Proliferation and AKT activity biomarker analyses after Capivasertib (AZD5363) treatment of patients with ER+ invasive breast cancer (STAKT)

Robertson, John F.R., Coleman, Robert E., Cheung, Kwok-Leung, Evans, Abigail, Holcombe, Chris, Skene, Anthony, Rea, Daniel, Ahmed, Samreen, Jahan, Ali, Horgan, Kieran, Rauchhaus, Petra, Littleford, Roberta, Cheung, S.Y. Amy, Cullberg, Marie, de Bruin, Elza C., Koulai, Loumpiana, Lindemann, Justin P. O., Pass, Martin, Rugman, Paul, Schiavon, Gaia, Deb, Rahul, Finlay, Pauline, Foxley, Andrew and Gee, Julia M.W. ORCID: https://orcid.org/0000-0001-6483-2015 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. 10.1158/1078-0432.CCR-19-3053

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Abstract

Purpose: The STAKT study examined short-term exposure (4.5 days) to 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. 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 bid (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg bid. 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 bid (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 bid (n=5) and 240 mg bid (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 bid 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Association for Cancer Research
ISSN:	1078-0432
Date of First Compliant Deposit:	7 January 2020
Date of Acceptance:	10 December 2019
Last Modified:	28 Nov 2024 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/128328

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