Objective <p>To identify predictive biomarkers of early progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with [¹⁷⁷Lu]Lu-PSMA-617 radioligand therapy (RLT).</p> Methods <p>This retrospective single-center study included all consecutive mCRPC patients who initiated [¹⁷⁷Lu]Lu-PSMA-617 RLT outside of clinical trials between July 2022 and May 2025, receiving at least 2 injections, and had a minimum follow-up period of 6 months. Early progression was defined as treatment discontinuation due to progression before the third injection or biochemical progression based on Prostate Cancer Working Group 3 without treatment discontinuation. Baseline clinical data, biological data, PSMA-ligand PET/CT and [¹⁸F]FDG PET/CT parameters were collected. Univariate and multivariate logistic regression were used to identify factors associated with early progression.</p> Results <p>A total of 87 patients were included. Early progression was observed in 27 (31%) of patients. Among baseline data, only a prior second-line chemotherapy with cabazitaxel and PSMA-ligand SUVmean &lt; 6.0 were significantly and independently associated with early progression (respectively adjusted OR = 3.2; 95% CI: 1.02–10.6; <i>p</i> = 0.049 and adjusted OR = 12.6 ; 95% CI: 3.7–50.9; <i>p</i> &lt; 0.001). PSMA-ligand SUVmean &lt; 6.0 was also significantly and independently associated with a poorer overall survival (median overall survival = 11 months (95% CI: 5–24) vs. 22 months (95% CI: 15 – not reach) for patients with PSMA-ligand SUVmean ≥ 6.0; <i>p</i> = 0.019).</p> Conclusions <p>PSMA-ligand SUVmean is an independent predictor of early progression confirming that baseline PSMA-ligand PET/CT may serve for risk stratification in mCRPC treated with [¹⁷⁷Lu]Lu-PSMA-617 RLT.</p>