Evolocumab in metastatic castration-resistant prostate cancer: study protocol for a single-arm, phase II trial, and initial experience with use of a validated lipid biomarker to direct therapy

Background: 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.

Objectives: Our primary objective is to assess whether treatment with evolocumab during standard anticancer therapy can safely modify the PCPro signature in men with mCRPC.

Design: This is a multicenter, open label phase II trial.

Methods: 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.

Discussion: 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.

Trial registration: 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).