A double-blind, phase III, randomised CAPItello-291 study showed that the addition of AKT inhibitor capivasertib to fulvestrant resulted in a significant improvement in progression-free survival (PFS) among patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC) that had progressed during previous aromatase inhibitor (AI) therapy with or without a CDK4/6 inhibitor. Randomisation was not stratified according to AKT pathway alteration.
The safety profile showed that diarrhoea and rash were the most common side effects. The incidence of discontinuation due to side effects was relatively low. The findings are published by Dr. Nicholas C. Turner of the Royal Marsden Hospital and the Institute of Cancer Research in London, UK and colleagues on 1 June 2023 in The New England Journal of Medicine.
The authors wrote that appropriate endocrine-based treatment for patients with HR-positive, HER2-negative ABC after disease progression during AI, with or without a CDK4/6 inhibitor, is unclear. The options include the selective oestrogen receptor degrader fulvestrant as monotherapy or as part of combination treatment.
They explained that AKT is the key node of the PI3K-AKT-PTEN signalling pathway. Overactivation of the pathway occurs in approximately half of HR-positive, HER2-negative breast cancers by activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN. Alterations may be present at the time of cancer recurrence and can also be acquired by previous treatment, including with CDK4/6 inhibitors. AKT signalling may also be activated in the absence of genetic alterations in patients with endocrine resistance.
The PI3K α-selective inhibitor alpelisib, combined with fulvestrant, in PIK3CA-mutated tumours in the SOLAR-1 study and the mTOR inhibitor everolimus, combined with exemestane, in the BOLERO-2 study had greater efficacy than endocrine treatment alone. Both randomised studies were conducted before the availability of CDK4/6 inhibitors, but in a follow-on phase II, single-group BYLieve study, investigators attempted to address the need for data in this context with alpelisib plus fulvestrant.
Capivasertib is an orally bioavailable, small-molecule inhibitor of all three AKT isoforms. Capivasertib inhibited AKT in preclinical models, resulting in dephosphorylation of key downstream targets; the drug also showed antiproliferative activity in breast cancer cell lines and had synergistic antitumour activity in combination with endocrine treatment in preclinical models. In the phase II, FAKTION study, treatment with capivasertib in combination with fulvestrant significantly improved PFS and overall survival as compared with fulvestrant alone among postmenopausal women with HR-positive ABC who had previously received endocrine treatment.
In the article published in The New England Journal of Medicine, the study team report the primary analysis of CAPItello-291 study. They enrolled eligible pre-, peri-, and post-menopausal women and men with HR-positive, HER2-negative ABC who had had a relapse or disease progression during or after treatment with an AI, with or without previous CDK4/6 inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary endpoint was investigator-assessed PFS assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumours. Safety was assessed.
In total, 708 patients underwent randomisation; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for ABC. In the overall population, the median PFS was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death 0.60, 95% confidence interval [CI] 0.51 to 0.71; p < 0.001). In the AKT pathway-altered population, the median PFS was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo–fulvestrant group (hazard ratio 0.50, 95% CI 0.38 to 0.65; p < 0.001).
The most frequent side effects of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash in 12.1% of patients versus 0.3% in those receiving placebo-fulvestrant and diarrhoea in 9.3% versus 0.3%. Side effects leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.
The authors commented that the safety profile of capivasertib compared favourably with that of other agents targeting the PI3K-AKT-PTEN pathway that are used in this patient population. The CAPItello-291 study implemented an intermittent administration schedule of capivasertib, which was selected early in clinical development and was due to in part to preclinical modelling to maximise AKT inhibition and optimise the therapeutic window. It is possible that the reduced side effects profile of capivasertib, with a low incidence of hyperglycaemia, reflects this intermittent schedule.
The study was supported by AstraZeneca and in part by a grant to the Memorial Sloan Kettering Cancer Center from the US National Cancer Institute.
Reference
Turner NC, Oliveira M, Howell SJ, et al. for the CAPItello-291 Study Group. Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. N Engl J Med 2023;388:2058-2070.