluating a PI3K inhibitor in advanced breast cancer in the post-CDK4/6 inhibitor setting. International guidelines recommend endocrine therapy plus CDK4/6 inhibitors as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer; however, resistance develops in the majority of patients. Alpelisib (PI3Kα-selective inhibitor and degrader) plus fulvestrant demonstrated efficacy versus placebo plus fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer in the SOLAR-1 trial, but at the time that this trial was enrolling, CDK4/6 inhibitors were not available in many areas around the world, and only a small proportion of patients who had progressed on CDK4/6 inhibitors were enrolled.
Added value of this study
To our knowledge, BYLieve is the first, prospective clinical study to examine the use of alpelisib plus fulvestrant for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer solely in the post-CDK4/6 inhibitor setting. The primary endpoint of the study, evaluating the proportion of patients who were alive and without disease progression at 6 months, was met. Side-effects were manageable, with diarrhoea and hyperglycaemia the most common any-grade adverse events observed.
Implications of all the available evidence
Our results support the use of alpelisib plus fulvestrant for treatment of hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in the post-CDK4/6 inhibitor setting.