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

Bastiaan M. Privé, Peter H.J. Slootbeek, Babette I. Laarhuis, Samhita Pamidimarri Naga, Maarten J. van der Doelen, Ludwike W.M. van Kalmthout, Bart de Keizer, Samer Ezziddin, Clemens Kratochwil, Alfred Morgenstern, Frank Bruchertseifer, Marjolijn J.L. Ligtenberg, J. Alfred Witjes, Inge M. van Oort, Martin Gotthardt, Sandra Heskamp, Marcel J.R. Janssen, Winald R. Gerritsen, James Nagarajah, Niven Mehra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)71-78
JournalProstate cancer and prostatic diseases
Volume25
Issue number1
DOIs
Publication statusPublished - Mar 2022

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