In the phase II FAKTION trial reported in The Lancet Oncology, Jones et al found that the addition of the AKT inhibitor capivasertib to endocrine therapy with fulvestrant prolonged progression-free survival in postmenopausal women with aromatase inhibitor–resistant, estrogen receptor (ER)-positive, HER2-negative metastatic or locally advanced inoperable breast cancer.

Capivasertib, a potent selective oral agent, inhibits all three isoforms of the AKT kinase.

Study Details

In the multicenter double-blind trial, 140 postmenopausal women who had relapsed or whose disease had progressed on an aromatase inhibitor were randomly assigned to receive intramuscular fulvestrant at 500 mg on day 1 every 28 days (with a loading dose on day 15 of cycle 1) plus either oral capivasertib at 400 mg (n = 69) or placebo (n = 71) twice daily on a 4-days-on/3-days-off schedule starting on day 15 of cycle 1. Treatment continued until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival in the intention-to-treat population. Patients were followed until all had had at least 6 months of follow-up and the minimum of 98 disease progression events required for analysis had been confirmed.

Progression-Free Survival

Median follow-up for progression-free survival analysis was 4.9 months. At the time of primary analysis for progression-free survival, 112 total progression-free survival events had occurred—in 49 patients (71%) in the capivasertib group vs 63 patients (89%) in the placebo group. Median progression-free survival was 10.3 months vs 4.8 months (hazard ratio [HR] = 0.58, 95% confidence interval = 0.39–0.84, P = .0018), including 7.6 months vs 3.2 months (HR = 0.61, P = .030) among 99 patients with measurable disease and 13.4 months vs 7.9 months among 41 with nonmeasureable disease at baseline (HR = 0.47, P = .046).

An objective response was observed in 29% vs 8% of patients (odds ratio = 4.42, P = .0031). Overall survival data were immature; with a median follow-up for survival of 12 months, death had occurred in 30% vs 44% of patients at data cutoff.

Adverse Events

The most common grade 3 or 4 adverse events in the capivasertib group were hypertension (32% vs 24% of placebo group), rash (20% vs 0%), diarrhea (14% vs 4%), infection (6% vs 3%), and fatigue (1% vs 4%). Serious adverse events were observed only in the capivasertib group and consisted of diarrhea in three patients; acute kidney injury and rash in two patients each; and hyperglycemia, loss of consciousness, sepsis, and vomiting in one patient each. A death due to atypical pulmonary infection was considered possibly related to capivasertib treatment.

The investigators concluded, “Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase III trials.”

Robert H. Jones, MRCP, of Velindre Cancer Centre, Cardiff University, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AstraZeneca and Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.