Female breast cancer is the most commonly diagnosed cancer, with an estimated 2.3 million new cases in 2020 (2). Approximately 70% of advanced breast cancers are considered HR-positive and HER2-low or negative. For these patients, endocrine therapy combined with CDK4/6 inhibitors is the mainstay of first-line treatment.
“Many patients with advanced disease develop resistance to first-line CDK4/6 inhibitors and estrogen receptor-targeting therapies, illuminating the need for additional treatment options. Current treatment strategies include fulvestrant, a selective estrogen receptor downregulator, either as monotherapy or in combination with targeted therapies,” says Mafalda Oliveira, Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), Clinical Investigator of the Vall d´Hebron Institute of Oncology´s (VHIO) Breast Cancer Group, and a co-author of this present study (1).
Over activation of the PI3K/AKT signaling pathway occurs in approximately half of HR+ HER2- breast cancers and promotes tumor progression and resistance to therapy. Developed by AstraZeneca, capivasertib is an orally bioavailable small-molecule AKT inhibitor designed to block AKT´s cancer-driving activity.
The phase III CAPItello-291 double-blind, randomized trial led by Nicholas C. Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, London, UK, assessed the efficacy and safety of capivasertib in combination with fulvestrant versus placebo plus fulvestrant for the treatment of patients with locally advanced or metastatic HR+/HER2- breast cancer whose disease had recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor.
“This multi-center international study enrolled 708 patients including a prespecified biomarker subgroup of patients whose tumors had alterations in the PIK3CA, AKT1 or PTEN genes, and patients with tumors lacking a qualifying alteration detected in any of these three genes or with an unknown test result. The heterogenous nature of the CAPItello-291 population reflects the patients attended in routine clinical practice,” adds Oliveira.
Capivasertib steps up in optimizing endocrine therapy
At primary analysis, a 40% decrease in the risk of disease progression or death was observed in the group of patients treated with capivasertib-fulvestrant, verus those who received placebo plus fulvestrant in the overall population. The median progression-free survival was 7.2 months in the capivasertib-fulvestrant group and 3.6 months in placebo-fulvestrant group.
In the AKT pathway-altered population the reduction in risk of disease progression or death was 50%, with a median progression-free survival of 7.3 months in patients treated with the new combination compared to 3.1 months with placebo-fulvestrant. The most common adverse events observed with capivasertib and fulvestrant were rash, diarrhea or hyperglycemia, but the combination was generally well tolerated.
“While greater clinical benefits were observed in patients with tumors harboring AKT alterations, results of this study show that the capivasertib-fulvestrant combination in the overall population —with our without alterations — is clearly superior to standard treatment with fulvestrant alone. Our data suggest that capivasertib plus fulvestrant could replace the standard of care for these patients and change clinical practice in the short to medium term,”concludes Mafalda Oliveira.
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