George Thomas J, Lee Ji-Hyun, DeRemer David L, Hosein Peter J, Staal Steven, Markham Merry Jennifer, Jones Dennie, Daily Karen C, Chatzkel Jonathan A, Ramnaraign Brian H, Close Julia L, Ezenwajiaku Nkiruka, Murphy Martina C, Allegra Carmen J, Rogers Sherise, Zhang Zhongyue, Li Derek, Srinivasan Gayathri, Shaheen Montaser, Hromas Robert
Division of Hematology Oncology, Department of Medicine, University of Florida, Gainesville, FL.
University of Florida Health Cancer Center, Gainesville, FL.
JCO Precis Oncol. 2024 Dec;8:e2400406. doi: 10.1200/PO-24-00406. Epub 2024 Dec 3.
BRCA1-associated protein 1 (BAP1) is a critical cell cycle and DNA damage response (DDR) regulator with mutations (mBAP1) causing a functional protein loss. PARP inhibitors (PARPis) demonstrate synthetic lethality in mBAP1 preclinical models, independent of underlying BRCA status. This study aimed to explore the clinical activity of niraparib in patients with advanced tumors likely to harbor mBAP1.
This was a phase II multicenter trial in which refractory solid tumor patients were assigned to cohort A (histology-specific tumors likely to harbor mBAP1) or cohort B (histology-agnostic tumors with other known non-BRCA-confirmed DDR mutations). All patients received niraparib 300 mg orally once daily on a 28-day cycle. The primary end point was objective response rate, and secondary end points included progression-free survival (PFS) and overall survival.
From August 2018 through December 2021, 37 patients were enrolled with 31 evaluable for response (cohort A, n = 18; cohort B, n = 13). In cohort A, the best response was one partial response (PR; 6%), eight stable disease (SD; 44%), and nine progressive disease (PD; 50%). This cohort stopped at the first stage following the prespecified Simon's design. mBAP1 was confirmed in 7/9 patients (78%) with PR or SD but in only 3/9 (33%) in those with PD. The median PFS in patients with mBAP1 (n = 10) was 6.7 months (95% CI, 1.0 to 9.2) versus 1.8 months (95% CI, 0.9 to 4.5) for wild-type (n = 8; = .020). In cohort B, the best response was six SD (46%) and seven PD (54%), with SD in those with , , , , and mutations.
Niraparib failed to meet the prespecified efficacy end point for response. However, clinical benefit was suggested in a proportion of patients who had a confirmed mBAP1, supporting further investigation.
乳腺癌1号相关蛋白1（BAP1）是一种关键的细胞周期和DNA损伤反应（DDR）调节因子，其突变（mBAP1）会导致功能性蛋白缺失。聚ADP核糖聚合酶抑制剂（PARPis）在mBAP1临床前模型中显示出合成致死性，与潜在的BRCA状态无关。本研究旨在探讨尼拉帕利在可能携带mBAP1的晚期肿瘤患者中的临床活性。
这是一项II期多中心试验，难治性实体瘤患者被分配到队列A（可能携带mBAP1的组织学特异性肿瘤）或队列B（具有其他已知非BRCA确认的DDR突变的组织学非特异性肿瘤）。所有患者接受尼拉帕利300mg口服，每日一次，每28天为一个周期。主要终点是客观缓解率，次要终点包括无进展生存期（PFS）和总生存期。
从2018年8月至2021年12月，共入组37例患者，其中31例可评估疗效（队列A，n = 18；队列B，n = 13）。在队列A中，最佳反应为1例部分缓解（PR；6%），8例疾病稳定（SD；44%），9例疾病进展（PD；50%）。根据预先指定的西蒙设计，该队列在第一阶段停止。在9例PR或SD患者中有7例（78%）确认存在mBAP1，但在9例PD患者中只有3例（33%）确认存在。mBAP1患者（n = 10）的中位PFS为6.7个月（95%CI，1.0至9.2），而野生型患者（n = 8）为1.8个月（95%CI，0.9至4.5）（P = 0.020）。在队列B中，最佳反应为6例SD（46%）和7例PD（54%），在具有、、、和突变的患者中为SD。
尼拉帕利未达到预先指定的确证疗效终点。然而，在一部分确认存在mBAP1的患者中显示出临床获益，支持进一步研究。
