Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is a widely accepted treatment option for metastatic castration-resistant prostate cancer (mCRPC). However, synthesized evidence regarding potential prognostic factors for oncologic outcomes in patients treated with PSMA-RLT is lacking. We aimed to synthesize prognosticators of oncologic outcomes in patients with mCRPC treated with PSMA-RLT.

PubMed®, Web of Science™, and Embase® databases were systemically searched in March 2025 for studies. Eligible studies investigated pretreatment clinical, hematologic, or radiographical prognostic factors for oncologic outcomes, such as progression-free (PFS) or overall survivals (OS) in patients with mCRPC treated with PSMA-RLT. Only parameters assessed through multivariable analysis adjusting for potential confounders were synthesized. (CRD42024598718) RESULTS: A total of 39 studies (n = 4819) were included in the systematic review and 32 studies (n = 3038) were included in the meta-analysis. Prior chemotherapy (pooled HR: 1.43, 95%CI: 1.10-1.85), visceral metastases (pooled HR: 1.41, 95%CI: 1.05-1.89), and liver metastasis (pooled HR: 1.75, 95%CI: 1.37-2.25) were associated with worse PFS. Poor performance status (PS) (pooled HR: 1.99, 95%CI: 1.45-2.74), prior chemotherapy (pooled HR: 1.39, 95%CI: 1.19-1.63), visceral metastasis (pooled HR: 1.65, 95%CI: 1.33-2.05), bone metastasis (pooled HR: 2.09, 95%CI: 1.39-3.13), liver metastasis (pooled HR: 2.15, 95%CI: 1.84-2.50), and lower pretreatment hemoglobin levels (pooled HR: 1.25, 95%CI: 1.09-1.43) were associated with poorer OS. Higher pretreatment SUV was associated with improved OS benefit (pooled HR: 0.91, 95%CI: 0.85-0.97). PSA decline after treatment initiation, particularly ≥50%, was associated with improved PFS and OS.

Prior chemotherapy use and location of metastases influence the prognosis of patients with mCRPC treated with PSMA-RLT. A higher pre-treatment SUV is predictive of better PSMA-RLT efficacy, and a greater PSA 'response is associated with improved survival outcomes. These findings may help guide clinical decision-making regarding PSMA-RLT and support prognostication of its oncological benefits.