Optimizing Treatment Selection and Sequencing in HR+/HER2– mBC

PI3K/AKT Pathway Inhibitors and Clinical Decision-Making

The PI3K/AKT pathway represents a critical resistance mechanism in hormone receptor–positive breast cancer, with 4 approved agents offering different targeting strategies and toxicity profiles. Alpelisib and inavolisib target PI3K directly, whereas capivasertib inhibits AKT and everolimus affects the downstream mTOR pathway. Each agent demonstrates class effects, including diarrhea, rash, hyperglycemia, and stomatitis, but with distinct individual toxicity patterns that influence clinical selection.

Capivasertib emerges as a preferred second-line option for patients with PIK3CA or AKT1 mutations due to its unique dosing schedule of 4 days on and 3 days off, which helps manage diarrhea that typically peaks by day 4. This intermittent dosing strategy, combined with generally good tolerability, makes capivasertib attractive for maintaining quality of life while targeting the PI3K pathway. Everolimus remains valuable for patients without specific pathway mutations, offering broad applicability with established combination data across multiple endocrine partners.

The inavolisib regimen, though approved, targets a narrow patient population limited to those who experienced recurrence during adjuvant aromatase inhibitor therapy or within 12 months of completion, further restricted to patients with PIK3CA mutations. This specificity limits clinical experience but provides an important frontline option for patients meeting these criteria. Clinical decision-making increasingly relies on biomarker testing, duration of prior therapy response, and patient-specific factors to optimize pathway inhibitor selection.