Mellor Rhiannon, Ardolino Luke, Scheinberg Tahlia, Fitzpatrick Michael, Lin Hui-Ming, Bonnitcha Paul, Sullivan David, Meikle Peter J, Stockler Martin R, Moujaber Tania, Joshua Anthony, Horvath Lisa
Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Ther Adv Med Oncol. 2024 Dec 16;16:17588359241307814. doi: 10.1177/17588359241307814. eCollection 2024.
Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), primary and secondary resistance to current therapies remains. Elevated circulating sphingolipids are associated with poor outcomes in patients with mCRPC, including therapeutic resistance and shorter overall survival. PCPro is a clinically accessible, regulatory compliant plasma lipid biomarker of poor prognosis in mCRPC, which incorporates prognostic sphingolipids. We hypothesize that reversal of the PCPro signature in men with mCRPC by sphingolipid-lowering agents will improve their clinical outcomes. However, the first step is to determine whether this poor prognostic lipid signature can be modulated. A potential sphingolipid-lowering agent is the PCSK9-inhibitor evolocumab, which is used in the management of hypercholesterolemia.
Our primary objective is to assess whether treatment with evolocumab during standard anticancer therapy can safely modify the PCPro signature in men with mCRPC.
This is a multicenter, open label phase II trial.
Men with mCRPC commencing docetaxel, cabazitaxel, abiraterone, enzalutamide, olaparib, or lutetium-177 PSMA for disease progression will be screened for the presence of PCPro. Those who are PCPro positive will receive a 12-week course of evolocumab concurrent with their standard therapy. Dosage is as per cardiovascular guidelines (420 mg subcutaneously every 4 weeks). PCPro will be repeated after 12 weeks. The primary endpoint is reversal of PCPro. The secondary endpoint is the safety of combination therapy with exploratory endpoints characterizing changes in comprehensive lipid profiles pre- and post-treatment.
This study will evaluate whether evolocumab can safely modify the PCPro signature in men with mCRPC, providing essential data to the development of precision metabolic therapy in the management of prostate cancer.
This study is approved by the Human Research Ethics Committee (X22-0072 and 2022/ETH00427). It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001003763).
尽管转移性去势抵抗性前列腺癌（mCRPC）的治疗取得了进展，但对当前疗法的原发性和继发性耐药仍然存在。循环鞘脂升高与mCRPC患者的不良预后相关，包括治疗耐药和较短的总生存期。PCPro是一种临床上可获取的、符合监管要求的mCRPC预后不良的血浆脂质生物标志物，它纳入了预后鞘脂。我们假设，使用鞘脂降低剂逆转mCRPC男性患者的PCPro特征将改善其临床结局。然而，第一步是确定这种不良预后的脂质特征是否可以被调节。一种潜在的鞘脂降低剂是PCSK9抑制剂阿利西尤单抗，它用于治疗高胆固醇血症。
我们的主要目的是评估在标准抗癌治疗期间使用阿利西尤单抗治疗是否能安全地改变mCRPC男性患者的PCPro特征。
这是一项多中心、开放标签的II期试验。
对于因疾病进展开始使用多西他赛、卡巴他赛、阿比特龙、恩杂鲁胺、奥拉帕利或镥-177 PSMA治疗的mCRPC男性患者，将筛查其是否存在PCPro。PCPro阳性的患者将在接受标准治疗的同时接受为期12周的阿利西尤单抗治疗。剂量按照心血管指南（每4周皮下注射420mg）。12周后将重复检测PCPro。主要终点是PCPro的逆转。次要终点是联合治疗的安全性，探索性终点为治疗前后综合脂质谱变化的特征。
本研究将评估阿利西尤单抗是否能安全地改变mCRPC男性患者的PCPro特征，为前列腺癌管理中精准代谢治疗的发展提供重要数据。
本研究已获得人类研究伦理委员会批准（X22-0072和2022/ETH00427）。它已在澳大利亚新西兰临床试验注册中心注册（ACTRN12622001003763）。
