Population Pharmacokinetics and Exposure–Response Analyses for Capivasertib in Combination With Fulvestrant in Patients With Breast Cancer
Year: 2025
Type: article
Abstract: ABSTRACT 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.
DOI: 10.1111/cts.70286
Authors: Carlos Fernandez Teruel, Marie Cullberg, Ignacio González‐García, Gaia Schiavon, Ling Zhang, Diansong Zhou
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,630
OpenAlex ID: W4412111202