Background: Combination immune checkpoint inhibitors (ICI) with ipilimumab and nivolumab has been shown to induce adaptive immune responses in patients with mCRPC, albeit resulting in modest clinical benefit. There is growing evidence that radiation may enhance the activity of ICI by modulating the tumour immune microenvironment. We hypothesize that the radionuclide ¹⁷⁷Lu-PSMA-617 may result in immunogenic cell death and therefore synergise with combination ICI to improve long term clinical outcomes. EVOLUTION aims to determine the activity and safety of ipilimumab and nivolumab in combination with ¹⁷⁷Lu-PSMA-617 in patients with mCRPC. Methods: This open label, multicentre, phase 2 study will randomly assign 100 participants with mCRPC in a 2:1 ratio stratified by site and prior exposure to docetaxel to either: the experimental combination of ¹⁷⁷Lu-PSMA-617 7.5 GBq every 6 weeks for up to 6 doses plus ipilimumab 3 mg/kg every 6 weeks x 4 doses and nivolumab 1 mg/kg every 3 weeks x 8 doses during induction, followed by nivolumab 480 mg every 4 weeks x 18 doses during maintenance or ¹⁷⁷Lu-PSMA-617 alone. Key eligibility criteria include progression on prior androgen receptor pathway inhibitors, no more than one line of prior chemotherapy, significant PSMA avidity on ⁶⁸GaPSMA-11 PET/CT (SUVmax ≥15 at one disease site and SUVmax ≥10 at measurable sites of disease > 10 mm), no FDG positive/PSMA negative disease and no contraindications to ICI. The primary endpoint is 12-month PSA progression-free survival (PSA-PFS). Secondary endpoints are PSA response rate, adverse events, radiographic-PFS, overall survival, objective response rate, duration of response and health-related quality of life. Correlative studies will evaluate exploratory biomarkers as potential predictive/prognostic factors. Assessments include clinical reviews and blood tests at baseline, then every 3-4 weeks; CT and bone scan at baseline, then every 12 weeks; ⁶⁸Ga-PSMA-11 and ¹⁸F FDG PET/CTs at baseline; ⁶⁸Ga-PSMA-11 PET/CT at week 24 and ¹⁷⁷Lu-PSMA-617 SPECT/CT 24 hours after each ¹⁷⁷Lu-PSMA-617 dose. Translational bloods include circulating tumour DNA and peripheral blood mononuclear cells collected at baseline, weeks 13 and 25, and at radiological progression. Optional fresh biopsies will be collected at baseline, weeks 3-5 and at progression. A sample size of 100 provides 90% power at the 10% level of significance to reject the null hypothesis (that 1 year PSA-PFS is 20%) if the alternative hypothesis is true (that 1 year PSA-PFS is 35%). Accrual as of the 11^th of October 2022 is 23. Clinical trial information: NCT05150236.