Pre-therapeutic PSMA PET Imaging Biomarkers Demonstrate Prognostic Value in Patients Undergoing [177Lu]Lu-PSMA Therapy: A Systematic Review and Meta-analysis.

INTRODUCTION: [177Lu]Lu-prostate-specific membrane antigen (PSMA) radioligand therapy can improve outcomes in patients with metastatic castration-resistant prostate cancer, though response is highly variable in clinical practice. We performed a systematic review and meta-analysis to evaluate the prognostic value of pre-therapeutic PSMA PET-derived imaging biomarkers to better inform patient selection for treatment. METHODS: PubMed, EMBASE, Web of Science, and Scopus were searched from inception to December 2025 in accordance with PRISMA guidelines (PROSPERO CRD420251074879). Pre-therapeutic PSMA PET biomarkers of interest were the mean and maximum standardised uptake value (SUVmean and SUVmax), PSMA tumour volume (PSMA-TV), total lesional uptake (PSMA-TLU), and total lesional quotient (PSMA-TLQ). Outcomes were overall survival (OS), prostate-specific antigen progression-free survival, and 50% reduction in prostate-specific antigen levels (PSA50). Random-effects meta-analyses were performed, prioritising multivariable-adjusted effect estimates. Risk of bias was assessed using the Quality In Prognosis Studies tool. RESULTS: Thirty-seven studies were included, with 33 contributing to quantitative synthesis (n = 2993). For each unit increase in SUVmean, there was a reduced risk of death (hazard ratio [HR] = 0.88, 95% CI, 0.85-0.92; P < .001) and PSA progression (HR = 0.870, 95% CI, 0.761-0.995; P = .042), along with higher odds of PSA50 response (odds ratio = 2.12, 95% CI: 1.20-3.74; P = .010). Higher PSMA-TV was associated with poorer OS. Composite metrics were prognostic, with PSMA-TLQ demonstrating stronger associations with survival than PSMA-TLU. SUVmax showed limited prognostic value. Most studies were retrospective and were classified as having moderate risk of bias. CONCLUSION: Baseline PSMA PET-derived biomarkers provide relevant prognostic information and may complement established clinical biomarkers to support risk stratification and patient selection for [177Lu]Lu-PSMA therapy.