A Meta-Analysis and Meta-Regression of the Efficacy, Toxicity, and Quality of Life Outcomes Following Prostate-Specific Membrane Antigen Radioligand Therapy Utilising Lutetium-177 and Actinium-225 in Metastatic Prostate Cancer.

Background and objective: Management of metastatic prostate cancer (mPCa) presents significant challenges. In this systematic review, meta-analysis, and meta-regression, the efficacy, safety, and quality of life (QoL) outcomes of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) utilising lutetium-177 ([¹⁷⁷Lu]Lu-PSMA) and actinium-225 ([²²⁵Ac]Ac-PSMA) were assessed.

Methods: A detailed literature search across PubMed/Medline, EMBASE, Web of Science, Scopus, and Cochrane Library was conducted, culminating in the inclusion of 100 studies involving 8711 patients. Data on prostate-specific antigen (PSA) responses, toxicity profiles, and QoL and survival outcomes were analysed. Proportional meta-analyses and meta-regression analyses were performed.

Key findings and limitations: The estimated proportion of patients with PSA decline ≥50% was 0.49 for [¹⁷⁷Lu]Lu-PSMA and 0.60 for [²²⁵Ac]Ac-PSMA in mPCa, particularly metastatic castration-resistant prostate cancer. A meta-regression analysis indicated an association between the cumulative amount of administered activity and the proportion of PSA ≥50% decline. Positive PSA responses were observed alongside improved overall survival across both therapies. Our analyses also identified the key factors associated with PSA responses and survival outcomes, including baseline haemoglobin level, and the presence of visceral metastases. Although anaemia was commonly observed, with [¹⁷⁷Lu]Lu-PSMA, severe toxicities were infrequent. Improved QoL was observed following [¹⁷⁷Lu]Lu-PSMA therapy, whereas it remained stable following the second cycle of [²²⁵Ac]Ac-PSMA treatment. Heterogeneity across studies for PSA responses and toxicity profiles is a limitation.

Conclusions and clinical implications: Our findings suggest an association between PRLT and reductions in PSA levels, as well as associations with enhanced survival outcomes in mPCa. Furthermore, our analysis shows a low incidence of severe toxicity associated with this treatment. These observations highlight the important role of PRLT in the management of mPCa.