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Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 25, pages 71–78 (2022)Cite this article

Subjects

Abstract

Purpose

Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a novel treatment for castration-resistant prostate cancer (mCRPC). While the majority of patients responds to PSMA-RLT, with 10–15% having an exceptional response, approximately 30% of patients is unresponsive to PSMA-RLT. The molecular underpinning may in part explain these varying responses. This study investigated alterations in DNA damage repair (DDR) genes in tumour biopsies and their association with response to PSMA-RLT.

Methods

A predefined retrospective cohort study was performed in mCRPC patients of whom the tumours had undergone next-generation sequencing of 40 DDR genes and received Lu-177-PSMA and/or Ac-225-PSMA-RLT. The primary outcome of this study was to compare the progression free survival (PFS) after PSMA-RLT for patients with and without pathogenic DDR aberrations in their tumour. Secondary outcomes were prostate-specific antigen (PSA) response and overall survival (OS).

Results

A total of 40 patients were included of which seventeen had a tumour with a pathogenic DDR aberration (DDR+), of which eight had defects in BRCA1/2. DDR+ patients had an equal varying response to PSMA-RLT compared to those without pathological DDR anomalies (DDR-) in terms of PFS (5.9 vs. 6.4 months, respectively; HR 1.14; 95% CI 0.58-2.25; p = 0.71), ≥50% PSA response (59% vs. 65%, respectively; p = 0.75) or OS (11.1 vs. 10.7 months, respectively; HR 1.40; 95% CI: 0.68–2.91; p = 0.36).

Conclusion

In this study of a selected cohort, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-RLT. Translational studies in larger prospective cohorts are warranted to associate DDR gene defects with differential responses to PSMA-RLT.

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Fig. 1: Swimmerplot with patient history.
Fig. 2: Oncoplot with the pathogenic alterations.
Fig. 3: Waterfall plot of prostate-specific antigen response.
Fig. 4: Kaplan-Meier plots.

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Data accessibility

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all the investigators of the study, the patients and their families.

Author information

Authors and Affiliations

  1. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Bastiaan M. Privé, Babette I. Laarhuis, Martin Gotthardt, Sandra Heskamp, Marcel J. R. Janssen & James Nagarajah

  2. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

    Peter H. J. Slootbeek, Samhita Pamidimarri Naga, Winald R. Gerritsen & Niven Mehra

  3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    Samhita Pamidimarri Naga & Marjolijn J. L. Ligtenberg

  4. Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands

    Maarten J. van der Doelen, J. Alfred Witjes & Inge M. van Oort

  5. Department of Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

    Ludwike W. M. van Kalmthout & Bart de Keizer

  6. Department of Nuclear Medicine, Saarland University, Homburg, Germany

    Samer Ezziddin

  7. Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Clemens Kratochwil

  8. Directorate for Nuclear Safety and Security, European Commission, Joint Research Centre (JRC), Karlsruhe, Germany

    Alfred Morgenstern & Frank Bruchertseifer

  9. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

    Marjolijn J. L. Ligtenberg

  10. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany

    James Nagarajah

Authors
  1. Bastiaan M. Privé
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Contributions

Conceptualisation: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Heskamp, Janssen, Nagarajah, Mehra Methodology: Privé, Slootbeek, van der Doelen, Heskamp, Janssen, Gerritsen, Nagarajah, Mehra Software: Privé, Slootbeek, Pamidimarri Naga; Validation: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Nagarajah, Mehra Formal Analysis: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Nagarajah, Mehra Investigation: Privé, van Kalmthout, Gotthardt, Janssen, Gerritsen, Nagarajah, Mehra Resources: de Keizer, Ezziddin, Kratochwil, Morgenstern, Bruchertseifer, Ligtenberg, Witjes, van Oort, Gotthardt, Janssen, Gerritsen, Nagarajah, Mehra Data Curation: Privé, Slootbeek, Laarhuis, Janssen, Gerritsen, Nagarajah, Mehra Writing – Original Draft: Privé, Laarhuis, Nagarajah, Mehra. Writing – Review & Editing: Slootbeek, van der Doelen, van Kalmthout, de Keizer, Ezziddin, Ligtenberg, Witjes, van Oort, Gotthardt, Heskamp, Janssen, Gerritsen, Nagarajah, Mehra Visualisation: Privé, Pamidimarri Naga Supervision: Gotthardt, Heskamp, Gerritsen, Nagarajah, Mehra Project Administration: Privé, Laarhuis, van der Doelen, Mehra.

Corresponding author

Correspondence to Niven Mehra.

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Competing interests

C. Kratochwil is co-inventor of some patents in the field of PSMA-targeting radio-ligand therapy. The other authors have declared that no competing interest exists for this study.

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Privé, B.M., Slootbeek, P.H.J., Laarhuis, B.I. et al. Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 25, 71–78 (2022). https://doi.org/10.1038/s41391-021-00424-2

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