Schepisi G, Urbini M, Casadei C, Gallà V, Rossetti S, Basso U, Lolli C, Gurioli G, Petracci E, Cecere S C, Ventriglia J, Zampiga V, Miserocchi A, Cangini I, De Santis I, Di Napoli M, Menna C, Mambelli G, Pignata S, De Giorgi U
Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.
ESMO Open. 2025 May;10(5):105056. doi: 10.1016/j.esmoop.2025.105056. Epub 2025 Apr 24.
Therapeutic options for patients with advanced germ-cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair.
In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ-cell cancer [IGG-02 study (NCT02533765)], patient eligibility included failure after high-dose chemotherapy or after at least two different cisplatin-based regimens.
Between September 2015 and February 2019, 18 patients, with a median age of 39 years (range 22-61 years) were enrolled. Severe adverse events (AEs) were observed in seven patients. There were no partial responses, five cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 43 months, and 13 (72.2%) progressive disease. A germline DNA repair profile panel showed only a BRCA1-mutated case associated with an SD lasting for 4 months. The long-lasting patient on olaparib (43 months) experienced a myelodisplastic syndrome (MDS) associated with the onset of a pathogenic mutation affecting PPM1D.
Olaparib as a single agent demonstrated no activity in heavily pretreated GCT patients. Future studies with PARP inhibitors should be planned in less-pretreated GCT patients based on molecular analysis to support better patient selection.
晚期生殖细胞肿瘤（GCT）患者在多次复发或疾病耐药后的治疗选择有限。奥拉帕利是一种聚（ADP - 核糖）聚合酶（PARP）抑制剂，PARP是一种参与DNA修复的酶。
在这项奥拉帕利300 mg每日两次用于复发/难治性转移性生殖细胞癌患者的开放标签、单臂、II期原理验证试验[IGG - 02研究（NCT02533765）]中，患者入选标准包括大剂量化疗失败或至少经过两种不同的含顺铂方案治疗后失败。
2015年9月至2019年2月，共纳入18例患者，中位年龄39岁（范围22 - 61岁）。7例患者观察到严重不良事件（AE）。无部分缓解，5例（27.8%）疾病稳定（SD）持续3、4、4、7和43个月，13例（72.2%）疾病进展。种系DNA修复谱分析显示仅1例BRCA1突变病例与持续4个月的SD相关。接受奥拉帕利治疗时间长（43个月）的患者发生了与影响PPM1D的致病突变发生相关的骨髓增生异常综合征（MDS）。
奥拉帕利单药治疗在经过大量预处理的GCT患者中未显示出活性。未来应基于分子分析，在预处理较少的GCT患者中开展PARP抑制剂研究，以支持更好的患者选择。
