Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto Canada.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res. 2020 Mar 1;26(5):1009-1016. doi: 10.1158/1078-0432.CCR-19-1638. Epub 2019 Dec 12.
Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.
Patients received either G+C (guadecitabine 30 mg/m s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).
Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.
Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.
卵巢癌的铂耐药与表观遗传修饰有关。低甲基化剂（HMA）已被研究作为卵巢癌中卡铂再敏化剂。这项随机 II 期试验比较了 Guadcitabine，一种第二代 HMA，和卡铂（G+C）与二线化疗在可测量或可检测的铂耐药卵巢癌患者中的疗效。
患者接受 G+C（ Guadcitabine 30mg/m 皮下注射，每天一次，连用 5 天，卡铂）或选择的治疗（TC；拓扑替康、聚乙二醇脂质体阿霉素、紫杉醇或吉西他滨），每 28 天为一个周期，直到疾病进展或不可接受的毒性。主要终点是无进展生存期（PFS）；次要终点是 RECIST v1.1 和 CA-125 缓解率、6 个月 PFS 和总生存期（OS）。
在 100 名接受治疗的患者中，51 名接受 G+C，49 名接受 TC，其中 27 名交叉到 G+C 组。该研究没有达到主要终点，因为两组之间的中位 PFS 没有统计学差异（G+C 组和 TC 组分别为 16.3 周和 9.1 周；=0.07）。然而，G+C 组的 6 个月 PFS 率显著更高（37%对 TC 组的 11%；=0.003）。G+C 和 TC 组的 3 级或以上毒性发生率相似（分别为 51%和 49%），G+C 组更常见中性粒细胞减少和白细胞减少。
尽管该试验没有显示 G+C 对 PFS 的优越性，但 G+C 治疗患者的 6 个月 PFS 增加。进一步完善这一策略应侧重于识别患者选择的预测标志物。
