Background: Docetaxel improves survival in people with metastatic castration resistant prostate cancer (CRPC) but is associated with toxicities which impact tolerability, particularly for patients who may be older and often with multiple co-morbidities. Biomarker-driven de-escalation of docetaxel chemotherapy may allow improved balance of cancer control and quality of life against toxicity. In patients with metastatic CRPC receiving docetaxel, a reduction to undetectable levels in circulating promoter methylated glutathione S-transferase Pi-1 (mGSTP1) DNA after 2 cycles of chemotherapy is associated with improved overall survival¹. This study aims to determine the efficacy and safety of intermittent docetaxel chemotherapy guided by the presence or absence of circulating mGSTP1 DNA in patients with metastatic CRPC. Methods: GUIDE (NCT04918810) is a randomized, two-arm, non-comparative phase 2 trial recruiting 120 patients at eight Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75mg/m² q3w will be pre-screened for detectable mGSTP1 at baseline +/- following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomized 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75mg/m² q3w in accordance with clinician’s usual practice) (Figure 1). The primary endpoint is radiographic progression-free survival (rPFS). Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use and cost associated with treatment. This study is powered to detect a rPFS curve with at least 50% rPFS at 12 months using a one-sided log-rank test with 2.5% alpha and 90% power. 3 of planned 120 patients have been enrolled. This novel study is the first to prospectively test the clinical utility of a circulating epigenetic biomarker (mGSTP1) in clinical decision-making in prostate cancer, building upon existing data supporting analytical and clinical validity. We anticipate that this novel biomarker will safely guide treatment de-escalation and improve the quality of survival for a group of patients with metastatic CRPC. Clinical trial information: NCT04918810.