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.

中文翻译：

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Capivasertib (AZD5363) 治疗 ER+ 浸润性乳腺癌 (STAKT) 患者后的增殖和 AKT 活性生物标志物分析。

目的 STAKT 研究检查了口服选择性泛 AKT 抑制剂 capivasertib (AZD5363) 的短期暴露（4.5 天）以确定该药物是否可以达到足够浓度的治疗目标以显着调节 AKT 通路和肿瘤增殖的关键生物标志物. 方法 STAKT 是一项两阶段、双盲、随机、安慰剂对照、“机会之窗”研究，对象是新诊断的 ER+ 浸润性乳腺癌患者。第一阶段评估 capivasertib 480 mg bid（推荐的单药治疗剂量）和安慰剂，第二阶段评估 capivasertib 360 和 240 mg bid 主要终点是 AKT 通路标志物 pPRAS40、pGSK3β 和增殖蛋白 Ki67 相对于基线的变化。从血液采样分析药理学和药效学特性，和不良事件监测的耐受性。结果 暴露 4.5 天后，capivasertib 480 mg bid (n = 17) 与安慰剂 (n = 11) 相比，pGSK3β（H 评分绝对变化：-55.3，P = 0.006）和 pPRAS40（-83.8， P < 0.0001）和 Ki67 减少（阳性细胞核百分比的绝对变化：-9.6%，P = 0.031）。次级信号生物标志物 pS6 也发生了显着变化（-42.3，P = 0.004），而 pAKT（和核 FOXO3a）也根据 capivasertib 的机制增加（pAKT：81.3，P = 0.005）。在 360 毫克 bid（n = 5）和 240 mg bid（n = 6）的剂量下，还观察到主要和次要生物标志物的变化，尽管幅度较小。生物标志物调节依赖于剂量和浓度，并且没有明显的新安全信号。