Azad Arun A, Gurney Howard, Underhill Craig, Horvath Lisa, Voskoboynik Mark, Li Xinghai, King Ivan, Shao Lisa, Dai Yiyun, Perabo Frank
Peter MacCallum Cancer Center, Melbourne, Australia.
Macquarie University, Sydney, Australia.
Invest New Drugs. 2025 Apr;43(2):435-445. doi: 10.1007/s10637-025-01533-8. Epub 2025 Apr 28.
HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader targeting the wild-type androgen receptor (WT-AR) and mutant AR ligand-binding domain (AR-LBD). A multicenter, first-in-human, open-label Phase 1 dose escalation study was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518. Twenty-two patients with mCRPC with disease progression on at least 1 novel androgen receptor pathway inhibitor (ARPI) and ≤ 1 line of chemotherapy received HP518 once daily orally in sequential cohorts. Patients were not selected for AR-LBD mutations. Objectives were to assess safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), as well as efficacy by PSA response and radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives included genomic profiling using cell-free DNA. The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common AEs were nausea and vomiting, fatigue, constipation, diarrhea, and decreased appetite. Only one (vomiting) out of 10 serious adverse events (SAE) was considered drug-related. No patient experienced a dose-limiting toxicity (DLT), and no AEs led to dose reduction or study discontinuation. Following multiple dosing of HP518, the PK appeared to plateau showing a less than dose-proportional relationship between exposure and dosage. Two patients demonstrated a partial response, and three patients showed a PSA50 response. In this initial Phase 1 study, HP518 demonstrated an acceptable safety profile and responses in a limited subset of mCRPC patients with progression after ARPI warranting further investigation. ClinicalTrials.gov Identifier: NCT05252364.
HP518是一种口服蛋白酶靶向嵌合体（PROTAC）蛋白降解剂，靶向野生型雄激素受体（WT-AR）和突变型AR配体结合域（AR-LBD）。在转移性去势抵抗性前列腺癌（mCRPC）患者中进行了一项多中心、首次人体、开放标签的1期剂量递增研究，以评估HP518的安全性、药代动力学和抗肿瘤活性。22例mCRPC患者在至少1种新型雄激素受体途径抑制剂（ARPI）和≤1线化疗后疾病进展，按序贯队列每日口服一次HP518。未对患者进行AR-LBD突变筛选。目的是评估安全性、耐受性、最大耐受剂量、药代动力学（PK），以及根据实体瘤疗效评价标准（RECIST）v1.1和前列腺癌工作组3（PCWG3）标准通过PSA反应和影像学反应评估疗效。探索性目标包括使用游离DNA进行基因组分析。大多数治疗中出现的不良事件（TEAE）为1级或2级。最常见的不良事件是恶心、呕吐、疲劳、便秘、腹泻和食欲下降。10例严重不良事件（SAE）中只有1例（呕吐）被认为与药物相关。没有患者发生剂量限制性毒性（DLT），也没有不良事件导致剂量减少或研究中断。多次给予HP518后，药代动力学似乎达到平台期，暴露量与剂量之间呈现小于剂量比例的关系。2例患者显示部分缓解，3例患者显示PSA50反应。在这项初始1期研究中，HP518在ARPI治疗后进展的mCRPC患者有限亚组中显示出可接受的安全性和反应，值得进一步研究。ClinicalTrials.gov标识符：NCT05252364。
