Joly Florence, Leary Alexandra, Ray-Coquard Isabelle, Asselain Bernard, Rodrigues Manuel, Gladieff Laurence, Meynard Guillaume, Abadie-Lacourtoisie Sophie, Lebreton Coriolan, Bengrine Lefevre Leïla, Fournel Pierre, Largillier Rémy, Selle Frédéric, Frenel Jean-Sébastian, Fernandez Diez Yolanda, Foa Cyril, Follana Philippe, Meunier Jérôme, Fabbro Michel, Hardy Bessard Anne-Claire, Cojean-Zelek Isabelle, Kaczmarek Emilie, Bonnet Elise, Arnaud Antoine, Roche Sophie, Leroy Karen, Just Pierre-Alexandre, Leman Raphaël, Jeanne Corinne, Callens Céline, You Benoit, Alexandre Jérôme
Medical Oncology Department, Centre François Baclesse, UniCaen University, Caen, France.
GINECO and Department of Medical Oncology, Gustave Roussy, Villejuif, France.
Nat Commun. 2025 Aug 26;16(1):7950. doi: 10.1038/s41467-025-62678-x.
Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65-1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.
单药维持聚（ADP - 核糖）聚合酶（PARP）抑制可能是晚期/转移性子宫内膜癌患者对铂类化疗有反应的一种有效策略，包括对那些选择有限的分子亚型患者。为了探索这种方法，我们启动了随机IIb期UTOLA试验（NCT03745950）。对于晚期/转移性子宫内膜癌接受一线铂类化疗后未进展的女性患者，按2:1随机分组，分别每日两次口服300mg奥拉帕利或安慰剂，直至疾病进展或出现不耐受，按p53状态、错配修复状态和对初始化疗的反应进行分层。主要终点是意向性治疗人群的无进展生存期（PFS）。次要终点包括亚组中的PFS、至第二次进展或死亡的时间、至首次和第二次后续治疗的时间、客观缓解率、总生存期、患者报告的结局以及安全性。在意向性治疗人群（n = 145）中，奥拉帕利和安慰剂之间的PFS无差异（中位时间分别为5.6个月和4.0个月；风险比0.94，95%置信区间0.65 - 1.35；p = 0.74）。然而，在预先指定亚组（p53异常、对初始化疗完全缓解、染色体不稳定）的探索性分析中观察到了有趣的PFS数值效应。治疗组之间的总生存期无差异。3/4级不良事件在接受奥拉帕利治疗的患者中发生率为36%，在接受安慰剂治疗的患者中为10%，且与奥拉帕利在其他癌症中的安全性特征一致。维持奥拉帕利未改善PFS，但在部分患者亚组中的数值效应值得进行前瞻性评估。
