Efficacy, safety, and biomarkers of neoadjuvant niraparib monotherapy in homologous recombination deficiency （HRD） advanced ovarian cancer: A prospective, multicenter, phase II, single-arm NANT study.


同源重组缺陷（HRD）的晚期卵巢癌中尼拉帕利单药新辅助治疗的疗效、安全性和生物标志物：一项前瞻性、多中心、II期、单臂NANT研究


First Author：Qing-lei Gao


Background


The efficacy of PARP inhibitors as neoadjuvant therapy and its clear association with tumor microenvironment （TME） status remain enigmatic. Here, for the first time, we reported the efficacy and safety of niraparib monotherapy, an oral low-toxicity PARP inhibitor, as the neoadjuvant therapy in patients （pts） with HRD high-grade serous ovarian cancer（HGSOC）, and directly linked pre-treatment TME components with response using cutting-edge technologies.


研究背景


PARP抑制剂作为新辅助治疗的疗效及其与肿瘤微环境（TME）状态的明确关联仍是一个谜。在这里，我们首次报告了尼拉帕利单药（一种口服低毒性PARP抑制剂）作为同源重组缺陷（HRD）高级别浆液性卵巢癌（HGSOC）患者新辅助治疗的疗效和安全性，并使用尖端技术直接将治疗前TME成分与疗效联系起来。


Methods


Treatment-naïve pts with newly diagnosed advanced unresectable HGSOC and those who could not endure primary debulking surgery were enrolled to receive laparoscopic biopsies. TME landscape was profiled by single-cell RNA sequencing and multiplex immunohistochemistry. Pts with HRD （BRCA1/2mutations and/or genomic instability score ≥ 42） HGSOC received daily oral niraparib for two 28-day cycles. Pts with complete response, partial response （PR）, or stable disease （SD） received interval debulking surgery （IDS）. The co-primary endpoints were objective response rate （ORR） and R0 resection rate.


研究方法


纳入新诊断晚期不可切除的初治HGSOC以及无法耐受初始肿瘤细胞减灭术的患者，进行腹腔镜活检。通过单细胞RNA测序和多重免疫组织化学对TME概况进行分析。HRD（BRCA1/2突变和/或基因组不稳定性评分≥42）的HGSOC患者接受每日口服尼拉帕利治疗两个28天周期。完全缓解、部分缓解（PR）或疾病稳定（SD）的患者接受间歇性肿瘤细胞减灭术（IDS）。双主要终点是客观缓解率（ORR）和R0切除率。


Results


Between January 18, 2021 and July 18, 2023, 127 pts from six centers were screened for eligibility. Totally, 67 HRD pts received neoadjuvant niraparib monotherapy, 48 pts completed response evaluations, and 40 pts underwent IDS. Thirty pts achieved PR and 12 pts reached SD, resulting in an ORR of 62.5% and a disease control rate （DCR） of 87.5%.BRCAm pts exhibited improved responses with increased ORR （77.3%） and DCR （100.0%）. For surgical outcomes, 80.0% of pts achieved R0 resection and 95.0% of pts accomplished optimal debulking. Treatment-related adverse events （TRAEs） of grade ≥3 were observed in 61.2% of pts and hematological toxicities were the most common. No fatal TRAEs were reported. Co-enrichment of MRC1+ macrophages, effector regulatory T cells, and myofibroblastic cancer-associated fibroblasts were associated with lack of response.


研究结果


在2021年1月18日至2023年7月18日期间，筛查了来自六个中心的127名患者。共有67名HRD患者接受了新辅助尼拉帕利单药治疗，48名患者完成了疗效评估，40名患者接受了IDS。30名患者达到PR，12名患者达到SD，ORR为62.5%，疾病控制率（DCR）为87.5%。BRCAm患者表现出更高的缓解率，ORR（77.3%）和DCR（100.0%）均有所增加。在手术结果方面，80.0%的患者实现了R0切除，95.0%的患者实现了最佳肿瘤细胞减灭。在61.2%的患者中观察到与治疗相关的3级或以上不良事件（TRAEs），血液学毒性是最常见的。未观察到致命的TRAEs。MRC1+巨噬细胞、效应调节性T细胞和肌成纤维样肿瘤相关成纤维细胞的共同富集与缓解率低相关。


Conclusions


Neoadjuvant niraparib monotherapy regimen achieved encouraging ORR and R0 resection rate with tolerable toxicities in pts with HRD unresectable HGSOC, offering an alternative option for those pts unwilling to receive or unable to tolerate neoadjuvant chemotherapy. Pre-treatment TME factors were correlated with clinical response to PARP inhibitors.


研究结论


在新辅助尼拉帕利单药治疗具有同源重组缺陷（HRD）且不可切除的高级别浆液性卵巢癌（HGSOC）患者获得了令人鼓舞的客观缓解率（ORR）和手术R0率，且毒性可耐受，为那些不愿接受或无法耐受新辅助化疗的患者提供了另一种选择。治疗前肿瘤微环境（TME）与PARP抑制剂的临床反应呈相关性。