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225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to 177Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter 225Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients’ quality-of-life. We hypothesized that when 177Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity 225Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity.

Methods

We retrospectively analyzed pilot experience with 1 course of 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to 177Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%).

Results

Median (minimum–maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5–7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0–11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum–maximum]: 1 [0–5] cycle). After a median (minimum–maximum) 22 (14–63) weeks’ follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12–26) weeks, and overall survival was 48 (4–92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20.

Conclusions

Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-activity 177Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

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References

  1. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-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 

  2. Kratochwil C, Giesel FL, Stefanova M, Benesova M, Bronzel M, Afshar-Oromieh A, et al. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with 177Lu-labeled PSMA-617. J Nucl Med. 2016;57:1170–6.

    Article  CAS  Google Scholar 

  3. Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58:85–90.

    Article  CAS  Google Scholar 

  4. Edler von Eyben F, Singh A, Zhang J, Nipsch K, Meyrick D, Lenzo N, et al. (177)Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer. Oncotarget. 2019;10:2451–61.

    PubMed  Google Scholar 

  5. Barber TW, Singh A, Kulkarni HR, Niepsch K, Billah B, Baum RP. Clinical outcomes of (177)Lu-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 

  6. Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, et al. 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. J Nucl Med. 2016;57:1006–13.

    Article  CAS  Google Scholar 

  7. Emmett L, Crumbaker M, Ho B, Willowson K, Eu P, Ratnayake L, et al. Results of a prospective phase 2 pilot trial of (177)Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer including imaging predictors of treatment response and patterns of progression. Clin Genitourin Cancer. 2019;17:15–22.

    Article  Google Scholar 

  8. Rahbar K, Bode A, Weckesser M, Avramovic N, Claesener M, Stegger L, et al. Radioligand therapy With 177Lu-PSMA-617 as a novel therapeutic option in patients with metastatic castration resistant prostate cancer. Clin Nucl Med. 2016;41:522–8.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. (2)(1)(3)Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41:2106–19.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Graf F, Fahrer J, Maus S, Morgenstern A, Bruchertseifer F, Venkatachalam S, et al. DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy. PLoS One. 2014;9:e88239.

    Article  Google Scholar 

  13. 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 

  14. Ma SJ, Rivers CI, Serra LM, Singh AK. Long-term outcomes of interventions for radiation-induced xerostomia: A review. World J Clin Oncol. 2019;10:1–13.

    Article  Google Scholar 

  15. Likhterov I, Ru M, Ganz C, Urken ML, Chai R, Okay D, et al. Objective and subjective hyposalivation after treatment for head and neck cancer: Long-term outcomes. Laryngoscope. 2018;128:2732–9.

    Article  Google Scholar 

  16. Halabi S, Lin CY, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671–7.

    Article  Google Scholar 

  17. Chi KN, Kheoh T, Ryan CJ, Molina A, Bellmunt J, Vogelzang NJ, et al. A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann Oncol. 2016;27:454–60.

    Article  CAS  Google Scholar 

  18. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. (225)Ac-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 

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Acknowledgments

Robert J. Marlowe, Spencer-Fontayne Corporation, Jersey City, NJ, USA, edited this manuscript.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Saarland University, 66421, Homburg, Germany

    Fadi Khreish, Niklas Ebert, Martin Ries, Stephan Maus, Florian Rosar, Hendrik Bohnenberger, Tobias Stemler, Mark Bartholomä & Samer Ezziddin

  2. Department of Urology, Saarland University, 66421, Homburg, Germany

    Matthias Saar

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  1. Fadi Khreish
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  2. Niklas Ebert
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  4. Stephan Maus
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Correspondence to Samer Ezziddin.

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The authors declare that they have no conflict of interest.

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All procedures performed in the patients described herein were in accordance with the ethical standards of the Institutional and/or National Research Ethics Committees and with the 1964 Helsinki Declaration and its later amendments or with comparable ethical standards. This report does not include any animal studies.

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Written informed consent was obtained from all study participants.

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Khreish, F., Ebert, N., Ries, M. et al. 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging 47, 721–728 (2020). https://doi.org/10.1007/s00259-019-04612-0

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