Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
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Colleges, School and Institutes
- University of Nottingham, Nottingham, UK. email@example.com.
- Sheffield Children’s Hospital and University of Sheffield, Sheffield, UK
- University of Nottingham, Royal Derby Hospital Centre, Derby, UK.
- Poole Hospital NHS Foundation Trust
- The Royal Liverpool University Hospital, Liverpool, UK.
- Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK.
- Genetics, Leicester Royal Infirmary, Leicester
- King's Mill Hospital, Nottingham, UK.
- Department of Gastroenterology, Leeds General Infirmary, Leeds, UK.
- DUNDEE UNIVERSITY
- Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK
- Department of Histopathology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK.
- Cardiff University and Velindre Cancer Centre, Cardiff, UK.
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+ 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.
|Journal||Clinical Cancer Research|
|Publication status||E-pub ahead of print - 13 Dec 2019|