Julia Foldi, MD, PhD; Elisa Krill-Jackson, MD; and Timothy J. Pluard, MD, discuss how the INAVO120 trial’s final overall survival (OS) analysis demonstrates a significant 7-month median OS benefit (34 vs 27 months) with inavolisib plus palbociclib plus fulvestrant in PIK3CA-mutated endocrine-resistant metastatic breast cancer, though the limited crossover rate (< 10%) to PIK3CA inhibitors in the control arm complicates interpretation of optimal sequencing strategies.