抽象：CTO71

从第三阶段试验EMBRACA的新数据的研究人员在领导乐动体育LDsports中国The University of Texas MD Anderson Cancer Centerfound the PARP inhibitor talazoparib did not demonstrate a statistically significant overall survival (OS) benefit for patients with metastatic HER2-negative breast cancer and mutations in the BRCA1/2 genes. Most patients included in the study went on to receive subsequent systemic therapies, which may have affected the survival outcome analysis. The research confirmed previous results showing talazoparib improved patient reported quality-of-life measures over available chemotherapies and had a tolerable safety profile.

从次级端点结果EMBRACA试验中今天提出了在美国癌症研究协会乐动体育LDsports中国(AACR) annual meeting by詹妮弗·利顿，医学博士，教授乳腺肿瘤内科。初步分析结果之前发表在新英格兰医学杂志并且发现，与talazoparib治疗的患者当与化疗相比，已经显著延长无进展生存期（PFS）中，用8.6个月，中位PFS与5.6个月，分别。这导致食品和药物管理局批准，于2018年talazoparib。

EMBRACAis the largest trial of PARP monotherapy to date in patients with germline BRCA-mutated HER2-negative advanced breast cancer. The final OS analysis was performed using the intent-to-treat population after 324 deaths had been observed. After a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died. The effect of treatment with talazoparib also was similar regardless of BRCA status.

“总体生存始终是一个重要的终点，同时也为转移性乳腺癌患者是一个挑战，因为有许多可用的治疗选择，”利顿说。“许多这些患者还接收到的后续疗法，包括PARP抑制剂和基于铂的治疗，这可能潜在地影响这些结果。”

Mutations in the BRCA1/2 genes, which account for 5 to 10% of all breast cancers, cause defects in normal DNA damage repair. PARP inhibitors block an additional DNA repair pathway, and the anti-tumor effects of PARP inhibitors can be intensified in patients with BRCA mutations. Talazoparib works by not only inhibiting the PARP enzyme, but by trapping the enzyme on DNA to further prevent DNA repair.

The international Phase III clinical trial, EMBRACA, enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Patients with HER2-positive disease were excluded as there are approved targeted therapies for those cancers. Patients were allowed up to three previous chemotherapies, including platinum-based therapies.

Participants were randomized 2:1 to receive either talazoparib (287) or physician’s choice of treatment (PCT) of single-agent therapy (144), either capecitabine, eribulin, gemcitabine or vinorelbine. Fifty-four percent of participants had HR+ disease and 46% had triple negative breast cancer; BRCA1 and BRCA2 mutations were split at 45 and 55%, respectively.

与患者的化疗组几乎60％相比，talazoparib组中的几乎一半的患者接受随后的PARP抑制剂或铂治疗。当在PARP抑制剂寻找具体地，患者的化疗组大约三分之一接收的后续PARP抑制剂，其变得越来越提供给患者或者通过试验或商业该试验的过程中，只有4.5％的谁收到talazoparib患者相比。

随后铂治疗物通过约46％的患者的talazoparib组中与患者的化疗组约42％相比，接收。

操作系统结果的解释可能已被随后的处理混淆，于是两个灵敏度分析占后续PARP抑制剂和/或铂治疗中进行。

分析表明，该OS的分析低估talazoparib的治疗益处。

患者报告的质量寿命的措施透露了一个时间的延长整体健康的恶化，26.3个月的talazoparib组相比，6.7个月的化疗组。

“Talazoparib仍然是治疗晚期乳腺癌和种系BRCA突变的选择，由于其无进展生存期的改善，说：”立顿“其他优势还包括它是一种口服每天一次的选项，以及在质量的证明改进生活转移性乳腺癌患者。”

3-4级血液学不良事件（AE）发生在接收talazoparib患者56.6％和化疗的38.9％。大部分3-4级的不良事件报告的talazoparib组为血液系统和最成功通过支持治疗和剂量修改管理。最常见的血液学AE在接收talazoparib患者是贫血，这是报告的接收talazoparib与接受化疗的患者19.0％的患者相比，54.9％。

Correlative studies currently are underway and analysis using the EMBRACA population to explore the effect of tumor BRCA zygosity and genomic loss-of-heterozygosity on efficacy outcomes also is being presented at AACR’s annual meeting by Lida Mina, M.D., associate director of Breast Programs at Banner MD Anderson Cancer Center.

The study was funded by Medivation, which was acquired by Pfizer in September 2016. Litton has research funding from Novartis, Pfizer, Genentech, GSK, EMD-Serono, AstraZeneca and Zenith Epigenetics, and she has served on advisory boards for AstraZeneca, Pfizer, and Ayala Pharmaceuticals, all uncompensated.

MD安德森研究人员已经确乐动体育LDsports中国定潜在生物标志物为高级浆液性的响应ovarian cancers（HGSC），以单纯手术切除或化疗之前手术, providing new avenues to explore for improvingovarian cancer treatment。

Their卵巢癌研究乐动体育LDsports中国findings, in collaboration with Inova Health System, were今天发表在细胞报告。

HGSC accounts for nearly 90% of ovarian cancer deaths. Patients who undergo complete surgical resection (R0) have better outcomes, but it is unknown whether this survival benefit is due to the aggressive surgery or to the biology of resectable high-grade serous ovarian cancers.

“我们的团队参与了癌症基因组图谱（TCGA）努力发现在卵巢癌的分子差异。然而，这些研究从接受手术切除的患者只用样品，并没有占到最积极的肿瘤需要化疗第一次手术前进行治疗，”说Anil Sood, M.D.在各部门教授和副主任的转化研究乐动体育LDsports中国Gynecologic OncologyandCancer Biology和纸张的资深作者。

TCGA还没有进行免疫或细胞的分析并没有包括来自转移部位的样品。

搜索生物标志物，以指导卵巢癌的治疗

为了了解这些肿瘤的深入，苏德，第一作者生物学Sanghoon Lee, Ph.D.，助理教授系统生物学和同事，进行了广泛的分析，包括高通全基因组测序，有针对性的深度测序，RNA测序，反相蛋白质阵列，基于质谱的蛋白组学/磷酸化蛋白质组学，免疫分析，和集成的数据的分析。该团队通过MD安德森进行了这项工作卵巢癌Moon Shot。

“Most studies just perform RNA analysis or one or two types of analyses, but we wanted to carry out an all-out effort to find biomarkers that can be used for clinical decision-making,” Sood says.

This study used baseline primary and metastatic tumor samples from 30 patients triaged by a systematic algorithm to either surgical resection or neoadjuvant chemotherapy and surgery: 10 patients had no visible residual disease after primary surgery (R0), 10 underwent neoadjuvant therapy but had a poor response, and 10 underwent neoadjuvant therapy with an excellent response. The researchers found significant molecular and cellular differences between the R0 and neoadjuvant therapy groups.

Genetic differences may help determine high-grade serous ovarian cancer treatment

他们发现，从R0组肿瘤样品具有的显著较低表达NF1基因，RNA和蛋白质比从新辅助治疗组样品。以前的研究已经表明，NF1有助于肿瘤发生和化疗耐药的HGSC。虽然生物机制尚不清楚，这些研究结果表明，NF1may serve as a biomarker that could predict response to surgical resection versus neoadjuvant therapy for patients with high-grade serous ovarian cancer.

相较于新辅助治疗的样品，R0样品也有较少chromothripsis状图案，其中一个染色体碎裂和不正确重新装配。R0样品具有更少的拷贝数开关，而chromothripsis状图案分别定位于染色体6和19，而chromothripsis状在肿瘤新辅助图案被富集在染色体8和17（NF1位于17号染色​​体上）。

研究人员乐动体育LDsports中国没有发现原发性肿瘤和转移性肿瘤之间有任何显著的基因组差异。这表明，HGSC的基因组不稳定性，包括拷贝数量和结构的变化，可能发生在疾病进展早期的点。

免疫反应的差异

R0 tumors and tumors with excellent response to neoadjuvant therapy had significantly higher levels of neoantigens than the tumors with poor response to neoadjuvant therapy, and the R0 tumors had significantly more strong-binding neoantigens. These high levels of neoantigens also were associated with a better immune profile, such as more infiltration of tumor immune cells and fewer macrophages. These tumor-associated neoantigens might be good immunotherapeutic targets that could spare healthy cells.

化疗反应的标记

相较于肿瘤不得不新辅助治疗反应差，是有优异的响应有LCK和YES1，Src家族激酶磷酸化位点的显著表达水平较低。这些磷酸化位已经牵涉在T细胞发育和迁移信令，并且这些差异可作为生物标志物来预测HGSC化疗反应。

高档浆液性卵巢癌研究的下一步乐动体育LDsports中国

由于治疗前对此进行了深入分析，高档浆液性卵巢癌常用的基线肿瘤样本中，研究小组计划将研究肿瘤样本的患者治疗后。乐动体育LDsports中国他们也将着眼于看好在本研究中鉴定的生物标记，看看是否可以用于临床决策或为治疗靶点这些遗传差异。

“Patients with high-grade serous ovarian cancer that does not respond to neoadjuvant therapy have the worst outcomes; we’d like to identify molecular/cellular targets and design drugs that can improve these patients’ outcomes,” Sood says. “Accurate biomarkers could help us tailor precise treatment strategies for all patients with HGSC.”

抽象：DDT01-03

在IPN60090的首次公开，代谢酶谷氨酰胺酶的小分子抑制剂（GLS1），研究人员从乐动体育LDsports中国The University of Texas MD Anderson Cancer Center的治疗师发现和易普森生物制药报道这种新型药物的临床前发现和早期临床开发阶段。IPN60090，现在正在在调查I期临床试验, may hold benefit for certain patients with lung and ovarian cancers.

MD安德森的GLS1程序已经启动，并通过先进的一队在科学家学院应用科学癌症（IACS）和转化研究推进治疗和创新肿瘤乐动体育LDsports中国（牵引）平台，治疗内发现两台发动机。该计划的发展继续与易普森，其合作行货治疗在2018年。

调查结果和关于正在进行的试验信息将在今天2020年呈现美国癌症研究协会的虚拟届年会我乐动体育LDsports中国by Jeffrey Kovacs, Ph.D., institute group leader with TRACTION and co-leader of the GLS1 program.

“这方面的努力是我们的治疗探索中的战略，采取了全面的方法来个性化医疗的一个很好的例子，说：”科瓦奇。“我们的临床前数据表明，IPN60090可有效的谁需要更好的治疗方案的患者不足的群体，我们期待着从我们正在进行的临床试验结果。”

细胞代谢失调是癌症发展的特点，以及GLS1酶在许多代谢过程中起关键作用。因此，它使对于癌症治疗有吸引力的目标，说明科瓦奇。

IACS药物发现科学家鉴定IPN60090作为适合于临床试验的GLS1一个有效的和选择性的抑制剂，而在牵引平移研究人员证明其活性针对肺癌和卵巢癌的临床前模型的子集。乐动体育LDsports中国

Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in theKEAP1andNFE2L2基因，从而调节响应于氧化应激，使细胞对治疗IPN60090。类似地，在卵巢癌的代谢蛋白质的天冬酰胺合成酶（ASNS）的低表达预示在临床前模型响应于IPN60090。

“识别响应这些假定预测生物标志物，是我们正在进行的临床努力，以确保我们能够为患者提供最相关的治疗关键，”说Timothy A. Yap, M.B.B.S., Ph.D.，F.R.C.P.，副教授研究性癌症治疗和IACS的医疗主任。“这些患者组中特别地，代表这些癌症类型内的不同龛，都需要更有效的治疗选择。”

For example, patients with lung cancers harboringKEAP1/NRF2mutations have not benefited from treatment with免疫抑制剂检查站并有更糟糕的结果，解释邑，谁领导在MD安德森的IPN60090临床试验。

IPN60090目前正在处于调查I期剂量递增和剂量扩展研究治疗晚期实体瘤港KEAP1 / NFE2L2突变或具有低ASNS水平。该团队已经开发出新颖的CLIA认证试验，确定可能的患者受益，并监测药物如何有效作用。从临床试验初始数据表明，IPN60090有效地从患者抑制外周血单核细胞GLS1活性。

未来的审判同伙计划调查IPN60090联合检查点抑制剂，化疗and靶向治疗经科研人员为具有GLS1抑制潜在的协乐动体育LDsports中国同效益确定。

正在进行的研究是由易普森乐动体育LDsports中国通过全球授权和开发协议的支持。这项研究乐动体育LDsports中国是根据MD安德森的管理Institutional Conflict of Interest Management and Monitoring Plan。Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson’s登月计划。

虽然转移性去势抗性prostate cancer（mCRPC）典型地具有以响应有限免疫治疗，患者在他们的肿瘤活性的T细胞反应预处理证据的一个子集有过长期生存在与易普利姆玛治疗的II期临床试验在The University of Texas MD Anderson Cancer Center。

结果，今天出版科学转化医学，认为某些患者可能mCRPC受益免疫抑制剂检查站和提供的生物标记，用于识别该亚组。

“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer,” said lead author萨米特Subudhi，医学博士，博士，助理教授泌尿生殖系统肿瘤内科。“We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”

与免疫检查点抑制剂，如最强的响应癌症黑色素瘤or肺癌，趋向于具有高含量的潜在基因突变，这导致生产突变蛋白，或新抗原的，可以由免疫系统识别为异常。前列腺癌具有相对较低水平的突变和更少的新抗原存在。

然而，更大的Ⅲ期临床试验中mCRPC患者的小团体已经看到了有利的结果来检验点抑制剂，解释Subudhi，这推动了研究人员询问是否有效的免疫应答可以通过检查站封锁在低层次的突变的肿瘤刺激。乐动体育LDsports中国

To investigate this question, the research team launched the Phase II trial in collaboration with MD Anderson’s免疫治疗平台, which is co-led by corresponding authorPadmanee夏尔马，医学博士，博士，泌尿生殖系肿瘤内科教授，免疫学。该平台是该机构的一部分登月计划^®，合作努力，加快科学发现的开发到临床进展是挽救患者的生命。

The trial enrolled 30 MD Anderson patients with mCRPC between January 2015 and May 2018. Of those, 29 received at least one dose of ipilimumab and were able to be included in the final analysis. Median follow-up after the first treatment was 45.5 months.

在所有患者中，根据射线摄影成像中位无进展生存期（PFS）为3个月，中位总生存期（OS）为24.3个月。8例（28％）经历3级毒性，其中最常见的是皮炎和腹泻，并且没有经验的分级4周或5的毒性。

研究人员乐动体育LDsports中国指出，59例PFS大于6个月，OS超过一年一个“利好”的队列，10患者的PFS不到半年的时间和OS不到一年的“不利”的队列。在分析的时候，六（67％）患者从“利好”队列还活着，带瘤生存为33个月和54之间。

通过这两个同伙比较预处理样品，一起检查站封锁改进反应相关的研究人员鉴定的标记。乐动体育LDsports中国那些在“有利的”队列中的肿瘤以及干扰素（IFN）-γ的信令的表达增加了细胞毒性和记忆T细胞的更高的密度。

Further, the researchers showed that T cells isolated from patients in the “favorable” cohort were capable of recognizing and responding to the neoantigens present in their tumor, whereas T cells from patients in the “unfavorable” group did not appear to have the same responses.

“我们感到鼓舞地看到，前列腺癌与低突变负担做实际上表达诱导T细胞反应是导致良好的临床效果，新抗原”夏尔马说。“我们的研究结果表明，抗CTLA-4的免疫检查点治疗令更多的研究，以开发可改善患者的转移性前列腺癌生存期的治疗策略。”

展望未来，笔者计划调查中较大的，多机构的研究这个问题，以验证当前试验的结果。

这项研究乐动体育LDsports中国是由免疫平台和前列腺癌登月的部分资助^®, both part of MD Anderson’s Moon Shots Program. The research also was supported by: Bristol Myers Squibb, the Stand Up To Cancer-Cancer Research Institute Immunology Dream Team Translational Research Grant, the Prostate Cancer Foundation Young Investigator Award, and the National Cancer Institute (CA1633793, P30CA016672). Padmanee Sharma and James Allison are members of the Parker Institute for Cancer Immunotherapy at MD Anderson.

除了Subudhi和夏尔马，MD安德森的研究人员合作的研究包括：路易斯·旺斯，博士，耗着，博士乐动体育LDsports中国，豪尔赫Blando，博士，Shalini亚达夫，博士和清熊，所有的免疫治疗平台;亚历山大·鲁本博士，胸/头颈部肿瘤内科的;安娜·阿帕里西奥，医学博士，保罗玉米，医学博士，博士和Christopher Logothetis，医学博士，泌尿生殖系所有肿瘤医学;布赖恩·蔡平，医学博士，和Louis Pisters，医学博士，既有泌尿外科;帕特里夏·特龙科索，医学博士，病理学;丽贝卡·蒂德韦尔和彼得Thall，博士，既有生物统计学;

昌林俊武，博士，张建华，博士和安德鲁Futreal，博士，所有基因组医学的;和吉姆·艾利森博士，Immnology和免疫治疗平台。作者的信息披露的完整列表可与全文中找到这里。