In patients with hormone receptor (HR)-positive, HER2-low or -negative, locally advanced or metastatic breast cancer resistant to aromatase inhibitors, the addition of the investigational first-in-class AKT inhibitor capivasertib (AZD5363) to fulvestrant (Faslodex) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo plus fulvestrant. The PFS benefit observed with capivasertib was even greater in a subset of patients with an AKT pathway alteration.
According to Nicholas Turner, MD, PhD, Professor, Molecular Oncology, The Institute of Cancer Research, The Royal Marsden NSH Foundation Trust, London, England, UK, who presented results from the CAPItello-291 trial during the 2022 San Antonio Breast Cancer Symposium, treatment with capivasertib plus fulvestrant demonstrated a 40% reduction in the risk for disease progression or death versus placebo plus fulvestrant in the overall patient population.
“After progression on CDK4/6 inhibitors, further endocrine therapies given alone have relatively low efficacy,” said Dr Turner. “We need new treatment options for these patients. Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with HR-positive advanced breast cancer who have progressed on an endocrine-based regimen.”
Study Details
The phase 3, double-blind, CAPItello-291 study enrolled 708 patients with histologically confirmed HR-positive, HER2-low or -negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to 1 line of chemotherapy for advanced disease. The trial has dual primary end points of PFS in the overall patient population and in a population of patients whose tumors have alterations in the AKT pathway (AKT1-3, PIK3CA, or PTEN genes). Secondary end points include overall response rate and overall survival.
The patients in the overall trial population were randomized to either the capivasertib plus fulvestrant arm (N = 355) or placebo plus fulvestrant (N = 353). Patients in the experimental cohort received 400 mg of capivasertib twice daily for 4 days on and 3 days off plus 500 mg of fulvestrant during cycle 1 on days 1 and 15 then every 4 weeks thereafter. In addition, the control arm received matched placebo plus the same fulvestrant backbone. A total of 155 and 134 patients in each arm, respectively, had AKT pathway-altered tumors.
The median PFS in the overall trial population was 7.2 months in the capivasertib plus fulvestrant arm and 3.6 months in the placebo plus fulvestrant arm, and 7.3 months and 3.1 months, respectively, in the subset of patients with an AKT pathway alteration. The overall response rate in the overall trial population was 22.9% among patients in the capivasertib plus fulvestrant arm and 12.2% in the placebo plus fulvestrant arm, and 28.8% and 9.7%, respectively, in the subset of patients with an AKT pathway alteration.
Although the overall survival data were immature at the time of the analysis, early data show a trend toward an improvement in the capivasertib arm in both the overall population and those with AKT pathway alterations.
The adverse event (AE) profile was manageable and consistent with data from previous studies of capivasertib. The most common grade ≥3 AEs among patients treated with capivasertib plus fulvestrant were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). The rate of discontinuation due to AEs was 13% among patients who received capivasertib plus fulvestrant versus 2.3% among patients who received placebo plus fulvestrant.
Expert Commentary
“I think it’s a new urgency to provide access to inhibitor in patients with AKT1-3 mutations and PTEN alterations,” remarked Fabrice André, MD, PhD, Director, Research Department of Medical Oncology, Breast Cancer Unit, Department of Medical Oncology, Gustave Roussy-Cancer Campus, Villejuif, France. “There is a clinically relevant benefit in the overall population and in PIK3CA-mutant and AKT1-3/PTEN-altered populations, from 0 to 7 months. What is missing is circulating tumor DNA analysis and exploration on other alterations in the PI3K pathway.”
