Association of fulvestrant and capivasertib increases progression free survival in patients with breast cancer

Through a phase II study recently published in the journal Lancet Oncology, an AKT inhibitor for the first time demonstrates effectiveness in the metastatic breast cancer scenario.
In FAKTION study, post-menopausal patients with life expectancy greater than 3 months, with histological confirmation of breast cancer with estrogen receptor positivity, unresectable or metastatic disease, without hematological, renal or hepatic dysfunction and with performance status 2 or less were randomized to receive capivasertib 480mg twice daily for 4 consecutive days of the week (the remaining days of the week without) associated with fulvestrant 250mg on the 1st and 15th days of the first cycle (each cycle lasting 28 days) and the remaining cycles of 500mg injection, while in the other arm of the study, the same doses of fulvestrant combined with placebo.
Of a total of 140 recruited patients, 69 were allocated to the experimental group and the rest to the fulvestrant group plus a placebo. The median progression-free survival (PFS) was 10.3 months (95% CI; 5-13.2) in the experimental group and 4.8 months (95% CI; 0.39-0, 84) in the placebo group with statistical significance (two-sided p=0·0044; one-sided log rank test p=0·0018). As for the clinical benefit, the rates were 55% and 41% respectively (odds ratio [OR] 1·78, 95% CI 0·91–3·47, 2-sided p=0·093). About median duration of response of those with measurable disease, during post-hoc analysis, it was 7.1 months and 5 months also respectively
Response rates were 29% in the experimental group and 8% in the control group (OR 4·42, 95% CI 1·65–11·84, 2-sided p=0·0031). In addition, 55% of the experimental group showed clinical benefit while 41% presented in the control group (OR 1·78, 95% CI 0·91–3·47, 2-sided p=0·093). Still immature data for overall survival.
Combination efficacy was also investigated in the subgroups with or without changes in the PI3K and PTEN pathways. Median of PFS among patients without these changes was 10.3 months in the capivasertib group (95% CI; 3.2-13.2) and 4.8 months in the placebo group (95% CI; 3.0-8.6). For the subgroups with the necessary changes, the medians of PFS were respectively 9.5 months (95% CI; 6.6-13.7) and 5.2 months (95% CI; 3.1-8, 4)
Regarding treatment tolerance, dose reduction in each arm of the study occurred in 41% of patients in the combination group and 1% in the placebo group. Discontinuation due to adverse events occurred in 12% in the first group due to rash, diarrhea, hypoglycemia, nausea, oral ulcers and sweating.
Grade 3-4 most common adverse events in the combination group and placebo respectively were hypertension (32% vs 24%), diarrhea (14% vs 4%), rash (20% vs 0%), infection (6% vs 3%) and fatigue (1% vs 4%). In all, 65% of the capivasertib group and 50% of the placebo group had grade 3-5 adverse events. A single patient only died in the study due to atypical pulmonary infection, which was attributed by capivasertib.
This study is the first to demonstrate the efficacy of an AKT inhibitor combined with fulvestrant in this oncological scenario and given the manageable toxicity and the promising character of the use of this drug, the development of a phase III study is expected. You can read it in full here.