SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is HR-positive, HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. Therapies overcoming this resistance is an area of active research in the breast cancer space.
Capivasertib is a novel pyrrolopyrimidine derivative, and is first-in-class orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy for a variety of human cancers. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor.
CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult 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, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).
The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.
Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.
The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.
The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.
It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.
Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Turner N, Oliveria M, Howell SJ, et al. Presented at the 2022 San Antonio Breast Cancer Symposium: December 6-10, 2022; San Antonio, TX. Abstract GS3-04.