Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

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.Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER þ 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, pGSK3b, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverseevent monitoring.Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n ¼ 17) produced significant decreases from baseline versus placebo (n ¼ 11) in pGSK3b (H-score absolute change: À55.3, P ¼ 0.006) and pPRAS40 (À83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: À9.6%, P ¼ 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (À42.3, P ¼ 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P ¼ 0.005). At doses of 360 mg b.i.d. (n ¼ 5) and 240 mg b.i.d. (n ¼ 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 AKTdependent breast cancers.

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

“…The Ki-67 proliferation index has also been evaluated in neoadjuvant trials in order to assess AKT inhibitors’ efficacy. In line with the reported data mentioned above, a decrease in Ki-67 was observed after treatment with capivasertib in the STAKT trial, while no significant differences in pre- and posttreatment Ki-67 emerged in the MK-2206 WoO trial ( Kalinsky et al, 2018 ; Robertson et al, 2020 ).…”

“…In the STAKT trial, patients with newly diagnosed HR-positive early BC received capivasertib for 4.5 days prior to surgery. Compared with baseline levels, posttreatment phosphorylation of the downstream effectors GSK3β, PRAS40, and S6 was significantly decreased, indicating that capivasertib effectively blocked its target ( Robertson et al, 2020 ). A meaningful decrease of phospho-GSK3β was also observed among metastatic BC patients treated with capivasertib in phase I/II trials ( Banerji et al, 2018 ; Turner et al, 2019 ).…”

Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer

“…The AKT inhibitor, capivasertib (AZD5363, AstraZeneca, UK), was used for in vitro studies. This compound is a novel synthetic AKT inhibitor that is orally bioavailable and was previously used in clinical trials [ 19 , 20 ]. For in vitro studies, capivasertib was dissolved in dimethyl sulfoxide (DMSO) at 10 mmol/L stock solution and stored at −20 °C.…”

<p>Aptamer-Functionalized Dendrimer Delivery of Plasmid-Encoding lncRNA <em>MEG3</em> Enhances Gene Therapy in Castration-Resistant Prostate Cancer</p>

“…Ki67 is a nuclear antigen associated with proliferating cells whose function is closely related to mitosis and is indispensable during cell proliferation; it can be used to identify cells outside the G0 phase of the cell cycle, and its expression levels are used to determine the cellular proliferation index. [36][37][38] Thus, higher the expression of Ki67, greater the proportion of cells in the proliferation cycle and faster is the rate of tumor growth. The Ki67 protein H-scores in the PAMAM-PEG-EpDT3/pDNA, PAMAM-PEG/pMEG3, and PAMAM-PEG-EpDT3/pMEG3 groups were 54.77, 34.71, and 12.64, respectively; but, the PAMAM-PEG-EpDT3 /pDNA group showed the most intense staining, highest H-score, and maximal expression of Ki67 (Figure 8).…”