早期临床试验的结果表明，针对DNA损伤反应（DDR）途径的两种药物 - ATR抑制剂Eumenusertib和PARP抑制剂AZD5305 - 对治疗晚期实体瘤患者的治疗且对临床有益。首席研究员Timothy Yap，M.B.B.S.，博士学位，研究性癌症治疗学副教授，今天介绍了来自该试验的新数据美国癌症研究协会（AACR）2022年会议。

“DDR orchestrates a complex network of mechanisms that detects and repairs damage to DNA, such as double strand breaks and replication stress,” Yap explained. “However, when DDR defects occur, it promotes uncontrolled cancer cell growth and enables cells to evade apoptosis. The studies suggest that PARP1-selective and ATR inhibitors, which block two key mediators of the DDR signaling pathway, are a promising class of new drugs that offer significant therapeutic potential for patients with cancers harboring synthetic lethal genomic alterations in DDR pathways.”

Expansion trial of ATR inhibitor shows encouraging clinical activity against DDR defects (摘要CT006）

在IB期扩张试验中，Elimusertib（一种有效且高度选择性的ATR抑制剂）表现出对具有不同推定有害DDR改变的染色性实体瘤范围的有希望的抗肿瘤活性。

ATR是DDR网络的关键组成部分，它被DNA损伤或复制应力激活。YAP解释说，通过与ATR结合并阻止ATR介导的信号传导，ATR抑制剂可防止DNA损伤检查点激活，破坏DNA损伤修复并阻止肿瘤细胞的生长。

在这项研究中，有143例患有不同推定有害DDR改变的晚期实体瘤患者，包括45例妇科癌，24种结直肠癌，19例HER2-Negativebreast Cancers，19个耐Castration抗性的前列腺癌和36个高级癌症ATM - 至少收到一剂的Limusertib。该研究的剂量升级部门招募了32例ATM蛋白损失和/或突变的患者。

最常见的与药物相关的级≥3级治疗出现的不良事件（TEAE）是血液学，包括贫血（65.7％）和中性粒细胞减少症（47.6％）。总体而言，这些血液学茶具是可逆的，可以通过剂量中断或减少和支持措施来控制，并且很少导致永久性药物中断。还探讨了三天和11天的休息时间的替代时间表，可能会降低血液学事件的风险，并提供潜在的替代方法，以在未来的Elimusertib研究中进一步评估。

Elimusertib achieved clinical benefit with disease control for at least 16 weeks in approximately 35% of patients enrolled in the three days on, four days off dose expansion, with durable objective responses observed across a variety of cancer types. Results showed a durable clinical benefit lasting greater than six months in 27.8% of patients with advanced ovarian cancer, including those resistant to platinum-based therapy and those who previously had received PARP inhibitor therapy. In patients with ATM loss, the best overall response included RECIST partial responses in 8.9% of patients and RECIST stable disease in 55.9% of patients, with durable clinical benefit lasting >6 months in 26.5% of patients.

“虽然我们观察到ATM改变患者的持久反应和长时间稳定疾病，并且BRCA1和BRCA2YAP说：“缺陷，包括先前接受过PARP抑制剂治疗的患者，需要进一步的研究以更好地识别分子生物标志物，以预测哪些患者最有可能从Elemusertib单一疗法中受益。”“理性组合研究也正在进行中，并研究了与PARP抑制剂Niraparib和PD-1抑制剂Pembrolizumab结合使用的Limusertib。”

The trial was supported by Bayer. A full list of co-authors and their disclosures can be found这里。

下一代PARP1选择性抑制剂表现出有希望的临床活动，具有良好的安全性（摘要CT007）

I/IIA期PETRA试验的结果表明，AZD5305是一种有效且具有高度选择性的下一代PARP1抑制剂和诱捕器，具有最大的目标参与度和有希望的临床活动，具有良好的安全性。与第一代PARP抑制剂相比，靶向疗法表现出明显改善的药代动力学和暴露于目标。

除了阻断PARP酶活性外，第一代PARP抑制剂捕获PARP1和PARP2（两种将DDR途径激活DDR途径的修复蛋白）到DNA损伤部位，以防止DNA修复并选择性地杀死癌细胞。然而，越来越多的证据表明，在同源重组修复（HRR）缺乏癌症中，仅需要PARP1抑制和捕获才能进行合成致死性。

“By selectively inhibiting and trapping PARP1, AZD5305 achieved greater antitumor efficacy across select tumor and molecular subtypes, more durable target inhibition and superior tolerability compared to first-generation dual PARP1/2 inhibitors in preclinical models,” Yap said. “These exciting trial results of AZD5305 demonstrate that we can build on the success of first-generation PARP inhibitors by providing important clinical proof of concept for this innovative strategy. We were able to achieve substantially improved safety, pharmacokinetics, pharmacodynamics and promising efficacy in patients with different molecularly-driven cancers with AZD5305.”

在第一类人类试验中，研究人员招募并治疗了61例晚期乳腺癌，卵巢，前列腺或胰腺癌携带种系或体细胞的患者BRCA1/2，，，，palb2orrad51c/d mutations with AZD5305.

Of the 40 evaluable patients, 10 achieved RECIST partial responses and 11 achieved RECIST stable disease across doses, tumor types and mutation types and were independent of prior PARP inhibitor use.

The most common grade ≥3 TEAE, irrespective of causality, was anemia (14.8%), followed by neutropenia (6.6%) and thrombocytopenia (3.3%). Only two patients (3.3%) required a dose reduction after experiencing treatment-related grade 3 neutropenia and grade 1 thrombocytopenia. At the time of data cutoff, there were no dose-limiting toxicities, treatment-related serious adverse events or treatment discontinuations. Overall, AZD5305 was well tolerated with low rates of nausea and hematological toxicity compared to first-generation PARP inhibitors.

该药物通过抑制聚ADP-核糖基化（parylation）来衡量所有剂量水平的强大和耐用的药效目标参与，这表明AZD5305导致最大目标参与至少90％。

研究人员目前正在进行扩展试验，以评估该药物在不接受PARP抑制剂群体中的功效，并升级组合疗法的剂量，包括曲妥珠单抗Deruxtecan和Datopotamab deruxtecan。

参考：yap ta，tan ds，Stathis A等。IB相扩展的试验，对毛细血管炎和RAD3相关（ATR）抑制剂的安全性和功效在具有DNA损伤反应（DDR）缺陷的晚期实体瘤中。呈现在American Association for Cancer Research Annual Meeting;2022年4月10日;路易斯安那州新奥尔良。https://www.abstractsonline.com/pp8/#!/10517/presentation/201482022年4月11日访问

Yap TA, Im S, Schram AM, et al. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations. Presented atAmerican Association for Cancer Research Annual Meeting;2022年4月10日;路易斯安那州新奥尔良。https://www.abstractsonline.com/pp8/#!/10517/presentation/201492022年4月11日访问

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