Maarten van der Doelen

Chapter 7

toxicity. Baseline genomic testing in mCRPC patients prior to starting systemic agents will become indispensable to identify patients most likely to benefit from each therapy. Several targeted agents are promising in the treatment of mCRPC patients with DDR and HRD alterations, and our results imply that these patients also appear to derive enhanced benefit from radium-223. This study has several limitations. Due to the retrospective nature of this study, risk of selection and information bias is present. The sample size of the cohort was based on the number of identified patients and was not determined using pre-defined statistical testing. Patients were treated at two different large university hospitals, and due to population differences results may not compare to practice in community hospitals. However, all patients were treated according to standard of care of radium-223 therapy as described in the ALSYMPCA trial. (2) NGS testing was carried out by different providers and not primarily initiated for study purposes. The findings in this study require prospective validation in larger cohorts. CONCLUSIONS Metastatic CRPC patients harboring somatic or germline deleterious DDR aberrations showed significantly longer OS when compared to DDR- patients in our study. While DDR+ patients more commonly completed radium-223, only a trend towards a longer TAP and TST was seen for DDR+ patients. DDR+ patients received significantly more subsequent therapies, including PARP inhibitors. Whether DDR+ mCRPC patients derive additional benefit form radium-223 needs prospective confirmation. Translational studies are ongoing to more clearly dissect underlying mechanisms, such as immunogenic modulation, that may result in the benefit seen in DDR+ patients.

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