Purpose <p>To improve [¹⁷⁷Lu]Lu-Prostate-specific membrane antigen therapy (LuPSMA) selection, this study investigates the prognostic value of PSMA and 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG)-PET in metastatic castration-resistant prostate cancer (mCRPC) patients considered for LuPSMA therapy.</p> Methods <p>We conducted a retrospective analysis in 152 mCRPC patients referred for LuPSMA therapy who underwent PSMA and [¹⁸F]FDG-PET/CT. Of these, 104 patients (68.4%) underwent LuPSMA therapy, while 48 (31.6%) received other standard of care (SOC). PET/CT analyses included visual assessment and semiquantitative measurements. Clinical and laboratory parameters were recorded. Overall survival (OS) and PSA response (decline &gt; 50%) were primary and secondary endpoints, respectively.</p> Results <p>Baseline [¹⁸F]FDG-derived total tumor volume was the only independent predictor of overall survival both in patients subsequently treated with LuPSMA (HR 1.28 [95%CI 1.02—1.61]; p = 0.03) or in those under other SOC (HR 1.61 [95%CI 1.02—2.56]; p = 0.04), respectively. In other SOC patients, additional independent predictors of OS were total lesion PSMA uptake (PSMA-TL; HR 1.14 [95%CI 1.03–1.26]; p = 0.01), [¹⁸F]FDG mean SUV (HR 20.88 [95%CI 1.2–364.74]; p = 0.04), and [¹⁸F]FDG total lesion glycolysis (HR 1.61 [95%CI 1.02–2.56]; p = 0.04). In LuPSMA patients, PSMA-PET SUVmean was a significant independent predictor of PSA decline ≥ 50% (OR 2.97 [95%CI 1.27–8.16]; p = 0.02).</p> Conclusion <p>PSMA-PET and [¹⁸F]FDG-PET provide imaging biomarkers of outcome in candidates for LuPSMA. FDG-PET total tumor volume was an independent predictor of overall survival in candidates for LuPSMA therapy, irrespective of subsequent treatment decision. PSMA-PET SUVmean was associated with biochemical response to LuPSMA. Dual tracer imaging should further be assessed in prospective trials for mCRPC treatment guidance.</p>