Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial
Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial
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DOI：
10.1016/s1470-2045(19)30029-4
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发表时间：
2019-05-01
期刊：
影响因子：
51.1
通讯作者：
Monk, Bradley J.
中科院分区：
文献类型：
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作者：
Moore, Kathleen N.;Secord, Angeles Alvarez;Monk, Bradley J.
卵巢癌患者的晚期治疗选择很少，达到总体缓解的患者比例通常低于10%，三线治疗后的中位总生存期为5-9个月。在这项研究（QUADRA）中，我们调查了尼拉帕尼单药治疗作为第四条或以后的治疗线的活性。QUADRA是一项多中心，开放标签，单臂，2期研究，评估尼拉帕尼在复发，高级别浆液性（2级或3级）上皮性卵巢癌，输卵管癌或原发性腹膜癌的成人患者（>= 18岁）的安全性和活性，这些患者先前接受过三种或更多化疗方案。该研究在美国和加拿大进行，56个地点对患者进行了筛查（50个地点至少治疗了一名患者）。患者口服尼拉帕尼300 mg，每日1次，从第1天开始，此后每个周期（28天）直到疾病进展。研究的主要目的是研究人员评估的同源重组缺陷（HRD）阳性肿瘤患者（包括BRCA和无BRCA突变的患者）对上次铂类药物治疗敏感的患者（先前接受过三到四种抗癌治疗方案的患者）达到经证实的总体缓解的患者比例（主要疗效人群）。对基线时可测量疾病的所有给药患者进行疗效分析。在2015年4月1日至2017年11月1日期间，我们筛选了729名患者，并招募了463名患者，他们开始接受尼拉帕尼治疗。在数据库锁定时（2018年4月11日），报名已经结束，研究仍在进行中，有21名患者仍在接受治疗。患者先前接受的治疗中位数为4次（IQR为3-5），总生存期的中位数随访为12次。2个月（IQR 3.7-22.1）。463例患者中151例（33%）耐药，463例患者中161例（35%）难治性。根据RECIST (95% CI 15.6-42.6；单侧p=0.00053)，主要疗效人群中47例患者中有13例（28%）达到了总体缓解。最常见的药物相关3级或更严重的治疗不良事件是贫血（463例患者中113例[24%]）和血小板减少症（463例患者中95例[21%]）。最常见的治疗后出现的严重不良事件是小肠阻塞（463例患者中34例[7%]）、血小板减少（463例患者中34例[7%]）和呕吐（463例患者中27例[6%]）。1例胃出血死亡被认为与治疗有关。我们观察到尼拉帕尼在重度预处理卵巢癌女性患者中的临床相关活性，特别是在hrd阳性铂敏感疾病患者中，其中不仅包括BRCA突变患者，还包括BRCA野生型疾病人群。我们没有发现新的安全信号。我们的数据支持将聚（adp -核糖）聚合酶抑制剂的治疗适应症扩大到BRCA突变患者以外的hrd阳性卵巢癌患者。Elsevier Ltd.版权所有版权所有。
Background Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.Methods QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (>= 18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.Findings Between April 1,2015 and Nov 1,2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12. 2 months (IQR 3.7-22.1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15.6-42.6; one-sided p=0.00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related.Interpretation We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations. Copyright (C) 2019 Elsevier Ltd. All rights reserved.