PURPOSE Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC. PATIENTS AND METHODS A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination. RESULTS Thirty-nine men were randomized to RE (n = 27) or enzalutamide (n = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51-0.81; P = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide (P = 0.024), correlated with decline in BMMs. CONCLUSIONS BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.

中文翻译：

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骨代谢标志物作为转移性去势抵抗性前列腺癌镭 223 治疗反应替代标志物的前瞻性评估。

目的 Radium-223 被批准用于转移性去势抵抗性前列腺癌 (mCRPC)，这是基于改善的总生存率和骨骼相关事件的延迟。然而，它与 PSA 或放射学反应无关，这对其功效的实时评估提出了挑战。通过限制镭 223 在这些患者中的治疗持续时间，治疗结果的替代标志物可能有助于调整镭 223 的治疗持续时间。在这里，我们试图研究骨代谢标志物 (BMM) 作为 mCRPC 中镭 223 反应替代标志物的效用。患者和方法 镭 223 加恩杂鲁胺 (RE) 与恩杂鲁胺单药的前瞻性 II 期试验旨在评估 BMM 对镭 223 的反应的代孕。由于疾病进展，使用恩杂鲁胺代替安慰剂作为对照。共同主要终点是血清 BMM N-端肽 (NTP) 水平从基线到两个组之间的相对变化以及组合的安全性和可行性。结果 39 名男性随机接受 RE（n = 27）或恩杂鲁胺（n = 12）。组合是安全可行的。达到主要终点。与恩杂鲁胺相比，两组之间 NTP 比率的统计学显着相对变化（0.64，95% 置信区间，0.51-0.81；P = 0.00048）有利于 RE。总体而言，与恩杂鲁胺相比，BMM 随 RE 治疗而降低。与恩杂鲁胺相比，RE 的 PSA 反应率提高（P = 0.024），与 BMM 的下降相关。结论 BMM 与联合治疗显着下降，并与改善的结果相关。