Autio Karen A, Kyriakopoulos Christos E, Palyca Paul, Xiao Han, Emamekhoo Hamid, Danila Daniel, Jan Mehrin, Catharine Victoria, Riedel Elyn, Devitt Michael, Laird A Douglas, Scher Howard I
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
Invest New Drugs. 2025 Sep 4. doi: 10.1007/s10637-025-01580-1.
As monotherapy, PARP inhibitors have little cytotoxic effect in tumors without homologous recombinant repair (HRR) alterations. Supported by preclinical models, we hypothesized that the PARP inhibitor talazoparib in combination with temozolomide chemotherapy could induce DNA damage leading to cell death and tumor response in patients with metastatic castration-resistant prostate cancer (mCRPC) without HRR alterations. In this phase 1b/2 trial (NCT04019327; registration date July 11, 2019), patients with progressive mCRPC without HRR mutations who failed at least one androgen receptor signaling inhibitor were enrolled in escalating doses of intermittent talazoparib plus temozolomide to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in Phase 1b. Phase 2 used a composite endpoint of overall response per RECIST v1.1, 50% decline in prostate-specific antigen (PSA), and/or circulating tumor cells (CTC) conversion from ≥ 1 cell/7.5 mL to 0. Sixteen patients were enrolled across 4 dose levels. The most common adverse events were thrombocytopenia, neutropenia, anemia, fatigue, and nausea. In phase 1b, one patient receiving talazoparib 1 mg and temozolomide 75 mg/m had a dose-limiting toxicity (grade 3 neutropenic fever, grade 4 thrombocytopenia). The RP2D was talazoparib 1 mg once daily (QD) (D1-6) and temozolomide 75 mg/m QD (D2-8) in 28D cycles. The phase 2 portion was terminated early. Across dose levels, three (18.8%) patients met the efficacy endpoint. Hematologic toxicity was dose-limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without HRR alterations. The risk/benefit profile did not support further evaluation.
作为单一疗法，聚（ADP-核糖）聚合酶（PARP）抑制剂在没有同源重组修复（HRR）改变的肿瘤中几乎没有细胞毒性作用。在临床前模型的支持下，我们假设PARP抑制剂他拉唑帕尼与替莫唑胺化疗联合使用可诱导DNA损伤，从而导致转移性去势抵抗性前列腺癌（mCRPC）且无HRR改变的患者发生细胞死亡和肿瘤反应。在这项1b/2期试验（NCT04019327；注册日期：2019年7月11日）中，将患有进展性mCRPC且无HRR突变且至少一种雄激素受体信号抑制剂治疗失败的患者纳入递增剂量的间歇性他拉唑帕尼加替莫唑胺治疗，以确定1b期的最大耐受剂量和推荐的2期剂量（RP2D）。2期采用了根据RECIST v1.1标准的总体缓解、前列腺特异性抗原（PSA）下降50%和/或循环肿瘤细胞（CTC）从≥1个细胞/7.5 mL转变为0的复合终点。16名患者分4个剂量水平入组。最常见的不良事件是血小板减少、中性粒细胞减少、贫血、疲劳和恶心。在1b期，一名接受他拉唑帕尼1 mg和替莫唑胺75 mg/m²的患者出现了剂量限制性毒性（3级中性粒细胞减少性发热，4级血小板减少）。RP2D为他拉唑帕尼1 mg每日一次（QD）（第1 - 6天）和替莫唑胺75 mg/m² QD（第2 - 8天），每28天为一个周期。2期部分提前终止。在所有剂量水平中，三名（18.8%）患者达到了疗效终点。在mCRPC且无HRR改变的患者中，使用间歇性给药的他拉唑帕尼和替莫唑胺的这种联合治疗策略中，血液学毒性是剂量限制性的。风险/获益情况不支持进一步评估。
