Robertson, J.F.R., Coleman, R.E. orcid.org/0000-0002-4275-1043, Cheung, K.-L. et al. (21 more authors) (2020) Proliferation and AKT activity biomarker analyses after capivasertib (AZD5363) treatment of patients with ER+ invasive breast cancer (STAKT). Clinical Cancer Research, 26 (7). pp. 1574-1585. ISSN 1078-0432
Abstract
Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation.
Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring.
Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident.
Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 American Association for Cancer Research. This is an author-produced version of a paper subsequently published in Clinical Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Capivasertib; AKT inhibitor; breast cancer; AZD5363; STAKT |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number Weston Park Hospital Cancer Charity CA101A National Institute for Health Research UNSPECIFIED Cancer Research UK C9267/A25152 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 17 Apr 2020 11:07 |
Last Modified: | 13 Dec 2020 01:38 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/1078-0432.ccr-19-3053 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:159608 |