Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer

Abstract

Background: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited.

Methods: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (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 end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed.

Results: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival 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 progression-free survival 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 adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.

Conclusions: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).

Figure 1.. Investigator-Assessed Progression-free Survival in the Overall Population and in Patients with AKT Pathway–Altered Tumors.

The median duration of follow-up for the primary analysis of progression-free survival in the overall population was 13.0 months (range, 0.0 to 25.0) in the capivasertib–fulvestrant group and 12.7 months (range, 0.0 to 22.3) in the placebo–fulvestrant group. Patients in the AKT pathway–altered population were those with a PIK3CA, AKT1, or PTEN alteration in tumor. The hazard ratio was estimated with the use of the Cox proportional-hazards model with stratification according to the presence or absence of liver metastases, previous use of an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6; yes or no), and geographic region in the overall population and according to the presence or absence of liver metastases and previous CDK4/6 inhibitor use in the population of patients with AKT pathway–altered tumors. Tick marks indicate censored data.

Figure 2.. Subgroup Analysis of Investigator-Assessed Progression-free Survival in the Overall Population.

Subgroup analysis within the overall population was performed at each subgroup level with the use of a Cox proportional-hazards model, including the trial-group term only. Selected subgroups of interest are shown. Race was determined by the person who filled out the case-report form. Menopausal status was assessed in women only.

Figure 3.. Overall Survival in the Overall Population and among Patients with AKT Pathway–Altered Tumors.

Tick marks indicate censored data. A 0.01% alpha penalty was assigned to the overall survival analyses of no detriment (i.e., with the hazard ratio not favoring the placebo–fulvestrant group); a sufficient number of deaths for a formal analysis of overall survival had not occurred by the data-cutoff date.