Background: [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and their surrounding microenvironment. In the phase 3 VISION trial, ¹⁷⁷Lu-PSMA-617 significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ≥1 androgen receptor pathway inhibitor (ARPI) and 1?2 taxanes. PSMAfore is investigating the effect on rPFS in taxane-naïve patients with mCRPC treated with either ¹⁷⁷Lu-PSMA-617 or a change in ARPI. Methods: PSMAfore (NCT04689828) is a multicenter, open-label, randomized phase 3 trial in adults with progressive mCRPC and confirmed PSMA expression by [⁶⁸Ga]Ga-PSMA-11 PET/CT. Eligible patients are taxane-naïve in the metastatic setting and have: received one prior ARPI and are candidates for a change in ARPI; an Eastern Cooperative Oncology Group performance status of 0 or 1; a castrate level of serum/plasma testosterone ( < 50 ng/dL or < 1.7 nmol/L); and recovered to grade ≤2 from toxicities related to prior therapies. Approximately 450 patients will be randomized 1:1 to receive ¹⁷⁷Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks for 6 cycles) or a change in ARPI to either abiraterone or enzalutamide. Best supportive care is allowed in both arms. Stratification factors are prior ARPI use in castration-resistant vs hormone-sensitive prostate cancer settings and pain symptomatology (score 0?3 vs 4?10 on the worst pain intensity item of the Brief Pain Inventory?Short Form). The primary endpoint is rPFS according to PCWG3-modified RECIST v1.1 criteria. Participants with blinded independent centrally confirmed radiographic progression in the ARPI arm can crossover to the ¹⁷⁷Lu-PSMA-617 arm. The planned sample size provides 95% power to detect a hazard ratio of 0.56 for rPFS after 156 events with an overall one-sided significance level of 0.025. The key secondary endpoint is OS; other secondary endpoints include safety and tolerability of ¹⁷⁷Lu-PSMA-617 and health-related quality of life. Previously presented at the 2021 European Society for Medical Oncology Congress, FPN 942, Morris M et al. Reused with permission. Clinical trial information: NCT04689828.