A Meta-analysis and Meta-regression of Efficacy, Toxicity and Quality of Life Outcomes Following Lutetium-177– and Actinium-225–PSMA Radioligand Therapy in Metastatic Prostate Cancer
Dai Y-H., Chen P-H., Lee D-J., Andrade G., VALLIS K.
Background and objective: Managing 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 regarding 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 proportions of patients with PSA decline ≥50% were 0.49 for [177Lu]Lu-PSMA and 0.60 for [225Ac]Ac-PSMA in mPCa, particularly metastatic castration-resistant prostate cancer. Meta-regression analysis indicated an association between the cumulative amount of administered activity (AA) and the proportions of PSA ≥50% decline. Positive PSA responses were observed alongside improved overall survival across therapies. These analyses also identified key factors associated with PSA responses and survival outcomes, including baseline haemoglobin levels, and the presence of visceral metastases. Although anaemia was commonly observed, with [177Lu]Lu-PSMA, severe toxicities were infrequent. [225Ac]Ac-PSMA therapy was associated with a higher incidence of xerostomia and anaemia, yet cases of severe anaemia were still uncommon (15%). 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 implication: 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 its potential role in the management of mPC.