Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia; Department of Medical Oncology, Monash Health, Melbourne, Australia.
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Oncology, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia.
Eur Urol. 2022 Mar;81(3):253-262. doi: 10.1016/j.eururo.2021.08.011. Epub 2021 Sep 4.
Immune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors.
To evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC.
DESIGN, SETTING, AND PARTICIPANTS: From November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor-directed therapy. Median follow-up was 18.0 mo.
Avelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments.
The primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non-complete response/non-progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3-modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method.
Thirty-one evaluable men were enrolled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30-67%) and ORR was 31% (five of 16; 95% CI 11-59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10-65%). Median rPFS was 8.4 mo (95% CI 4.5-not reached [NR]) and median OS was 14.1 mo (95% CI 8.9-NR). Grade 3-4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher's exact test). Limitations include the small sample size and the absence of a control arm.
Avelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation.
In this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.
免疫检查点抑制剂单药治疗转移性去势抵抗性前列腺癌（mCRPC）的效果有限。高剂量放疗可能与检查点抑制剂具有协同作用。
评估 PD-L1 抑制剂avelumab 联合立体定向消融放疗（SABR）治疗 mCRPC 的疗效和安全性。
设计、地点和参与者：本前瞻性 2 期研究于 2017 年 11 月至 2019 年 7 月间入组了 31 例至少接受过一种雄激素受体靶向治疗后进展的 mCRPC 男性患者。中位随访时间为 18.0 个月。
avelumab 10mg/kg 静脉注射，每 2 周 1 次，共 12 个周期。在首次和第二次 avelumab 治疗前 5 天内，单次给予 20Gy 的 SABR 治疗一个或两个疾病部位。
主要终点是疾病控制率（DCR），定义为任何持续时间的完全或部分缓解，或稳定疾病/非完全缓解/非进展性疾病≥6 个月（前列腺癌临床研究工作组 3 修订的实体瘤反应评估标准 1.1）。次要终点是客观缓解率（ORR）、放射学无进展生存期（rPFS）、总生存期（OS）和安全性。DCR 和 ORR 使用 Clopper-Pearson 精确二项式方法计算。
31 例可评估的患者入组（中位年龄 71 岁，71%的患者有≥2 种 mCRPC 治疗线，81%的患者有>5 个总转移灶）。DCR 为 48%（15/31；95%置信区间 [CI] 30-67%），ORR 为 31%（5/16；95%CI 11-59%）。未放疗病灶的 ORR 为 33%（4/12；95%CI 10-65%）。中位 rPFS 为 8.4 个月（95%CI 4.5-NR），中位 OS 为 14.1 个月（95%CI 8.9-NR）。6 例（16%）患者发生 3-4 级治疗相关不良事件，其中 3 例（10%）需要高剂量皮质类固醇治疗。血浆雄激素受体改变与较低的 DCR 相关（22%比 71%，p=0.13；Fisher 确切检验）。局限性包括样本量小和缺乏对照组。
avelumab 联合 SABR 在难治性 mCRPC 中显示出令人鼓舞的疗效和可接受的毒性。这种联合治疗值得进一步研究。
在这项研究中，31 例晚期和预处理的前列腺癌男性患者接受了立体定向放疗联合avelumab 免疫治疗，结果安全，近一半的患者癌症得到控制，时间超过 6 个月。立体定向放疗可能提高前列腺癌免疫治疗的效果。
