Maarten van der Doelen

General discussion and future perspectives

associated with inferior OS in patients treated with radium-223. (45, 48, 49, 51) However, although the implications of baseline ALP levels on outcome have been studied, studies on the impact of ALP dynamics during radium-223 treatment are limited. (67) In chapter 6 of this thesis, we investigated the prognostic value of early ALP dynamics during radium-223 therapy, using a large real-world study cohort of men with mCRPC treated in two university medical centers. We found that an early decline in ALP levels was significantly associated with longer OS and longer times to ALP progression and the occurrence of a skeletal-related event (e.g. radiotherapy to the bone, pathological fractures). A post hoc analysis of the ALSYMPCA trial found that there was a near-linear relationship between percentage change in ALP frombaseline and the risk of death. In contradiction to our findings, the authors concluded that, although dynamic changes in ALP may be useful for monitoring during treatment with radium-223, ALP decreases at 12 weeks from baseline are only a moderate predictor of survival. (54) A combination of multiple biomarkers, such as the combination of changes in ALP and hemoglobin during radium-223 therapy, might have a higher prognostic value. (68) Alternative biomarkers during radium-223 therapy, such as other markers of bone turnover (e.g. N-telopeptide and N-terminal propeptide of type 1 collagen) or circulating tumor cells, may also serve as biomarker of response to radium-223 therapy. In conclusion, clinical variables, such as performance status and cancer-related pain, together with biochemical markers and imaging characteristics related to bone turnover are currently having the highest prognostic value for patients receiving radium-223 therapy. Molecular stratification for targeted alpha-radionuclide therapies The treatment landscape of mCRPC is evolving and moves towards personalized medicine. Especially in this setting, genomic testing may guide management and treatment decisions. A variety of actionable somatic and germline genetic alterations can be detected in advanced prostate cancer, such as BRCA1 , BRCA2 , ATM mutations. (69, 70) Knowledge of molecular aberrations is beginning to influence patient selection for systemic therapies. (71) Furthermore, novel targeted therapies have recently reached the clinic, including inhibitors of the poly (ADP-ribose) polymerase (PARP) and PI3K pathway. (72, 73)

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Patients with defective DNA damage repair (DDR) mechanisms might be more susceptible to TAT, due to inability to repair the excessive double-strand DNA breaks

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