A Systematic Review and Meta-analysis of the Effectiveness and Toxicities of Lutetium-177-labeled Prostate-specific Membrane Antigen-targeted Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer

Abstract

Context: Castration-resistant prostate cancer (CRPC) treatment is an evolving challenge. Prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) with small-molecule, urea-based agents labeled with the β-particle-emitting radionuclide lutetium-177 (¹⁷⁷Lu) is a promising new approach.

Objective: In this systematic review and meta-analysis, we evaluated the efficacy and toxicity of PRLT.

Evidence acquisition: A systematic search was performed in PubMed/Medline (last updated February 18, 2019). A total of 250 studies were reviewed, and 24 studies with 1192 patients were included in the analysis. Proportions of patients with ≥50% serum prostate-specific antigen (PSA) decrease, any PSA decrease, and any PSA increase were extracted. Proportions of patients showing any grade toxicity and those with grade 3/4 toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) grading were extracted from manuscripts. Overall survival and progression-free survival were evaluated. A meta-analysis of single proportions was carried out. Furthermore, we compared the two most common PRLT agents, ¹⁷⁷Lu-PSMA with ¹⁷⁷Lu-PSMA-I&T, for effectiveness and toxicity.

Evidence synthesis: Among the 24 included studies, 20 included data on ¹⁷⁷Lu-PSMA-617, three included data on ¹⁷⁷Lu-PSMA-I&T, and one study had aggregated data for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T. The estimated proportion of ¹⁷⁷Lu-PSMA-617-treated patients who showed a serum PSA decrease of ≥50% with at least an 8-wk interval between therapy and PSA measurement was 0.44 (0.39; 0.50). Therapy with ¹⁷⁷Lu-PSMA-I&T demonstrated an estimated proportion of patients with ≥50% PSA reduction to be 0.36 (0.26; 0.47). The aggregate results for men treated with more than one cycle of any kind of PRLT showed an estimated proportion of 0.46 (0.41; 0.51) for PSA response ≥50%. Regarding aggregate data from all of the PRLT agents, we found that grade 3 and 4 toxicities were uncommon, with estimated proportions from 0.01 (0.00;0.04) for nausea, fatigue, diarrhea, and elevated aspartate transaminase up to 0.08 (0.05; 0.12) for anemia. There was considerable heterogeneity among the studies in the "any-grade toxicity" groups. Meta-regression showed that more than one cycle of PRLT is associated with a greater proportion of patients with ≥50% PSA reduction. Overall survival according to pooled hazard ratios (HRs) for any PSA decline was 0.29 (0.18; 0.46), and for >50% PSA reduction was 0.67 (0.43; 1.07). Progression-free survival according to a pooled HR of >50% PSA reduction was 0.53 (0.32; 0.86).

Conclusions: The relatively high number of PSA responders alongside the low rate of severe toxicity reflects the potentially promising role of PRLT in treating CRPC. The ultimate utility of this treatment modality will become clearer as multiple prospective studies continue to accrue. In the interim, this systematic review and meta-analysis can serve as a compendium of effectiveness and adverse events associated with PRLT for treating clinicians.

Patient summary: Prostate-specific membrane antigen-targeted endoradiotherapy/radioligand therapy (PRLT) is associated with ≥50% reduction in prostate-specific antigen level in a large number of patients and a low rate of toxicity, reflecting its potential in treating castration-resistant prostate cancer. This systematic review and meta-analysis presents as a compendium of the effectiveness and adverse events related to PRLT for treating clinicians.

Keywords: Endoradiotherapy; Prostate cancer; Prostate-specific membrane antigen–targeted endoradiotherapy/radioligand therapy.

Fig. 1 –

Flow chart of the systematic review. PRISMA = Preferred Reporting Items for Systematic Review and Meta-analyses; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen.

Fig. 2 –

Forest plots demonstrating the proportions of patients showing ≥50% decrease in PSA (A) after therapy with ¹⁷⁷Lu-PSMA-I&T or ¹⁷⁷Lu-PSMA-617, (B) after more than one cycle of therapy with ¹⁷⁷Lu-PSMA-I&T or ¹⁷⁷Lu-PSMA-617, (C) after therapy with ¹⁷⁷Lu-PSMA-617, and (D) after therapy with ¹⁷⁷Lu-PSMA-I&T. CI = confidence interval; df = degree of freedom; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RLT = radioligand therapy.

Fig. 3 –

Forest plots demonstrating the proportions of patients showing (A) any decrease in PSA after therapy with ¹⁷⁷Lu-PSMA-I&T or ¹⁷⁷Lu-PSMA-617, (B) any decrease in PSA after therapy with ¹⁷⁷Lu-PSMA-617, and (C) any increase in PSA after therapy with ¹⁷⁷Lu-PSMA-I&T or ¹⁷⁷Lu-PSMA-617. CI = confidence interval; df = degree of freedom; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen.

Fig. 4 –

Bubble plots demonstrating the proportions of patients with ≥50% PSA decline after radioligand therapy, regressed against (A) the time interval between PRLT and PSA measurement (<8- vs ≥8-wk interval) and (B) the cycles of radioligand therapy (therapy with one cycle vs more than one cycle). PRLT = PSMA-targeted endoradiotherapy/radioligand therapy; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen.