Multicenter, Randomized, Phase II Trial of Olaparib Plus Radium-223 Versus Radium-223 in Men With Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE).
Rana R McKay, Wanling Xie, Archana Ajmera, Arlene Araneta, Christina Jamieson, Edmund Folefac, Arif Hussain, Christos E Kyriakopoulos, Danielle K Manning, Adam Olson, Mamta Parikh, Rahul Parikh, Biren Saraiya, Lincoln W Pasquina, Russell Madison, Sarah Clifford, Merrida Childress, Amaya Gasco, Percy Ivy, Eliezer Van Allen, Bose Kochupurakkal, Geoffrey I Shapiro
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引用次数: 0
Abstract
Purpose: Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223.
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. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS).
Results: A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. 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). 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]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). 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%).
Conclusion: Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.
目的：镭-223是一种α-放射药物，可提高转移性去势抵抗性前列腺癌（mCRPC）的生存率。临床前数据表明，多聚adp核糖聚合酶（PARP）抑制与辐射之间存在协同作用。在I期剂量发现后，我们进行了一项随机II期试验，以评估该组合与镭223的疗效和安全性。患者和方法：mCRPC和≥2个骨转移（BM）的男性随机按1:1分配给奥拉帕尼（200mg，每日2次）加镭-223 （55kbq /kg静脉注射，每4周1次× 6剂量）或镭-223。在进程中允许交叉。主要终点是研究者评估的放射学无进展生存期（rPFS）。结果：共120例患者被随机分配。大多数患者既往有雄激素受体途径抑制剂暴露（96%），52%接受过多西他赛，47%接受过bbb20 BM， 90%接受过骨保护剂。联合用药显著提高rPFS（中位8.9 v 4.7个月；风险比[HR]， 0.50[单侧90% CI， 0.35 ~ 0.70]；单侧P = 0.0042）。在先前没有多西他赛的患者（13.7 v 5.7个月；HR, 0.24 [90% CI， 0.15至0.40]）和≤20 BM的患者（13.4 v 4.2个月；HR, 0.21 [90% CI， 0.13至0.33]）中获益最为明显。联合用药的1年累积症状性骨骼相关事件发生率较低（12.7% vs 22.9%）。中位总生存期相似（20.2个月vs 21.1个月）。≥3级治疗相关不良事件发生率为56% vs 33%（联合治疗vs镭-223），主要是血液学，包括淋巴细胞减少（31% vs 9.1%）、贫血（22% vs 16%）和血小板减少（6.8% vs 3.6%）。结论：与镭223相比，奥拉帕尼加镭223可显著延长mCRPC和BM患者的rPFS。尽管血液学毒性增加，但该方案是可控的，并支持在该人群中进一步探索DNA损伤靶向策略。
期刊介绍：
The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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