Background: High-risk prostate cancer accounts for approximately 15% of newly diagnosed prostate cancers. For patients with high-risk, locally advanced prostate cancer, prostatectomy alone may be insufficient therapy. Cure rates from radical prostatectomy alone are less than 25%. Ipilimumab increases overall survival in men with post-docetaxel mCRPC who received radiotherapy to bone metastases followed by ipilimumab in comparison to placebo. Final results of the VISION trial (NCT03511664), a phase III study designed to assess the efficacy of [¹⁷⁷Lu]Lu-PSMA-617 in patients with PSMA-positive mCRPC, show a significant prolongation of survival in a setting without established therapy. Since both ipilimumab combined with radiation and [¹⁷⁷Lu]Lu-PSMA-617 have been proven to be effective in the treatment of mCRPC, we hypothesize, that CTLA-4-inhibitors exert synergistic effects on [¹⁷⁷Lu]Lu-PSMA-617 RLT-induced tumor damage and immune priming. Methods: Patients diagnosed with highest risk prostate cancer (ISUP-GG 4+5 and cT3 plus cN+ or PSA > 20ng/ml) who are candidates for radical prostatectomy receive 12 weeks of neoadjuvant treatment with ADT plus [¹⁷⁷Lu]Lu-PSMA-617 (LuPSMA) with randomized allocation with or without ipilimumab. Prior to initiation of the randomized set, we will conduct a Safety-Run-In-Phase. The initial 3-6 patients will receive a reduced dose of 3.7 Gb [¹⁷⁷Lu]Lu-PSMA-617 and 3 mg/kg Ipilimumab, which will be increased to the target dose of 7.4Gb [¹⁷⁷Lu]Lu-PSMA-617 and 3 mg/kg Ipilimumab in the following 3-6 patients if sufficiently well tolerated. The safety and feasibility of the combination will be assessed after 6-12 patients based on toxicity or delay of prostatectomy (max. 3 weeks). In the absence of serious toxicity signals a total of 46 patients will be randomized 1:1 (ipilimumab + ADT + LuPSMA vs. ADT + LuPSMA) to receive 2 cycles of 7.4 GBq LuPSMA with or without 4 cycles of ipilimumab 3mg/kg prior to prostatectomy. Scheduled Imaging with mpMRI and PSMA PET CT is performed prior to neoadjuvant therapy and prior to radical prostatectomy. Co-primary endpoints of the study are feasibility of radical prostatectomy after neoadjuvant therapy, and complete pathologic response. Secondary endpoints are evaluation of the safety profile of neoadjuvant treatment according to "National Cancer Institute Common Terminology Criteria for Adverse Events" (NCI CTCAE) v5.0 and disease-free survival. Enrollment of the first patient in NEPI Trial is expected to be completed in late September 2023. A total of up to 3 German centers will participate. Clinical trial information: EudraCT-Nr.: 2021-004894-30.