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Research ArticleEditor's Page

177Lu-PSMA617 and the VISION Trial: One of the Greatest Success Stories in the History of Nuclear Medicine

Johannes Czernin and Jeremie Calais
Journal of Nuclear Medicine August 2021, 62 (8) 1025-1026; DOI: https://doi.org/10.2967/jnumed.121.262710
Johannes Czernin
Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
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Jeremie Calais
Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
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The recently published results of the VISION trial (1) represent the culmination of translational research efforts that started in the 1980s and early 1990s with the discovery of the prostate-specific membrane antigen (PSMA) (2). Because of favorable biodistribution and tissue expression, PSMA was soon recognized as a promising molecular imaging target. The first Food and Drug Administration–approved PSMA-targeted ligand was 111In-capromab pendetide, a mouse monoclonal antibody that binds to the intracellular domain of PSMA. It failed in the clinic because of low sensitivity and specificity. Subsequently, the Weill Cornell group developed an antibody (J591) that binds to the extracellular domain of PSMA and provided the first insights into the therapeutic potential of targeting PSMA (3,4). Small-molecule inhibitors of PSMA were pioneered by Pomper’s group (5) and were subsequently modified and successfully translated by the Heidelberg group (6,7), among others.

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Johannes Czernin

A German retrospective multicenter trial (8) provided the impetus to conduct prospective studies determining the therapeutic efficacy of 177Lu-PSMA617. To date, the results of 3 of these studies from Australia and the United States have been published in full (9–12). All suggested therapeutic effectiveness when a 50% reduction in serum PSA levels was used as a surrogate intermediate endpoint biomarker. Another recent pivotal randomized trial found that 177Lu-PSMA was superior to cabazitaxel in patients with advanced castration-resistant prostate cancer (11).

On June 3, the results of the international randomized, multicenter VISION trial were presented during a meeting of the American Society of Clinical Oncology and provided the first hard evidence for a significant improved progression-free (−60%) and overall survival (−38%) in late-stage prostate cancer patients who were treated with 177Lu-PSMA when compared with the standard of care (1).

This success is a tribute to the scientific talents and achievements of preclinical and clinical nuclear medicine scientists. Many will take credit, but it should be very clear: this one is on nuclear medicine (and biology) primarily; it is a testament to what nuclear medicine scientists can accomplish with their unique basic biology, radiochemistry, physics, and instrumentation competence. It also provides evidence for a powerful emerging translational and clinical research infrastructure with a rapidly evolving capability to conduct appropriate prospective clinical trials that are designed in close collaboration with leaders from oncology and urooncology.

Fendler et al. have recently commented on the impact of the VISION results on the practice of nuclear medicine and the clinical expansion of theranostics (13). We now need to prepare for a large number of prostate cancer patients who will benefit from our services. We must also continue and intensify prospective research to determine the best placement of radioligand therapy throughout the various progressive stages of prostate cancer. Finally, we need to decipher treatment resistance mechanisms to identify and exploit cancer liabilities with rational combination therapies to further improve patient outcomes.

But for now, let’s celebrate the successful clinical translation of PSMA-targeted theranostics, which is among the greatest success stories in the history of nuclear medicine.

  • © 2021 by the Society of Nuclear Medicine and Molecular Imaging.

REFERENCES

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    1. Morris MJ,
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    3. Chi KN,
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    . Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION) [abstract]. J Clin Oncol. 2021;39(suppl 15):LBA4.
    OpenUrl
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    1. Horoszewicz JS,
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    Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res. 1987;7:927–935.
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    1. Israeli RS,
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    Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res. 1993;53:227–230.
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    1. Vallabhajosula S,
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    Radioimmunotherapy of prostate cancer in human xenografts using monoclonal antibodies specific to prostate specific membrane antigen (PSMA): studies in nude mice. Prostate. 2004;58:145–155.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Pomper MG,
    2. Musachio JL,
    3. Zhang J,
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    . 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol Imaging. 2002;1:96–101.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Eder M,
    2. Schäfer U,
    3. Bauder-Wüst U,
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    . 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjugate Chem. 2012;23:688–697.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Eder M,
    2. Eisenhut M,
    3. Babich J,
    4. Haberkorn U.
    PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging. 2013;40:819–823.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Rahbar K,
    2. Ahmadzadehfar H,
    3. Kratochwil C,
    4. et al
    . German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58:85–90.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Hofman MS,
    2. Violet J,
    3. Hicks RJ,
    4. 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;19:825–833.
    OpenUrlCrossRefPubMed
  10. 10.
    1. Violet J,
    2. Sandhu S,
    3. Iravani A,
    4. et al
    . Long-term follow-up and outcomes of retreatment in an expanded 50-patient single-center phase II prospective trial of 177Lu-PSMA-617 theranostics in metastatic castration-resistant prostate cancer. J Nucl Med. 2020;61:857–865.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Hofman MS,
    2. Emmett L,
    3. Sandhu S,
    4. et al
    .; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397:797–804.
    OpenUrl
  12. 12.↵
    1. Calais J,
    2. Gafita A,
    3. Eiber MR,
    4. et al
    . Prospective phase 2 trial of PSMA-targeted molecular radiotherapy with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (RESIST-PC): efficacy results of the UCLA cohort. J Nucl Med. May 20, 2021 [Epub ahead of print].
  13. 13.↵
    1. Fendler WP,
    2. Herrmann K,
    3. Eiber M.
    Nuclear medicine beyond VISION. J Nucl Med. April 23, 2021 [Epub ahead of print].
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Journal of Nuclear Medicine: 62 (8)
Journal of Nuclear Medicine
Vol. 62, Issue 8
August 1, 2021
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177Lu-PSMA617 and the VISION Trial: One of the Greatest Success Stories in the History of Nuclear Medicine
Johannes Czernin, Jeremie Calais
Journal of Nuclear Medicine Aug 2021, 62 (8) 1025-1026; DOI: 10.2967/jnumed.121.262710

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177Lu-PSMA617 and the VISION Trial: One of the Greatest Success Stories in the History of Nuclear Medicine
Johannes Czernin, Jeremie Calais
Journal of Nuclear Medicine Aug 2021, 62 (8) 1025-1026; DOI: 10.2967/jnumed.121.262710
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