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Clinical Trial
. 2025 May 9;16(1):4324.
doi: 10.1038/s41467-025-59210-6.

Capivasertib plus fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer: phase 3 CAPItello-291 study extended Chinese cohort

Xichun Hu #  1 , Qingyuan Zhang #  2 , Tao Sun  3 , Huihua Xiong  4 , Wei Li  5 , Yuee Teng  6 , Yen-Shen Lu  7 , Ling-Ming Tseng  8 , Min Yan  9 , Hongsheng Li  10 , Danmei Pang  11 , Shin-Cheh -Chen  12 , Wenyan Chen  13 , Ou Jiang  14 , Jingfen Wang  15 , Xinhong Wu  16 , Xian Wang  17 , Aimin Zang  18 , Xiaojia Wang  19 , Julie M Collins  20 , Ethan Fan  21 , Lin Jiang  21 , Xiaoling Zeng  21 , Nicholas C Turner  22
Affiliations
Clinical Trial

Capivasertib plus fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer: phase 3 CAPItello-291 study extended Chinese cohort

Xichun Hu et al. Nat Commun. .

Abstract

In the global CAPItello-291 randomized phase 3 study (NCT04305496) in patients with hormone receptor-positive/HER2-negative advanced breast cancer and progression during/after aromatase inhibitor treatment, capivasertib-fulvestrant significantly improved progression-free survival (PFS) in the overall population and patients with PIK3CA/AKT1/PTEN-altered tumors versus placebo-fulvestrant. We assessed efficacy and safety of capivasertib-fulvestrant in a prespecified exploratory analysis of a Chinese cohort (n = 24) and extended study with the same protocol (n = 110). Clinically meaningful PFS benefit for capivasertib-fulvestrant was observed in the overall population (median PFS: 6.9 [capivasertib-fulvestrant] versus 2.8 [placebo-fulvestrant] months; hazard ratio 0.51, 95% CI 0.34-0.76), patients with PIK3CA/AKT1/PTEN-altered tumors (n = 46; 5.7 versus 1.9 months; hazard ratio 0.41, 95% CI 0.19-0.85) and PIK3CA/AKT1/PTEN-non-altered tumors (patients with confirmed next-generation sequencing results [n = 68]; 9.2 versus 2.7 months; hazard ratio 0.38; 95% CI 0.21-0.68). The most frequent adverse events (AEs) with capivasertib-fulvestrant were diarrhea (60.6% versus 11.3% with placebo-fulvestrant) and hyperglycemia (57.7% versus 17.7%). AEs leading to capivasertib-fulvestrant discontinuation were reported in 11.3% of patients versus 3.2% for placebo-fulvestrant. The benefit-risk profile of capivasertib-fulvestrant in the Chinese cohort was favorable; further exploration in patients with PIK3CA/AKT1/PTEN-non-altered tumors is warranted.

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Conflict of interest statement

Competing interests: X.H. has participated on advisory boards for AstraZeneca, received institutional funding for an investigator-initiated trial from Merck Sharpe and Dohme, and has served as a local Principal Investigator for AstraZeneca and Novartis. Y-S.L. has participated on advisory boards for Novartis, Eli Lilly, Merck Sharpe and Dohme, Roche, Pfizer, AstraZeneca, Eisai, Daiichi Sankyo, and Gilead Sciences, has been an invited speaker for Novartis, Eli Lilly, Merck Sharpe and Dohme, Roche, Pfizer, AstraZeneca, Eisai, Daiichi Sankyo, and Gilead Sciences, has served as a local Principal Investigator for Novartis, Roche, Pfizer, Merck Sharpe and Dohme, Eli Lilly, Eisai, AstraZeneca, Gilead Sciences and Jellox, has served as a chair/co-chair of a clinical trial steering committee for Novartis, and has held an uncompensated advisory role for AstraZeneca. J.M.C., E.F., L.J., and X.Z. are full-time employees of AstraZeneca. N.C.T. has participated in advisory boards AstraZeneca, Eli Lilly, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Health, Inivata, Novartis, Pfizer, Roche/Genentech, Relay Therapeutics, Repare Therapeutics and Zentalis Pharmaceuticals, has received institutional research funding from AstraZeneca, Inivata, Invitae, Merck Sharpe and Dohme, Natera, Personalis, Pfizer and Roche/Genentech, and has received research assays/materials from Guardant Health and Bio-Rad. Q.Z., T.S., H.X., W.L., Y.T., L-M.T., M.Y., H.L., D.P., S-C.C., W.C., O.J., J.W., X. Wu, Xian Wang, A.Z. and Xiaojia Wang declare no competing interests.

Figures

Fig. 1
Fig. 1. Investigator-assessed PFS.
Reported for A, the Chinese cohort overall population and B, patients with PIK3CA/AKT1/PTEN-altered tumors. The hazard ratio of the capivasertib–fulvestrant (purple) and placebo–fulvestrant (blue) curves was estimated with the use of the Cox proportional hazards model, with stratification according to the presence or absence of liver metastases and previous use of a CDK4/6 inhibitor (yes or no) in the overall population, and according to previous CDK4/6 inhibitor use in the population of patients with PIK3CA/AKT1/PTEN-altered tumors. Tick marks indicate censored data. AKT1 Akt serine/threonine kinase 1, CDK4/6 cyclin-dependent kinase 4/6, CI confidence interval, PIK3CA catalytic subunit alpha of phosphatidylinositol-3-kinase, PFS progression-free survival, PTEN phosphatase and tensin homolog.
Fig. 2
Fig. 2. Subgroup analysis of investigator-assessed PFS in the Chinese cohort 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. Data are presented as unstratified HRs and 95% CI. Selected subgroups of interest are shown. Menopausal status was assessed in women only. aHazard ratio and 95% CI were not calculated due to an insufficient number of events (<20 across treatment groups). CDK4/6 cyclin-dependent kinase 4/6, CI confidence interval, NC not calculated, PFS progression-free survival.
Fig. 3
Fig. 3. Overall survival.
Reported for A, the Chinese cohort overall population and B, patients with PIK3CA/AKT1/PTEN-altered tumors. The hazard ratio of the capivasertib–fulvestrant (purple) and placebo–fulvestrant (blue) curves was estimated with the use of the Cox proportional hazards model, with stratification according to the previous use of a CDK4/6 inhibitor (yes or no) in the overall population. Results for the population of patients with PIK3CA/AKT1/PTEN-altered tumors are not presented due to an insufficient number of events (<20 across treatment groups). A sufficient number of deaths for a formal analysis of overall survival had not occurred by the data cutoff date (8 May 2023). 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). AKT1 Akt serine/threonine kinase 1, CDK4/6 cyclin-dependent kinase 4/6, CI confidence interval, NA non-applicable, NC not calculated, OS overall survival, PIK3CA catalytic subunit alpha of phosphatidylinositol-3-kinase, PFS progression-free survival, PTEN phosphatase and tensin homolog.
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