Boudadi Karim, Suzman Daniel L, Anagnostou Valsamo, Fu Wei, Luber Brandon, Wang Hao, Niknafs Noushin, White James R, Silberstein John L, Sullivan Rana, Dowling Donna, Harb Rana, Nirschl Thomas R, Veeneman Brendan A, Tomlins Scott A, Wang Yipeng, Jendrisak Adam, Graf Ryon P, Dittamore Ryan, Carducci Michael A, Eisenberger Mario A, Haffner Michael C, Meeker Alan K, Eshleman James R, Luo Jun, Velculescu Victor E, Drake Charles G, Antonarakis Emmanuel S
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Oncotarget. 2018 Jun 19;9(47):28561-28571. doi: 10.18632/oncotarget.25564.
AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in , two in , one in ; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1-NR) months, PFS was 3.7 (95%CI 2.8-7.5) months, and OS was 8.2 (95%CI 5.5-10.4) months. Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0%; =0.14, nonsignificant), ORR (40% vs. 0%; =0.46, nonsignificant), PSA-PFS (HR 0.19; <0.01, significant), PFS (HR 0.31; =0.01, significant), and OS (HR 0.41; =0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population.
表达AR-V7的转移性前列腺癌是一种侵袭性表型，无进展生存期（PFS）和总生存期（OS）较差。初步证据表明，AR-V7阳性肿瘤可能富集了DNA修复缺陷，这或许使它们对免疫检查点阻断更敏感。我们将15例有表达AR-V7循环肿瘤细胞的转移性前列腺癌患者纳入一项前瞻性2期试验。患者每3周接受一次纳武利尤单抗3mg/kg加伊匹木单抗1mg/kg，共4剂，然后每2周接受纳武利尤单抗3mg/kg维持治疗。进行靶向二代测序以确定DNA修复缺陷（DRD）状态。结果包括PSA缓解率、客观缓解率（ORR）、PSA无进展生存期（PSA-PFS）、临床/影像学PFS和OS。参与者的中位年龄为65岁，中位PSA为115ng/mL，67%有内脏转移，60%既往接受过≥4种全身治疗。15名男性中有6名（40%）有DRD突变（3名在 ，2名在 ，1名在 ；均无微卫星不稳定性）。总体而言，PSA缓解率为2/15（13%），可测量疾病患者的ORR为2/8（25%），中位PSA-PFS为3.0（95%CI 2.1-NR）个月，PFS为3.7（95%CI 2.8-7.5）个月，OS为8.2（95%CI 5.5-10.4）个月。在PSA缓解方面（33%对0%； =0.14，无统计学意义）、ORR（40%对0%； =0.46，无统计学意义）、PSA-PFS（HR 0.19； <0.01，有统计学意义）、PFS（HR 0.31； =0.01，有统计学意义）和OS（HR 0.41； =0.11，无统计学意义）方面，DRD+肿瘤的结果总体上似乎比DRD-肿瘤更好。没有新的安全性问题。伊匹木单抗加纳武利尤单抗在有DRD突变的AR-V7阳性前列腺癌中显示出令人鼓舞的疗效，但在总体研究人群中并非如此。
