Phase 3 trial of rising ESR1 mutation-guided switch from aromatase-palbociclib to fulvestrant-palbociclib in advanced breast cancer

In advanced ER-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors (AIs) frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The phase 3 PADA-1 trial, in 83 centers in France, included patients with ER-positive, HER2-negative ABC on first-line AI-palbociclib, and monitored ESR1-mutation in blood (bESR1^mut). Patients with rising bESR1^mut were randomized to continue AI-palbociclib or switch to fulvestrant-palbociclib. Switching resulted in significantly improved progression-free survival, which was evident in almost all prespecified subgroups. The authors conclude that the therapeutic targeting of bESR1^mut resulted in significant clinical benefit.