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.


同源重組缺陷（HRD）的晚期卵巢癌中尼拉帕利單藥新輔助治療的療效、安全性和生物標(biāo)志物：一項(xiàng)前瞻性、多中心、II期、單臂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抑制劑作為新輔助治療的療效及其與腫瘤微環(huán)境（TME）狀態(tài)的明確關(guān)聯(lián)仍是一個(gè)謎。在這里，我們首次報(bào)告了尼拉帕利單藥（一種口服低毒性PARP抑制劑）作為同源重組缺陷（HRD）高級(jí)別漿液性卵巢癌（HGSOC）患者新輔助治療的療效和安全性，并使用尖端技術(shù)直接將治療前TME成分與療效聯(lián)系起來。


Methods


Treatment-na?ve 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


納入新診斷晚期不可切除的初治HGSOC以及無法耐受初始腫瘤細(xì)胞減滅術(shù)的患者，進(jìn)行腹腔鏡活檢。通過單細(xì)胞RNA測(cè)序和多重免疫組織化學(xué)對(duì)TME概況進(jìn)行分析。HRD（BRCA1/2突變和/或基因組不穩(wěn)定性評(píng)分≥42）的HGSOC患者接受每日口服尼拉帕利治療兩個(gè)28天周期。完全緩解、部分緩解（PR）或疾病穩(wěn)定（SD）的患者接受間歇性腫瘤細(xì)胞減滅術(shù)（IDS）。雙主要終點(diǎn)是客觀緩解率（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.


研究結(jié)果


在2021年1月18日至2023年7月18日期間，篩查了來自六個(gè)中心的127名患者。共有67名HRD患者接受了新輔助尼拉帕利單藥治療，48名患者完成了療效評(píng)估，40名患者接受了IDS。30名患者達(dá)到PR，12名患者達(dá)到SD，ORR為62.5%，疾病控制率（DCR）為87.5%。BRCAm患者表現(xiàn)出更高的緩解率，ORR（77.3%）和DCR（100.0%）均有所增加。在手術(shù)結(jié)果方面，80.0%的患者實(shí)現(xiàn)了R0切除，95.0%的患者實(shí)現(xiàn)了最佳腫瘤細(xì)胞減滅。在61.2%的患者中觀察到與治療相關(guān)的3級(jí)或以上不良事件（TRAEs），血液學(xué)毒性是最常見的。未觀察到致命的TRAEs。MRC1+巨噬細(xì)胞、效應(yīng)調(diào)節(jié)性T細(xì)胞和肌成纖維樣腫瘤相關(guān)成纖維細(xì)胞的共同富集與緩解率低相關(guān)。


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.


研究結(jié)論


在新輔助尼拉帕利單藥治療具有同源重組缺陷（HRD）且不可切除的高級(jí)別漿液性卵巢癌（HGSOC）患者獲得了令人鼓舞的客觀緩解率（ORR）和手術(shù)R0率，且毒性可耐受，為那些不愿接受或無法耐受新輔助化療的患者提供了另一種選擇。治療前腫瘤微環(huán)境（TME）與PARP抑制劑的臨床反應(yīng)呈相關(guān)性。