Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Clinical Research
  • Published:

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

Prostate Cancer and Prostatic Diseases volume 24, pages 880–890 (2021)Cite this article

Subjects

Abstract

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-à-vis other approved treatment modalities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Study selection process.
Fig. 2: Pooled biochemical response rate.

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Helgstrand JT, Røder MA, Klemann N, Toft BG, Lichtensztajn DY, Brooks JD, et al. Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—a population‐based analysis of 2 national cohorts. Cancer. 2018;124:2931–8.

    Article  Google Scholar 

  3. Ingrosso G, Detti B, Scartoni D, Lancia A, Giacomelli I, Baki M, et al. Current therapeutic options in metastatic castration-resistant prostate cancer. Semin Oncol. 2018;45:303–15.

    Article  CAS  Google Scholar 

  4. Wright GL Jr, Haley C, Beckett ML, Schellhammer PF. Expression of prostate-specific membrane antigen in normal, benign, and malignant prostate tissues. Urol Oncol. 1995;1:18–28.

    Article  Google Scholar 

  5. Yadav MP, Ballal S, Sahoo RK, Dwivedi SN, Bal C. Radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. AJR Am J Roentgenol. 2019;213:275–85.

    Article  Google Scholar 

  6. Kratochwil C, Giesel FL, Heussel CP, Kazdal D, Endris V, Nientiedt C, et al. Patients resistant against PSMA-targeting α-radiation therapy often harbor mutations in DNA damage-repair-associated genes. J Nucl Med. 2020;61:683–8.

    Article  Google Scholar 

  7. Tafreshi NK, Doligalski ML, Tichacek CJ, Pandya DN, Budzevich MM, El-Haddad G, et al. Development of targeted alpha particle therapy for solid tumors. Molecules. 2019;24:4314.

    Article  CAS  Google Scholar 

  8. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57:1941–4.

    Article  CAS  Google Scholar 

  9. De Vincentis G, Gerritsen W, Gschwend JE, Hacker M, Lewington V, O’Sullivan JM, et al. Advances in targeted alpha therapy for prostate cancer. Ann Oncol. 2019;30:1728–39.

    Article  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  Google Scholar 

  11. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402–18.

    Article  Google Scholar 

  12. Seitz AK, Rauscher I, Haller B, Krönke M, Luther S, Heck MM, et al. Preliminary results on response assessment using 68Ga-HBED-CC-PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy. Eur J Nucl Med Mol Imaging. 2018;45:602–12.

    Article  CAS  Google Scholar 

  13. Schmitz S, Maguire Á, Morris J, Ruggeri K, Haller E, Kuhn I, et al. The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma. BMC Med Res Methodol. 2018;18:66.

    Article  Google Scholar 

  14. Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: dosimetry estimate and empiric dose finding. J Nucl Med. 2017;58:1624–31.

    Article  CAS  Google Scholar 

  15. Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: swimmer-plot analysis suggests efficacy regarding duration of tumor control. J Nucl Med. 2018;59:795–802.

    Article  CAS  Google Scholar 

  16. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46:129–38.

    Article  CAS  Google Scholar 

  17. Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Knoesen O, Mahapane J, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving 225Ac-PSMA-617 radioligand therapy. J Nucl Med. 2020;61:62–9.

    Article  CAS  Google Scholar 

  18. Khreish F, Ebert N, Ries M, Maus S, Rosar F, Bohnenberger H, et al. 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging. 2020;47:721–8.

    Article  CAS  Google Scholar 

  19. Yadav MP, Ballal S, Sahoo RK, Tripathi M, Seth A, Bal C. Efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy in metastatic castration-resistant Prostate Cancer patients. Theranostics. 2020;10:9364–77.

    Article  CAS  Google Scholar 

  20. Zacherl MJ, Gildehaus FJ, Mittlmeier L, Boening G, Gosewisch A, Wenter V, et al. First clinical results for PSMA targeted alpha therapy using 225Ac-PSMA-I&T in advanced mCRPC patients. J Nucl Med. 2020. https://doi.org/10.2967/jnumed.120.251017.

  21. Satapathy S, Mittal BR, Sood A, Das CK, Singh SK, Mavuduru RS, et al. Health-related quality-of-life outcomes with actinium-225-prostate specific membrane antigen-617 therapy in patients with heavily pretreated metastatic castration-resistant prostate cancer. Indian J Nucl Med. 2020;35:299–304.

    Article  Google Scholar 

  22. Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C, et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium-177-PSMA. Eur Urol. 2021;79:343–50.

  23. van der Doelen MJ, Mehra N, van Oort IM, Looijen-Salamon MG, Janssen MJR, Custers JAE, et al. Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with 225Ac-PSMA-617 targeted alpha-radiation therapy. Urol Oncol. 2020. https://doi.org/10.1016/j.urolonc.2020.12.002.

  24. Barber TW, Singh A, Kulkarni HR, Niepsch K, Billah B, Baum RP. Clinical outcomes of 177Lu-PSMA radioligand therapy in earlier and later phases of metastatic castration-resistant prostate cancer grouped by previous taxane chemotherapy. J Nucl Med. 2019;60:955–62.

    Article  CAS  Google Scholar 

  25. Kessel K, Seifert R, Schäfers M, Weckesser M, Schlack K, Boegemann M, et al. Second line chemotherapy and visceral metastases are associated with poor survival in patients with mCRPC receiving 177Lu-PSMA-617. Theranostics. 2019;9:4841–8.

    Article  CAS  Google Scholar 

  26. Satapathy S, Mittal BR, Sood A. Visceral metastases as predictors of response and survival outcomes in patients of castration-resistant prostate cancer treated With 177Lu-labeled prostate-specific membrane antigen radioligand therapy: a systematic review and meta-analysis. Clin Nucl Med. 2020;45:935–42.

    Article  Google Scholar 

  27. Suman S, Parghane RV, Joshi A, Prabhash K, Bakshi G, Talole S, et al. Therapeutic efficacy, prognostic variables and clinical outcome of 177Lu-PSMA-617 PRLT in progressive mCRPC following multiple lines of treatment: prognostic implications of high FDG uptake on dual tracer PET-CT vis-à-vis Gleason score in such cohort. Br J Radio. 2019;92:20190380.

    Article  Google Scholar 

  28. Mínguez Gabiña P, Roeske JC, Mínguez R, Rodeño E, Gómez de Iturriaga A. Microdosimetry-based determination of tumor control probability curves for treatments with 225Ac-PSMA of metastatic castration resistant prostate cancer. Phys Med Biol. 2020;65:235012.

    Article  Google Scholar 

  29. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825–33.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Swayamjeet Satapathy, Ashwani Sood & Bhagwant Rai Mittal

  2. Medical Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Chandan Krushna Das

Authors
  1. Swayamjeet Satapathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashwani Sood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandan Krushna Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bhagwant Rai Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SS was responsible for designing the review protocol, conducting the search, screening potentially eligible studies, extracting and analyzing data, and writing the manuscript. AS was responsible for conducting the search, screening potentially eligible studies, extracting and analyzing data, interpreting results, and revising the manuscript. CKD and BRM critically reviewed the manuscript and provided feedback on the same.

Corresponding author

Correspondence to Ashwani Sood.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Satapathy, S., Sood, A., Das, C.K. et al. Evolving role of 225Ac-PSMA radioligand therapy in metastatic castration-resistant prostate cancer—a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 24, 880–890 (2021). https://doi.org/10.1038/s41391-021-00349-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-021-00349-w

This article is cited by

Search

Advanced search

Quick links