Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA.
NRG Oncology; Clinical Trial Development Division; Biostatistics & Bioinformatics; Roswell Park Comprehensive Cancer Center, Buffalo, NY.
J Clin Oncol. 2022 Jul 1;40(19):2138-2147. doi: 10.1200/JCO.21.02011. Epub 2022 Mar 15.
Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.
NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline -mutated or wild-type subgroups and patient-reported outcomes (PROs).
Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; = .077). In women with germline mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.
Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline mutation, both olaparib and olaparib/cediranib had significant clinical activity.
铂类化疗是铂类敏感卵巢癌的标准治疗方法，但重复铂类治疗会引起并发症。我们评估了两种全口服非铂类替代药物奥拉帕利或奥拉帕利/西地尼布与铂类化疗相比的活性。
NRG-GY004 是一项在美国和加拿大进行的开放标签、随机、III 期临床试验。合格患者患有高级别浆液性或子宫内膜样铂类敏感卵巢癌。患者按 1:1:1 随机分配接受铂类化疗、奥拉帕利或奥拉帕利/西地尼布治疗。主要终点是在意向治疗人群中的无进展生存期（PFS）。次要终点包括在种系突变或野生型亚组中的活性和患者报告的结果（PROs）。
2016 年 2 月 4 日至 2017 年 11 月 13 日，565 名符合条件的患者被随机分配。化疗、奥拉帕利和奥拉帕利/西地尼布组的中位 PFS 分别为 10.3（95%CI，8.7 至 11.2）、8.2（95%CI，6.6 至 8.7）和 10.4（95%CI，8.5 至 12.5）个月。奥拉帕利/西地尼布与化疗相比并未改善 PFS（风险比[HR]0.86；95%CI，0.66 至 1.10； =.077）。在种系 突变的女性中，与化疗相比，奥拉帕利/西地尼布的 PFS HR 为 0.55（95%CI，0.32 至 0.94），奥拉帕利为 0.63（95%CI，0.37 至 1.07）。在没有种系 突变的女性中，与化疗相比，奥拉帕利/西地尼布的 PFS HR 为 0.97（95%CI，0.73 至 1.30），奥拉帕利为 1.41（95%CI，1.07 至 1.86）。化疗组更常发生血液学不良事件；然而，奥拉帕利/西地尼布组的非血液学不良事件发生率更高。在 489 名可评估 PROs 的患者中，接受奥拉帕利/西地尼布治疗的患者在 NFOSI-DRS-P 子量表上的平均评分低 1.1 分（97.5%CI，-2.0 至-0.2， =.0063）；与化疗相比，奥拉帕利与化疗之间无差异。
与化疗相比，奥拉帕利/西地尼布联合治疗并未改善 PFS，并导致 PROs 降低。值得注意的是，在种系 突变的患者中，奥拉帕利和奥拉帕利/西地尼布均具有显著的临床活性。
