The phase 3 AFFIRM-205 trial shows that the combination of afuresertib and fulvestrant significantly improves outcomes in patients with advanced HR-positive HER2-negative breast cancer with PIK3CA/AKT1/PTEN pathway alterations. Many of these patients had already developed resistance after prior treatments, including CDK4/6 inhibitors.
The study met its main goal, showing that the combination delayed disease progression compared with fulvestrant alone. Median progression-free survival was 7.6 months versus 2.0 months, and the treatment reduced the risk of progression or death by 67%.
Afuresertib works by blocking AKT signaling, a key pathway that drives treatment resistance in hormone-sensitive breast cancer. By inhibiting this pathway, it helps restore tumor sensitivity to hormone therapy. The drug was generally well tolerated, with fewer discontinuations than earlier drugs in the same class, and it is now being positioned as a potential new option in the second-line treatment setting.