Background: ¹⁷⁷Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesize that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA combined with enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone; and to identify prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomized, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more risk factors for early cancer progression on enzalutamide (LDH ≥ULN; ALP ≥ULN; albumin < 35 g/L; M1 disease at diagnosis; < 3 years since initial diagnosis; > 5 bone metastases; visceral metastases; PSA doubling time < 3 months; pain requiring opiates > 14 days; for castration-sensitive disease), no prior treatment with an androgen receptor pathway inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with ⁶⁸Ga-PSMA. Participants are randomly assigned (1:1) to enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the ⁶⁸Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks; ⁶⁸Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and ¹⁸F FDG PET at baseline and first progression. Translational samples including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from ⁶⁸Ga-PSMA, ¹⁸F FDG PET/CT, CTCs, and ctDNA. A sample size of 160 provides 80% power with a 2-sided type 1- error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 90 on 12 October 2021. Clinical trial information: NCT04419402.