Maarten van der Doelen

Chapter 8

induced by alpha emitters. Small studies suggest that mCRPC patients with DDR alterations, including BRCA1 , BRCA2 , ATM , RAD51C , RAD51D , and mutations in the Fanconi anemia complementation group, confer increased sensitivity to radium-223. (74-76) In chapter 7 of this thesis, we explored whether DDR mutation status is associated with efficacy of radium-223 therapy and OS of mCRPC patients. We found that patients with DDR mutations showed significantly longer OS and more frequently completed radium-223 therapy. A multivariate model identified DDR mutation status as the only independent prognostic factor of OS. In contrast to the prior study by Isaacsson Velho et al, we found no differences in biochemical response rates and the time to ALP progression after radium-223 therapy between patients with and without DDR mutations. (76) Furthermore, no differences in time to initiation of subsequent systemic therapy were found. In comparison to other studies in this thesis, the OS of the population described in chapter 7 was exceptionally long (median 21 months). This finding may be explained by the selection of patients with good performance status in an academic care setting. Therefore, thepatients in this studymay bedifferent compared to thegeneral population of mCRPC patients. The findings in this retrospective cohort study need confirmation in large, prospective clinical trials with next-generation sequencing prior to initiation of radium-223 therapy. Likewise, explorative next-generation sequencingwas carried out in the study described in chapter 2 . In this study, pathogenic DDR alterations were identified in two of thirteen patients; both in the BRCA1 gene. Although these patients showed numerically longer survival (median 16.1 versus 7.6 months), the cohort size was too small to draw definite conclusions on the impact of DDR alterations on the outcome of patients receiving 225 Ac-PSMA TAT. Interestingly, Kratochwil et al described that patients resistant against 225 Ac-PSMA TAT often harbored metastases containing mutations in DDR-associated genes. (16) In this pilot study, patients underwent tissue sampling of lesions with poor response to PSMA TAT despite sufficient tumor-uptake of PSMA on 68 Ga-PSMA PET/CT. However, no control biopsies were taken in patients who responded well to 225 Ac-PSMA TAT, which limits the comparability of responders and non-responders. In a recent pooled study of patients who underwent 177 Lu-PSMA RLT or 225 Ac-PSMA TAT, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-targeting RLT. (77) In addition,

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