Multicenter, Randomized, Phase II Trial of Olaparib Plus Radium-223 Versus Radium-223 in Men With Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE).

Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation.

临床前数据表明，聚(ADP-核糖)聚合酶（PARP）抑制与放射治疗之间存在协同作用。

After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223.

在 I 期剂量发现后，我们开展了一项随机 II 期试验，以评估这种联合疗法与镭-223相比的有效性和安全性。

patients_and_methods

Men with mCRPC and ≥2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223.

患有转移性去势抵抗性前列腺癌（mCRPC）且骨转移（BM）≥2处的男性被随机分配为1:1，接受奥拉帕利（每日两次，每次200毫克）加镭-223（每4周静脉注射一次，每次55千贝克/千克，共6次剂量）或仅接受镭-223。

Crossover was allowed at progression.

允许在疾病进展后进行交叉治疗。

The primary end point was investigator-assessed radiographic progression-free survival(rPFS).

主要终点是研究者评估的影像学无进展生存期（rPFS）。

Results

A total of 120 patients were randomly assigned.

共有120名患者被随机分配。

Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents.

大多数患者之前接受过雄激素受体通路抑制剂治疗（96%），52%的患者接受过多西他赛治疗，47%的患者有超过20个脑转移灶，90%的患者接受了骨保护剂治疗。

The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio[HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042).

联合治疗显著改善了rPFS（中位数8.9个月对比4.7个月；风险比[HR]，0.50 [单侧90%置信区间，0.35至0.70]；单侧P = .0042）。

The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]).

在未接受过多西他赛治疗的患者中（13.7个月对比5.7个月；HR，0.24 [90%置信区间，0.15至0.40]）以及脑转移灶数量≤20个的患者中（13.4个月对比4.2个月；HR，0.21 [90%置信区间，0.13至0.33]），获益最为显著。

The 1-year cumulative incidenceof symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%).

联合治疗组1年内有症状的与骨骼相关的事件累积发生率较低（12.7%对比22.9%）。

Median overall survivalwas similar (20.2 v 21.1 months).

中位总生存期相似（20.2个月对比21.1个月）。

Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%).

治疗相关性3级或以上不良事件的发生率为56%对比33%（联合治疗对比镭-223），主要为血液学不良事件，包括淋巴细胞减少症（31%对比9.1%）、贫血（22%对比16%）和血小板减少症（6.8%对比3.6%）。

Conclusions

Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM.

奥拉帕利联合镭-223显著延长了伴有骨转移的转移性去势抵抗性前列腺癌（mCRPC）男性的rPFS，与单独使用镭-223相比。

Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.

尽管血液毒性增加，但该方案是可管理的，并支持在这一人群中进一步探索针对DNA损伤的策略。