Mutation or amplification in the PIK3CA gene is one of the most frequent somatic mutations in hormone-dependent Her2neu-negative breast cancer (HR+ Her2neu- breast cancer) and is associated with an increased risk of relapse, progression or death. Understanding the mechanisms leading to hyperactivation of the PI3K-mediated signaling cascade has led to a new class of drugs aimed at inhibiting/suppressing it. Studies of the efficacy of the pan-PI3K inhibitor buparlisib and the beta isoform inhibitor taselisib were formally positive and reached their planned primary sites, but were discontinued due to high levels of toxicity. To date, the only phosphatidylinositol 3-kinase (PI3K) inhibitor approved in clinical practice is alpelsib, which selectively inhibits the alpha isoform of the enzyme's catalytic subunit. The efficacy and safety of alpelisib in combination with fulvestrant for the treatment of postmenopausal women and men with HR+ HER2- PIK3CA-mutated advanced or metastatic breast cancer after prior therapy with aromatase inhibitors was demonstrated in the SOLAR-1 study. The next step proving the efficacy of combination therapy in patients previously treated with endocrine therapy in combination with CDK4/6 inhibitors was the open, multicenter, noncomparative three-arm study BYLieve. The current accumulated clinical experience confirms and complements the findings. In this article, we review clinical cases of the use of alpelisib in patients who previously received hormone therapy, including CDK4/6 inhibitors.