Population Pharmacokinetics and Exposure–Response Analyses for Capivasertib in Combination With Fulvestrant in Patients With Breast Cancer

Capivasertib is a potent, selective pan-AKT inhibitor. In the Phase III CAPItello-291 trial in patients with aromatase inhibitor-resistant, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, the addition of capivasertib (400 mg twice daily, 4 days on, 3 days off) to fulvestrant significantly improved the dual primary endpoints of progression-free survival in the overall and PIK3CA/AKT1/PTEN-altered population compared with placebo plus fulvestrant and had an acceptable safety profile. Based on data from six Phase I-III trials (N = 851), a three-compartment population pharmacokinetic model was used to generate individual Bayes' capivasertib steady-state exposure parameters (AUC, C_max, and C_min). No relationship between exposure and efficacy (progression-free survival or objective response rate) was identified in CAPItello-291 (n = 394). The safety analysis, which pooled data from CAPItello-291 and a Phase I trial (n = 468), identified significant relationships between capivasertib exposure and the likelihood of an adverse event (AE) leading to dose modification, AE grade ≥ 3, and diarrhea AE grade ≥ 2; whereas, no significant relationships were identified between capivasertib exposure and AE leading to dose discontinuation, serious AE, AE grade ≥ 1, rash AE grade ≥ 2, hyperglycemia AE grade ≥ 1, hyperglycemia AE grade ≥ 3, or increased blood glucose > 13.9 mmol/L. These results support the consistent benefit observed with the intermittent capivasertib dosing schedule of 400 mg twice daily, in combination with fulvestrant, in patients with aromatase inhibitor-resistant, HR-positive/HER2-negative advanced breast cancer without dose adjustment based on intrinsic factors, such as race, age, body weight, renal or hepatic function.