Bastiaan M Privé1, Peter H J Slootbeek2, Babette I Laarhuis1, Samhita Pamidimarri Naga2,3, Maarten J van der Doelen4, Ludwike W M van Kalmthout5, Bart de Keizer5, Samer Ezziddin6, Clemens Kratochwil7, Alfred Morgenstern8, Frank Bruchertseifer8, Marjolijn J L Ligtenberg3,9, J Alfred Witjes4, Inge M van Oort4, Martin Gotthardt1, Sandra Heskamp1, Marcel J R Janssen1, Winald R Gerritsen2, James Nagarajah1,10, Niven Mehra11. 1. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. 5. Department of Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. 6. Department of Nuclear Medicine, Saarland University, Homburg, Germany. 7. Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany. 8. Directorate for Nuclear Safety and Security, European Commission, Joint Research Centre (JRC), Karlsruhe, Germany. 9. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. 10. Department of Nuclear Medicine, Technical University of Munich, Munich, Germany. 11. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. Niven.Mehra@radboudumc.nl.
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.
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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