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 the surrounding microenvironment. Androgen receptor pathway inhibitors (ARPI) may alter PSMA expression and radiosensitivity. PSMAddition will assess the efficacy and safety of ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in adults with metastatic hormone-sensitive prostate cancer (mHSPC). Methods: PSMAddition (NCT04720157) is an international, prospective, open-label, randomized, phase 3 trial in adults with mHSPC. Eligible patients are treatment-naïve or minimally treated candidates for hormonal therapy, with PSMA-positive disease (determined by [⁶⁸Ga]Ga-PSMA-11 PET/CT), Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate major organ function. Patients are excluded if they have rapidly progressing tumors that require chemotherapy. Approximately 1126 patients will be randomized 1:1 to receive ¹⁷⁷Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks, ≤6 cycles) plus SOC or SOC alone (control arm). SOC is ARPI and androgen deprivation therapy. Stratification factors are tumor volume (high/low), age (≥70/ < 70 years) and previous/planned prostatectomy or radiation treatment of the primary prostate tumor (yes/no). The primary endpoint is radiographic progression-free survival (rPFS), as assessed by blinded independent centralized review. Upon centrally confirmed radiographic progression, participants in the control arm can cross over to the ¹⁷⁷Lu-PSMA-617 arm. The planned sample size provides 95% power to detect a hazard ratio of 0.7 for rPFS after 418 events with an overall one-sided significance level of 0.025. The key secondary endpoint is overall survival. Other secondary endpoints are the proportion of patients with a prostate-specific antigen (PSA) decline of ≥90% from baseline, time to development of metastatic castration-resistant prostate cancer, composite progression-free survival (radiographic, clinical or PSA progression), safety and tolerability, and health-related quality of life. Previously presented at the 2021 European Society for Medical Oncology Congress, FPN 3035, Tagawa S et al. Reused with permission. Clinical trial information: NCT04720157.