Evolving role of 225 Ac-PSMA radioligand therapy in metastatic castration-resistant prostate cancer-a systematic review and meta-analysis

Background Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen ligands (225Ac-PSMA) has emerged as a promising treatment modality in the management of metastatic castration-resistant prostate cancer (mCRPC). With its high linear energy transfer and short path length, 225Ac induces double-stranded DNA breaks and is expected to have excellent efficacy and safety profile. This systematic review was conducted to precisely evaluate the role of 225Ac-PSMA radioligand therapy (RLT) in mCRPC. Methods This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Searches were made using relevant keywords in the PubMed, Embase, and Scopus databases, and articles up to December 2020 were included. Data on efficacy and toxicity were extracted from the individual articles. Random-effects model was used for generating pooled estimates through meta-analysis. Results Ten articles comprising 256 patients were included. Overall, 62.8% (95% confidence interval, CI: 53.4-71.7%) of the patients treated with 225Ac-PSMA RLT achieved biochemical response, i.e., ≥50% decline in the serum prostate-specific antigen levels from baseline. Molecular response on Gallium-68 PSMA positron emission tomography/computed tomography was noted in 74% (95% CI: 50.1-92.1%) of the patients. The pooled estimates of median progression-free survival and overall survival were 9.1 months (95% CI: 3.6-14.5 months) and 12.8 months (95% CI: 4.5-21.0 months), respectively. The most commonly reported adverse event was xerostomia, which was observed in 72.7% (95% CI: 50.5-90.1%) of the patients. However, clinically significant toxicity was limited with grade ≥3 xerostomia, anemia, leucopenia, thrombocytopenia, and nephrotoxicity occurring in 1.2%, 12.3%, 8.3%, 6.3%, and 3.8% of the patients, respectively. Treatment discontinuation due to adverse events was noted in 20/208 patients. Conclusions 225Ac-PSMA RLT is an efficacious and safe treatment option for patients with mCRPC. Future randomized controlled trials are required to establish its therapeutic efficacy and survival benefit vis-a-vis other approved treatment modalities.