Lee Jung-Min, Brady Mark F, Miller Austin, Moore Richard G, MacKay Helen, McNally Leah, Lea Jayanthi, Street Daron, Lheureux Stephanie, McDonald Megan E, Duska Linda R, Cantuaria Guilherme, Kavecansky Juraj, Leath Charles A, Powell Matthew, Cadungog Mark G, Rose Peter G, Kim Yong-Man, Huang Helen Q, Provencher Michèle, Wenzel Lari B, Bookman Michael A, Kohn Elise C, Secord Angeles Alvarez
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY.
J Clin Oncol. 2024 Dec 20;42(36):4305-4316. doi: 10.1200/JCO.24.00683. Epub 2024 Oct 3.
We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC).
NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes.
Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib ( SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, -1.3 to 1.5, = .8725).
The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.
我们评估了西地尼布、奥拉帕利以及西地尼布/奥拉帕利与铂耐药或铂难治性上皮性卵巢癌（PROC）的标准治疗化疗（SOC）相比的疗效。
NRG-GY005是一项开放标签、四臂、II/III期优效性试验，纳入高级别浆液性/子宫内膜样PROC患者且既往接受过一至三种治疗。主要排除标准包括既往接受过聚（ADP-核糖）聚合酶抑制剂治疗或在复发阶段接受过抗血管生成治疗。治疗组（SOC[每周一次紫杉醇、拓扑替康或聚乙二醇化脂质体阿霉素]、西地尼布、奥拉帕利或西地尼布/奥拉帕利）进行等比例随机分组。基于无进展生存期（PFS）进行的预先计划的中期无效性分析选择治疗组进入III期。PFS和总生存期（OS）是III期共同主要终点，对PFS进行分层检验，随后对OS进行检验以保持I类错误控制，设计为对于0.625的PFS风险比（HR）具有90%的检验效能。在多重分层检验程序中，PFS之后对OS进行检验。次要终点包括客观缓解率（ORR）和患者报告的结局。
562例符合条件的患者被纳入II/III期。三个治疗组达到PFS标准进入III期（SOC、西地尼布/奥拉帕利和西地尼布）。SOC、西地尼布/奥拉帕利和西地尼布的中位PFS分别为3.4个月、5.2个月和4个月，中位随访时间为42.2个月。西地尼布/奥拉帕利和西地尼布（对比SOC）的PFS HR估计值分别为0.796（98.3%CI，0.597至1.060）和0.972（98.3%CI，0.726至1.300）。中位OS分别为13.6个月、12.8个月和10.5个月，在443例有可测量疾病的患者中，SOC、西地尼布/奥拉帕利和西地尼布的ORR分别为8.6%、24.7%和13.1%。未发现新的安全信号。在接受西地尼布/奥拉帕利治疗的患者中，与SOC相比，在NFOSI-DRS-P子量表上未观察到统计学显著差异（98.3%CI，-1.3至1.5，P = 0.8725）。
含西地尼布的治疗组基于PFS显示出临床活性，但与SOC相比并不更优。
