Maarten van der Doelen

Summary

In chapter 5, we describe a retrospective cohort study that evaluated the outcomes of radium-223 therapy in 45 mCRPC patients treated in an academic care setting. In general, radium-223 was well tolerated. However, only 47% of the patients completed radium-223 therapy. We found a statistically significant difference in overall survival between patients who completed and discontinued radium-223 therapy (median overall survival 19.7 months versus 5.9 months, respectively). Baseline performance status and lactate dehydrogenase levels were identified as prognostic parameters for overall survival. The outcomes of our study and several other retrospective real-world series indicate that earlier utilization of radium-223 during treatment of mCRPC is likely to result in more frequent completion of radium-223 therapy and better treatment responses. Therefore, pretherapeutic variables that reflect early disease stage may help physicians to select the right patients for radium-223 therapy. Bone-related biochemical parameters may serve as biomarker of response to life prolonging therapies in patients with bone metastatic prostate cancer. Of these parameters, ALP is most widely used and monthly tested in patients who undergo radium-223 therapy. In a large retrospective study cohort of mCRPC patients, described in chapter 6 of this thesis, we investigated whether early ALP dynamics during radium-223 therapy can act as prognostic marker for overall survival. We found that patients with normal baseline ALP levels had significantly longer overall survival when compared to patients with elevated baseline ALP levels (median overall survival 19.5 months versus 10.8 months, respectively). Furthermore, patients with elevated baseline ALP without subsequent ≥10% ALP decline after the first injection had significantly worse overall survival when compared to all other patients (median overall survival 7.9 months versus 15.7 months, respectively). A multivariate model selected an elevated baseline ALP without subsequent ≥10% ALP decline after the first injection, baseline lactate dehydrogenase level, baseline performance status and the number of prior systemic therapies as prognostic factors of overall survival. In recent studies, genomic defects in DNA damage repair genes have been identified in about 20-25% of the patients with advanced prostate cancer. Patients with defective DNA damage repair mechanisms might be more susceptible to TAT, due to inability to repair the double-strand DNA breaks induced by alpha emitters such as radium-223. For the study described in chapter 7 , we hypothesized that patients with DNA damage repair alterations would have longer overall survival and more pronounced responses to radium-223. We collected real-world data from 93 mCRPC patients who received radium-223 therapy and underwent comprehensive analysis of DNA damage repair genes in two large academic care centers. We found that, when compared to patients without DNA damage repair alterations, patients with DNA damage repair mutations

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