奥拉帕利联合贝伐珠单抗一线维持治疗卵巢癌：PAOLA-1/ENGOT-ov25 试验的最终总生存结果。

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

机构信息

Department of Medical Oncology, Centre Léon Bernard, Lyon, France; GINECO, France.

GINECO, France; Gynecological Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif France.

出版信息

Ann Oncol. 2023 Aug;34(8):681-692. doi: 10.1016/j.annonc.2023.05.005. Epub 2023 May 19.

DOI:10.1016/j.annonc.2023.05.005

PMID:37211045

Abstract

BACKGROUND

In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.

PATIENTS AND METHODS

Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.

RESULTS

After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.

CONCLUSIONS

Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

摘要

背景

在 PAOLA-1/ENGOT-ov25 主要分析中，在一线含铂化疗联合贝伐珠单抗治疗后有临床缓解的新诊断晚期卵巢癌患者中，奥拉帕利联合贝伐珠单抗维持治疗显示出显著的无进展生存期（PFS）获益，无论手术状态如何。根据分子生物标志物状态进行的预设探索性分析显示，在 BRCA1/BRCA2 突变（BRCAm）或同源重组缺陷（HRD；BRCAm 和/或基因组不稳定性）患者中存在显著获益。我们报告了预设的最终总生存期（OS）分析，包括根据 HRD 状态进行的分析。

患者按 2:1 随机分配接受奥拉帕利（每日 2 次，每次 300 mg；最多 24 个月）加贝伐珠单抗（每 3 周 15 mg/kg；总疗程 15 个月）或安慰剂加贝伐珠单抗。OS 分析是分层检验的关键次要终点，计划在主要分析后约 60%成熟度或 3 年后进行。

结果

奥拉帕利组和安慰剂组的中位随访时间分别为 61.7 和 61.9 个月后，在意向治疗人群中，中位 OS 分别为 56.5 个月和 51.6 个月[风险比（HR）0.92，95%置信区间（CI）0.76-1.12；P=0.4118]。奥拉帕利组有 105 例（19.6%）患者随后接受了多聚（ADP-核糖）聚合酶抑制剂治疗，而安慰剂组有 123 例（45.7%）患者随后接受了治疗。在 HRD 阳性人群中，奥拉帕利联合贝伐珠单抗的 OS 更长（HR 0.62，95%CI 0.45-0.85；5 年 OS 率，65.5% vs. 48.4%）；5 年时，更新的 PFS 也显示出奥拉帕利联合贝伐珠单抗组无复发的患者比例更高（HR 0.41，95%CI 0.32-0.54；5 年 PFS 率，46.1% vs. 19.2%）。骨髓增生异常综合征、急性髓系白血病、再生障碍性贫血和新发原发性恶性肿瘤的发生率仍然较低且在两组之间平衡。