Here we have evaluated the antitumor activity of Elacestrant, the oral selective estrogen receptor degrader (SERD) and antagonist, in combination with the σ-sparing PI3K inhibitor MEN1611, in vitro and in vivo in different clinically relevant BC Patient-Derived Xenograft (PDX) models....In the PDX HBxC-3, wild-type for PIK3CA and ESR1 genes, the Tumor Volume-Inhibition (TVI) was 56.2%, 48.7% and 71.7% for MEN1611, Elacestrant and the combination group, respectively. In this model, the combination showed improved anti-tumor activity in comparison to the single agent treatments.