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



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.


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).


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).


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.

Data accessibility

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


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

Author information




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 (2021).

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