van Wilpe S, Kloots I S H, Slootbeek P H J, den Brok M, Westdorp H, Franken M D, Coskunturk M, Osinga T, Bloemendal H, Adema G, Smeenk R J, Nagarajah J, van Ipenburg J, Kroeze L I, Ligtenberg M J L, Schalken J, Gerritsen W R, Mehra N
Department of Medical Oncology.
Department of Radiation Oncology.
Ann Oncol. 2024 Dec;35(12):1126-1137. doi: 10.1016/j.annonc.2024.09.004. Epub 2024 Sep 16.
Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC.
This single-arm, phase II trial included 69 molecularly selected mCRPC patients with mismatch repair deficiency (dMMR), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR > 6), aiming to surpass a DCR > 6 of 22%.
Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had dMMR (32%), 8 had hTMB (12%), 20 had BRCAm (31%), and 16 had CDK12i (25%). DCR > 6 was achieved in 38% of patients [95% confidence interval (CI) 27% to 51%], and was highest in dMMR (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective response rate in cohort A was 38% (95% CI 22% to 55%) and 47% (95% CI 34% to 60%) exhibited a 50% decline in prostate-specific antigen levels. Median progression-free survival (PFS) was 4.0 months (95% CI 3.5-12.0 months) in cohort A, and 32.7 months (95% CI 21.8 months-not reached) in dMMR patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity.
This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR > 6 in 38% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR.
转移性去势抵抗性前列腺癌（mCRPC）通常对免疫检查点抑制剂（ICI）表现出耐药性。然而，一部分mCRPC患者表现出更强的免疫原性特征。本研究探讨分子筛选的mCRPC患者接受双重ICI治疗的疗效和安全性。
这项单臂II期试验纳入了69例分子筛选的mCRPC患者，这些患者存在错配修复缺陷（dMMR）、非同义肿瘤突变负荷≥7.1个突变/Mb（hTMB）、BRCA2突变（BRCAm）或双等位基因CDK12失活（CDK12i）。对未接受过ICI治疗的患者（队列A），根据实体瘤疗效评价标准（RECIST）1.1（A1）和前列腺癌工作组3（A2）标准评估可测量疾病的疗效。对队列A和队列B（先前接受过ICI单药治疗）的患者评估安全性。治疗方案为每3周给予纳武利尤单抗3mg/kg和伊匹木单抗1mg/kg，共四个周期，随后每4周给予纳武利尤单抗480mg，持续1年。主要终点是6个月以上的疾病控制率（DCR>6），目标是超过22%的DCR>6。
患者于2021年1月至2024年2月开始治疗。队列A包括65例患者。其中，21例为dMMR（32%），8例为hTMB（12%），20例为BRCAm（31%），16例为CDK12i（25%）。38%的患者实现了DCR>6[95%置信区间（CI）为27%至51%]，在dMMR患者中最高（81%），其次是hTMB（25%）、CDK12i（19%）和BRCAm（15%）。队列A的客观缓解率为38%（95%CI为22%至55%），47%（95%CI为34%至60%）的患者前列腺特异性抗原水平下降了50%。队列A的中位无进展生存期（PFS）为4.0个月（95%CI为3.5至12.0个月），dMMR患者为32.7个月（95%CI为21.8个月至未达到）。69例患者中有14例（20%）因治疗相关不良事件（TRAEs）导致永久停药。48%的患者发生≥3级TRAEs，腹泻和转氨酶升高各占10%。有1例因肠穿孔导致的治疗相关死亡和1例在4级毒性后安乐死导致的死亡。
这项针对分子筛选的mCRPC患者的双重ICI试验达到了主要终点，38%的患者实现了DCR>6。双重ICI在hTMB、BRCAm和CDK12i亚组中表现出适度反应，但在dMMR患者中显示出卓越疗效。
