Skip to main content

PSMA-Based Therapy of Metastasized Castrate-Resistant Prostate Cancer

  • Chapter
  • First Online:
Clinical Applications of Nuclear Medicine Targeted Therapy

Abstract

Despite clinically established therapeutic regimens, mCRPC patients have a poor prognosis indicating the need for more effective therapies. In recent years, therapeutic radiolabelled PSMA-ligands have shown promising results in therapy of mCRPC patients with favourable safety and efficacy. A positive response to therapy in terms of PSA decline occurs in about 70% of patients; PSA reduction ≥50% is observed in up to 50% of patients. Pain release and improvement of quality of life are observed in a major proportion of symptomatic patients. Preliminary data show that decline of PSA values is accompanied by morphological and/or metabolic changes which can be assessed by CT, bone scintigraphy and/or 68Ga-PSMA PET/CT. The most common side effects of RLT are mild fatigue as well as mild and in most cases transient xerostomia. In the majority of studies, no acute or long-term side effects and high-grade haematological or renal toxicity were observed. Even though currently therapeutic PSMA-ligands have not yet been approved, 177Lu-PSMA RLT is a promising treatment option to be potentially offered following approved therapies in patients with mCRPC. In the future the use of PSMA-ligands labelled with alpha emitters such as 225Ac could be beneficial in patients with compromised bone marrow. Additionally, other novel theranostic agents addressing the gastrin-releasing peptide receptor (GRPR) might be promising treatment options in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  1. Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A. 2011;108(23):9578–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Eder M, Neels O, Muller M, Bauder-Wust U, Remde Y, Schafer M, et al. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer. Pharmaceuticals (Basel). 2014;7(7):779–96.

    Article  CAS  Google Scholar 

  3. Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benesova M, Eder M, Neels OC, et al. The theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med. 2015;56(11):1697–705.

    Article  CAS  PubMed  Google Scholar 

  4. Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, et al. 68Ga- and 177Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med. 2015;56(8):1169–76.

    Article  CAS  PubMed  Google Scholar 

  5. Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med. 2012;53(12):1883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rowe SP, Macura KJ, Ciarallo A, Mena E, Blackford A, Nadal R, et al. Comparison of prostate-specific membrane antigen-based 18F-DCFBC PET/CT to conventional imaging modalities for detection of hormone-naive and castration-resistant metastatic prostate cancer. J Nucl Med. 2016;57(1):46–53.

    Article  CAS  PubMed  Google Scholar 

  7. Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, et al. Initial evaluation of [(18)F]DCFPyL for prostate-specific membrane antigen (PSMA)-targeted PET imaging of prostate cancer. Mol Imaging Biol. 2015;17(4):565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Giesel FL, Hadaschik B, Cardinale J, Radtke J, Vinsensia M, Lehnert W, et al. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2017;44(4):678–88.

    Article  CAS  PubMed  Google Scholar 

  9. Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol. 2016;70(6):926–37.

    Article  PubMed  Google Scholar 

  10. Seruga B, Tannock IF. Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol. 2011;29(27):3686–94.

    Article  CAS  PubMed  Google Scholar 

  11. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375(9724):1437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23.

    Article  CAS  PubMed  Google Scholar 

  14. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65(1):124–37.

    Article  PubMed  Google Scholar 

  15. Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, et al. Radiation dosimetry and first therapy results with a (124)I/(131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014;41(7):1280–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kassis AI. Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med. 2008;38(5):358–66.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fendler WP, Eiber M, Beheshti M, Bomanji J, Ceci F, Cho S, et al. 68Ga-PSMA PET/CT: joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2017;44(6):1014–24.

    Article  PubMed  Google Scholar 

  18. Liu T, LY W, Fulton MD, Johnson JM, Berkman CE. Prolonged androgen deprivation leads to downregulation of androgen receptor and prostate-specific membrane antigen in prostate cancer cells. Int J Oncol. 2012;41(6):2087–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Meller B, Bremmer F, Sahlmann CO, Hijazi S, Bouter C, Trojan L, et al. Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy. EJNMMI Res. 2015;5(1):66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wright GL Jr, Grob BM, Haley C, Grossman K, Newhall K, Petrylak D, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48(2):326–34.

    Article  PubMed  Google Scholar 

  21. Ljungberg M, Celler A, Konijnenberg MW, Eckerman KF, Dewaraja YK, Sjogreen-Gleisner K, et al. MIRD pamphlet No. 26: joint EANM/MIRD guidelines for quantitative 177Lu SPECT applied for dosimetry of radiopharmaceutical therapy. J Nucl Med. 2016;57(1):151–62.

    Article  CAS  PubMed  Google Scholar 

  22. Lassmann M, Chiesa C, Flux G, Bardies M, Committee EDEANM. Dosimetry Committee guidance document: good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging. 2011;38(1):192–200.

    Article  CAS  PubMed  Google Scholar 

  23. Fendler WP, Kratochwil C, Ahmadzadehfar H, Rahbar K, Baum RP, Schmidt M, et al. 177Lu-PSMA-617 therapy, dosimetry and follow-up in patients with metastatic castration-resistant prostate cancer. Nuklearmedizin. 2016;55(3):123–8.

    PubMed  Google Scholar 

  24. Fleming JS. A technique for the absolute measurement of activity using a gamma camera and computer. Phys Med Biol. 1979;24(1):176–80.

    Article  CAS  PubMed  Google Scholar 

  25. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40(2):37S–61S.

    CAS  PubMed  Google Scholar 

  26. Ogawa K, Harata Y, Ichihara T, Kubo A, Hashimoto S. A practical method for position-dependent Compton-scatter correction in single photon emission CT. IEEE Trans Med Imaging. 1991;10(3):408–12.

    Article  CAS  PubMed  Google Scholar 

  27. Ljungberg M, Gleisner KS. Hybrid imaging for patient-specific dosimetry in radionuclide therapy. Diagnostics (Basel). 2015;5(3):296–317.

    Article  CAS  Google Scholar 

  28. Sandstrom M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients undergoing therapy with (177)Lu-DOTA-D-Phe (1)-Tyr (3)-octreotate. Eur J Nucl Med Mol Imaging. 2010;37(2):212–25.

    Article  PubMed  Google Scholar 

  29. He B, Wahl RL, Du Y, Sgouros G, Jacene H, Flinn I, et al. Comparison of residence time estimation methods for radioimmunotherapy dosimetry and treatment planning – Monte Carlo simulation studies. IEEE Trans Med Imaging. 2008;27(4):521–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bolch WE, Eckerman KF, Sgouros G, Thomas SR. MIRD pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry – standardization of nomenclature. J Nucl Med. 2009;50(3):477–84.

    Article  CAS  PubMed  Google Scholar 

  31. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46(6):1023–7.

    PubMed  Google Scholar 

  32. Kletting P, Schimmel S, Hanscheid H, Luster M, Fernandez M, Nosske D, et al. The NUKDOS software for treatment planning in molecular radiotherapy. Z Med Phys. 2015;25(3):264–74.

    Article  PubMed  Google Scholar 

  33. Hindorf C, Glatting G, Chiesa C, Linden O, Flux G, Committee EDEANM. Dosimetry Committee guidelines for bone marrow and whole-body dosimetry. Eur J Nucl Med Mol Imaging. 2010;37(6):1238–50.

    Article  PubMed  Google Scholar 

  34. Fendler WP, Reinhardt S, Ilhan H, Delker A, Boning G, Gildehaus FJ, et al. Preliminary experience with dosimetry, response and patient reported outcome after 177Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer. Oncotarget. 2017;8(2):3581–90.

    Article  PubMed  Google Scholar 

  35. 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(7):1006–13.

    Article  CAS  PubMed  Google Scholar 

  36. Delker A, Fendler WP, Kratochwil C, Brunegraf A, Gosewisch A, Gildehaus FJ, et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43(1):42–51.

    Article  CAS  PubMed  Google Scholar 

  37. Hohberg M, Eschner W, Schmidt M, Dietlein M, Kobe C, Fischer T, et al. Lacrimal glands may represent organs at risk for radionuclide therapy of prostate cancer with [(177)Lu]DKFZ-PSMA-617. Mol Imaging Biol. 2016;18(3):437–45.

    Article  CAS  PubMed  Google Scholar 

  38. Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. Nucl Med Commun. 2017;38(1):91–8.

    Article  PubMed  Google Scholar 

  39. Okamoto S, Thieme A, Allmann J, D’Alessandria C, Maurer T, Retz M, et al. Radiation dosimetry for 177Lu-PSMA I&T in metastatic castration-resistant prostate cancer: absorbed dose in normal organs and tumor lesions. J Nucl Med. 2017;58(3):445–50.

    Article  CAS  PubMed  Google Scholar 

  40. Scarpa L, Buxbaum S, Kendler D, Fink K, Bektic J, Gruber L, et al. The 68Ga/177Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates. Eur J Nucl Med Mol Imaging. 2017;44(5):788–800.

    Article  CAS  PubMed  Google Scholar 

  41. Kabasakal L, AbuQbeitah M, Aygun A, Yeyin N, Ocak M, Demirci E, et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42(13):1976–83.

    Article  CAS  PubMed  Google Scholar 

  42. Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys. 1995;31(5):1249–56.

    Article  CAS  PubMed  Google Scholar 

  43. Dale R. Use of the linear-quadratic radiobiological model for quantifying kidney response in targeted radiotherapy. Cancer Biother Radiopharm. 2004;19(3):363–70.

    Article  PubMed  Google Scholar 

  44. Cremonesi M, Ferrari M, Bodei L, Tosi G, Paganelli G. Dosimetry in peptide radionuclide receptor therapy: a review. J Nucl Med. 2006;47(9):1467–75.

    CAS  PubMed  Google Scholar 

  45. Sundlov A, Sjogreen-Gleisner K, Svensson J, Ljungberg M, Olsson T, Bernhardt P, et al. Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017;44(9):1480–9.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35(10):1847–56.

    Article  CAS  PubMed  Google Scholar 

  47. Kulkarni HR, Singh A, Schuchardt C, Niepsch K, Sayeg M, Leshch Y, et al. PSMA-based radioligand therapy for metastatic castration-resistant prostate cancer: the Bad Berka experience since 2013. J Nucl Med. 2016;57(Suppl 3):97S–104S.

    Article  CAS  PubMed  Google Scholar 

  48. Ahmadzadehfar H, Rahbar K, Kurpig S, Bogemann M, Claesener M, Eppard E, et al. Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Res. 2015;5(1):114.

    PubMed  Google Scholar 

  49. Ahmadzadehfar H, Eppard E, Kurpig S, Fimmers R, Yordanova A, Schlenkhoff CD, et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget. 2016;7(11):12477–88.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 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(8):1170–6.

    Article  CAS  PubMed  Google Scholar 

  51. 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(7):522–8.

    Article  PubMed  Google Scholar 

  52. Rahbar K, Schmidt M, Heinzel A, Eppard E, Bode A, Yordanova A, et al. Response and tolerability of a single dose of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: a multicenter retrospective analysis. J Nucl Med. 2016;57(9):1334–8.

    Article  CAS  PubMed  Google Scholar 

  53. Heck MM, Retz M, D’Alessandria C, Rauscher I, Scheidhauer K, Maurer T, et al. Systemic radioligand therapy with (177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy in patients with metastatic castration resistant prostate cancer. J Urol. 2016;196(2):382–91.

    Article  CAS  PubMed  Google Scholar 

  54. Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment. Eur J Nucl Med Mol Imaging. 2017;44(1):81–91.

    Article  CAS  PubMed  Google Scholar 

  55. 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(1):85–90.

    Article  CAS  PubMed  Google Scholar 

  56. Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J. Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017;64(1):52–60.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 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(12):1941–4.

    Article  CAS  PubMed  Google Scholar 

  58. Zhu C, Bandekar A, Sempkowski M, Banerjee SR, Pomper MG, Bruchertseifer F, et al. Nanoconjugation of PSMA-targeting ligands enhances perinuclear localization and improves efficacy of delivered alpha-particle emitters against tumor endothelial analogues. Mol Cancer Ther. 2016;15(1):106–13.

    Article  CAS  PubMed  Google Scholar 

  59. Kahkonen E, Jambor I, Kemppainen J, Lehtio K, Gronroos TJ, Kuisma A, et al. In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548. Clin Cancer Res. 2013;19(19):5434–43.

    Article  PubMed  Google Scholar 

  60. Minamimoto R, Hancock S, Schneider B, Chin FT, Jamali M, Loening A, et al. Pilot comparison of (6)(8)Ga-RM2 PET and (6)(8)Ga-PSMA-11 PET in patients with biochemically recurrent prostate cancer. J Nucl Med. 2016;57(4):557–62.

    Article  CAS  PubMed  Google Scholar 

  61. Roivainen A, Kahkonen E, Luoto P, Borkowski S, Hofmann B, Jambor I, et al. Plasma pharmacokinetics, whole-body distribution, metabolism, and radiation dosimetry of 68Ga bombesin antagonist BAY 86-7548 in healthy men. J Nucl Med. 2013;54(6):867–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sarah Marie Schwarzenböck .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Schwarzenböck, S.M., Kurth, J., Nitsch, S., Krause, B.J. (2018). PSMA-Based Therapy of Metastasized Castrate-Resistant Prostate Cancer. In: Bombardieri, E., Seregni, E., Evangelista, L., Chiesa, C., Chiti, A. (eds) Clinical Applications of Nuclear Medicine Targeted Therapy . Springer, Cham. https://doi.org/10.1007/978-3-319-63067-0_34

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-63067-0_34

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-63066-3

  • Online ISBN: 978-3-319-63067-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics