Sartor O, Coleman R E, Nilsson S, Heinrich D, Helle S I, O'Sullivan J M, Vogelzang N J, Bruland Ø, Kobina S, Wilhelm S, Xu L, Shan M, Kattan M W, Parker C
Departments of Medicine and Urology, Tulane Cancer Center, New Orleans, USA.
Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Sheffield, UK.
Ann Oncol. 2017 May 1;28(5):1090-1097. doi: 10.1093/annonc/mdx044.
Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established.
The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy.
Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively.
Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.
基线临床变量对去势抵抗性前列腺癌（CRPC）患者的总生存期（OS）具有预后价值。其对于靶向骨转移的药物（如镭-223）的预后和预测价值尚未明确。
镭-223 ALSYMPCA试验纳入了患有CRPC和有症状骨转移的患者。使用Cox模型评估基线变量的预后潜力。在试验期间评估生物标志物水平相对于基线的百分比变化；评估从基线到第12周的变化与总生存期和替代指标的相关性。
在意向性治疗人群（镭-223组，N = 614；安慰剂组，N = 307）中，东部肿瘤协作组（ECOG）体能状态、总碱性磷酸酶（tALP）、乳酸脱氢酶（LDH）和前列腺特异性抗原（PSA）在基线时与总生存期相关（P≤0.0003）。开始使用镭-223后4周内，tALP从基线水平下降，到第12周时，87%的镭-223组患者和23%的安慰剂组患者的tALP下降（P<0.001）。LDH在镭-223组和安慰剂组中的下降率分别为51%和34%（P = 0.003），而PSA的下降率分别为27%和14%（P = 0.160）。与基线相比，镭-223组患者的tALP平均变化为降低32.2%，安慰剂组为升高37.2%。从基线到第12周tALP下降（从第12周起确认≥3周）的镭-223组患者与未确认tALP下降的患者相比，死亡风险降低55%（风险比=0.45；95%置信区间0.34 - 0.61）。在第12周时，tALP、LDH和PSA相对于基线变化作为总生存期替代标志物的比例治疗效应（PTE）值分别为0.34（95%置信区间：0 - 0.746）、0.07（95%置信区间：0 - 0.211）和0（95%置信区间：0 - 0.082）。
开始镭-223治疗后最早4周就出现了与安慰剂相比显著的tALP下降。第12周时tALP或LDH下降与更长的总生存期相关，但未达到统计学替代指标要求。镭-223治疗期间tALP和LDH的动态变化可能有助于监测，但不能作为生存替代指标。
