Maarten van der Doelen

General discussion and future perspectives

and monocytic myeloid-derived suppressor cells, we found mainly signs of increased immune suppression during radium-223 therapy. These immunosuppressive properties might prevent excessive immune activity during radium-223 therapy. However, an important limitation of our small hypothesis-generating study was the lack of a control arm, to examine a causal relation between our immunophenotypic findings and radium-223 therapy. A recent clinical trial performed exosomal transcriptome analysis in plasma derived from preclinical mouse models and plasma from patients who underwent radium-223 therapy. (30) In line with our findings, an increase in immune checkpoint modulators was observed at end of radium-223 therapy. Moreover, the upregulation of exosomal immune suppressors, in particular PD-L1 expression, was associated with unfavorable OS in radium-223 treated patients. Treatment of the Myc-CaP mouse model with a combination of radium-223 and immune checkpoint inhibitors (anti-PD-1 and anti CTLA-4) resulted in greater efficacy (tumor regression on MRI) when comparted to radium-223 monotherapy. (30) These findings suggest that the combination of radium-223 plus immune checkpoint inhibition may lead to enhanced treatment outcomes. Expansion of knowledge on the mechanism of action and the immunological effects of radium-223 is crucial to improve the outcome and monitoring of patients who are treated with radium-223. Follow-up studies are necessary to verify our findings and to correlate immunophenotypic findings with response to radium-223 therapy. Several phase 1-2 clinical trials evaluating the combination of radium-223 plus immune checkpoint inhibitors are currently underway. (31) Health-related quality of life evaluation during radium-223 therapy Bone metastases of prostate cancer may cause considerable pain, impaired mobility, pathological fractures, and spinal cord or nerve root compression. (32) These complications affect the HR-QoL of patients, diminish patients’ functional capacities, and lead to a reduction in survival. (33-36) The PCWG3 recommendations have recognized the importance of the patient perspective in prostate cancer clinical trials and the need to further optimize the assessment, collection, analysis, and presentation of patient-reported outcome (PRO) data. (2) They recommend measuring disease related symptoms including pain intensity and interference, and physical functioning, using validated instruments. (2)

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In the recent decade, the pivotal phase 3 clinical trials on life-prolonging therapies (abiraterone, cabazitaxel, enzalutamide, olaparib and radium-223) incorporated PRO

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