Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
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DOI：
10.1186/s40425-018-0463-2
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发表时间：
2018-12-04
影响因子：
10.9
通讯作者：
Dahut, William L.
中科院分区：
文献类型：
--
作者：
Karzai, Fatima;VanderWeele, David;Dahut, William L.
背景：检查点抑制剂作为单一药物对前列腺癌无效。Durvalumab是一种靶向程序性死亡配体1的人IgG 1-K单克隆抗体，已被美国食品药品监督管理局批准用于局部晚期或转移性尿路上皮癌和局部晚期、不可切除的3期非小细胞肺癌。奥拉帕尼是一种聚（ADP-核糖）聚合酶抑制剂，已证明可改善部分转移性去势抵抗性前列腺癌（mCRPC）患者的中位无进展生存期（PFS）。来自其他试验的数据表明，使用检查点抑制剂治疗的DNA损伤修复（DDR）突变的男性可能会改善活性。该试验评估了durvalumab和olaparib在有和没有体细胞或生殖系DDR突变的mCRPC患者中的作用。患者每28天接受durvalumab 1500 mg i. v.和olaparib 300 mg片剂p.o.每12小时一次，直至疾病进展或出现不可接受的毒性。所有患者的转移性病变活检与生殖细胞和体细胞突变的评价。结果：17例患者接受durvalumab和olaparib。恶心是唯一的非血液学3级或4级毒性，发生在> 1例患者（2/17）中。没有患者因毒性而退出试验。所有患者的中位放射学无进展生存期（rPFS）为16.1个月（95% CI：4.5-16.1个月），12个月rPFS为51.5%（95% CI：25.7- 72.3%）。在DDR基因改变的患者中观察到活性，中位rPFS为16.1个月（95% CI：7.8-18.1个月）。17例患者中有9例（53%）有放射学和/或PSA缓解。外周髓源性抑制细胞较少和DDR基因改变的患者更有可能有反应。循环肿瘤细胞计数和先天性和适应性免疫特征的早期变化与responsibility.Conclusions：Durvalumab加上奥拉帕尼具有可接受的毒性，并结合证明疗效，特别是在男性DDR异常。
Background: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.Methods: Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.Results: Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7- 72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.Conclusions: Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.