Capivasertib for Advanced ER+/HER2− Breast Cancer

Aberrant AKT signaling, through the PI3K–AKT–PTEN pathway, is often present in tumor cells that develop endocrine resistance. Capivasertib, an investigational oral, small-molecule inhibitor of AKT, has antiproliferative properties and demonstrated synergy with endocrine therapy. A phase 2 trial (FAKTION) previously showed fulvestrant plus capivasertib improved progression-free survival (PFS) and overall survival (OS) over fulvestrant alone in postmenopausal patients with ER-positive/HER2-negative breast cancer who previously received endocrine therapy (Lancet Oncol 2020; 21:345).

Now, the industry-sponsored phase 3 CAPItello-291 trial evaluated fulvestrant plus capivasertib in pre-, peri-, and postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had relapse or progression following treatment with an aromatase inhibitor with or without a CDK4/6 inhibitor. A total of 708 patients were randomized to fulvestrant (500 mg intramuscularly every 14 days for three injections and every 28 days thereafter) plus either capivasertib (400 mg orally twice daily for 4 days each week) or matching placebo; 41% had AKT pathway alterations and 69% had previously received a CDK/6 inhibitor.

Median PFS was 7.2 months in the capivasertib group compared with 3.6 months in the placebo group (hazard ratio for progression or death, 0.60; P<0.001). In patients with AKT pathway alterations, the median PFS was 7.3 versus 3.1 months, respectively (HR, 0.50; P<0.001). The most frequent grade 3 or higher adverse events with capivasertib were rash (12.1% vs. 0.3% with placebo) and diarrhea (9.3% vs. 0.3%, respectively). Baseline global health status and quality of life were maintained longer in the capivasertib arm than the placebo arm.