Department of Oncology, UCL Cancer Institute, University College London, London, UK.
Oncogynecological Department, Saint Petersburg City Oncological Dispensary, Saint Petersburg, Russia.
Lancet Oncol. 2022 Apr;23(4):465-478. doi: 10.1016/S1470-2045(22)00122-X. Epub 2022 Mar 14.
Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting.
In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing.
Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause).
Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma.
Clovis Oncology.
很少有前瞻性研究比较聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂与化疗用于治疗 BRCA1 突变或 BRCA2 突变的卵巢癌。我们旨在评估在这种情况下鲁卡帕利与基于铂类和非铂类化疗的疗效。
在这项在 12 个国家的 64 家医院和癌症中心进行的开放标签、随机、对照、3 期研究（ARIEL4）中，我们招募了年龄在 18 岁及以上、BRCA1 突变或 BRCA2 突变、东部合作肿瘤学组体能状态为 0 或 1、且接受过两次或两次以上先前化疗方案的卵巢癌患者。符合条件的患者采用交互式响应技术和区组随机化（区组大小为 6），并根据最近一次含铂治疗后无进展间隔分层，随机分配（2:1）接受口服鲁卡帕利（600mg 每日两次）或化疗（根据机构指南给药）。分配到化疗组的铂耐药或部分铂敏感疾病患者给予紫杉醇（起始剂量 60-80mg/m2，第 1、8 和 15 天）；完全铂敏感疾病患者接受基于铂类化疗（单药顺铂或卡铂，或铂类双联化疗）。患者在 21 天或 28 天周期中进行治疗。主要终点是研究者评估的无进展生存期，在疗效人群（所有携带有害 BRCA1 或 BRCA2 突变而无回复突变的随机分配患者）中进行评估，然后在意向治疗人群（所有接受至少一剂研究治疗的随机分配患者）中进行评估。在接受至少一剂研究治疗的所有患者中评估安全性。这项研究在 ClinicalTrials.gov 注册，NCT02855944；招募已经完成，研究正在进行中。
在 2017 年 3 月 1 日至 2020 年 9 月 24 日期间，对 930 名患者进行了筛选，其中 349 名符合条件的患者被随机分配到鲁卡帕利组（n=233）或化疗组（n=116）。中位年龄为 58 岁（IQR 52-64），332 名（95%）患者为白人。截至 2020 年 9 月 30 日数据截止时，中位随访时间为 25.0 个月（IQR 13.8-32.5）。在疗效人群（鲁卡帕利组 220 例；化疗组 105 例）中，鲁卡帕利组的中位无进展生存期为 7.4 个月（95%CI 7.3-9.1），化疗组为 5.7 个月（5.5-7.3）（风险比[HR]0.64[95%CI 0.49-0.84]；p=0.0010）。在意向治疗人群（鲁卡帕利组 233 例；化疗组 116 例）中，鲁卡帕利组的中位无进展生存期为 7.4 个月（95%CI 6.7-7.9），化疗组为 5.7 个月（5.5-6.7）（HR 0.67[95%CI 0.52-0.86]；p=0.0017）。大多数治疗期间出现的不良事件为 1 级或 2 级。最常见的 3 级或更严重的治疗期间出现的不良事件为贫血或血红蛋白减少（在鲁卡帕利组 232 例患者中有 52 例[22%]，化疗组 113 例患者中有 6 例[5%]）。鲁卡帕利组有 62 例（27%）患者发生严重治疗期间出现的不良事件，化疗组有 13 例（12%）（研究者认为与治疗相关的严重不良事件发生在鲁卡帕利组 32 例[14%]和化疗组 6 例[5%]）。有 3 例死亡被认为可能与鲁卡帕利有关（1 例死于心脏疾病，1 例死于骨髓增生异常综合征，1 例死因不明）。
ARIEL4 研究的结果支持鲁卡帕利作为复发性 BRCA1 突变或 BRCA2 突变卵巢癌患者化疗的替代治疗选择。
Clovis Oncology。
