Author(s): Nicholas C. Turner, M.D., Ph.D., Mafalda Oliveira, M.D., Ph.D., Sacha J. Howell, M.D., Ph.D., Florence Dalenc, M.D., Ph.D., Javier Cortes, M.D., Ph.D., Henry L. Gomez Moreno, M.D., Ph.D., Xichun Hu, M.D., Komal Jhaveri, M.D., Petr Krivorotko, M.D., Ph.D., Sibylle Loibl, M.D., Ph.D., Serafin Morales Murillo, M.D., Meena Okera, M.D., Yeon Hee Park, M.D., Ph.D., Joohyuk Sohn, M.D., Masakazu Toi, M.D., Ph.D., Eriko Tokunaga, M.D., Ph.D., Samih Yousef, M.D., Lyudmila Zhukova, M.D., Ph.D., Elza C. de Bruin, Ph.D., Lynda Grinsted, M.Sc., Gaia Schiavon, M.D., Ph.D., Andrew Foxley, M.F.P.M., and Hope S. Rugo, M.D. for the CAPItello-291 Study Group*
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. opens in new tab.)
Author Affiliations
From the Royal Marsden Hospital, Institute of Cancer Research, London (N.C.T.), the Christie NHS Foundation Trust, Manchester (S.J.H.), and Oncology Research and Development, AstraZeneca, Cambridge (E.C.B., L.G., G.S., A.F.) — all in the United Kingdom; the Department of Medical Oncology, Vall d’Hebron University Hospital (M. Oliveira), the Breast Cancer Unit, Vall d’Hebron Institute of Oncology (M. Oliveira), the Department of Oncology, International Breast Cancer Center, Pangaea Oncology, Quiron Group, Medica Scientia Innovation Research (J.C.), and Institut de Recerca Biomèdica (S.M.M.), Barcelona, and the Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid (J.C.) — all in Spain; Institut Claudius Regaud, Institut Universitaire du Cancer–Oncopole Toulouse, Toulouse, France (F.D.); Departamento de Oncología Médica, Instituto Nacional de Enfermedades Neoplásicas, and Universidad Ricardo Palma — both in Lima, Peru (H.L.G.M.); Shanghai Cancer Center, Fudan University, Shanghai, China (X.H.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College — both in New York (K.J.); Petrov Research Institute of Oncology, St. Petersburg (P.K.), and Loginov Moscow Clinical Scientific Center, Moscow (L.Z.) — both in Russia; GBG Forschungs, Neu-Isenburg, and the Center for Hematology and Oncology, Bethanien, Frankfurt — both in Germany (S.L.); Icon Cancer Centre, Adelaide, SA, Australia (M. Okera); Sungkyunkwan University School of Medicine, Samsung Medical Center (Y.H.P.), and Yonsei University College of Medicine, Yonsei Cancer Center (J.S.) — both in Seoul; Kyoto University Hospital, Kyoto (M.T.), and National Hospital Organization Kyushu Cancer Center, Fukuoka (E.T.) — both in Japan; Emek Medical Center, Afula, Israel (S.Y.); and the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.).
