Maarten van der Doelen

Summary

SUMMARY Prostate cancer is the second most frequently diagnosed cancer in men and the fifth cause of cancer-related death in men worldwide. For decades androgen deprivation therapy was the only therapeutic agent available for patients with metastatic prostate cancer. However, the therapeutic landscape of metastatic prostate cancer has changed significantly in the past twenty years with the registration of several new life-prolonging agents and the earlier application of these therapies already in hormone-sensitive stage. Targeted alpha-radionuclide therapy (TAT) with radium-223 was registered as life-prolonging therapy for metastatic castration-resistant prostate cancer (mCRPC) in 2013. Actinium-225 labeled PSMA-617 ( 225 Ac-PSMA) TAT gained increasing interest in the recent years after promising results in small cohorts of patients. The aim of this thesis was to evaluate TAT with radium-223 and 225 Ac-PSMA in patients with mCRPC using real-world data, with a focus on effect evaluation and the identification of prognostic parameters, in order to optimize patient selection for these therapies in the future. The studies described in part I of this thesis focused on effect evaluation of TAT. One of the cornerstones of oncological care at the outpatient clinic is the effect evaluation of life-prolonging therapies. Assessment of the change in tumor burden by biochemical or radiological measurements is an important feature of the clinical evaluation of cancer therapeutics. The benefit from a patient perspective, such as improvement in daily functioning and reduction of cancer-related pain, should also be assessed. The observational cohort study described in chapter 2 of this thesis assessed the efficacy, safety and toxicity of 225 Ac-PSMA TAT in thirteen advanced mCRPC patients. We observed high response rates to 225 Ac-PSMA TAT, with 69% of the patients achieving ≥50% prostate-specific antigen (PSA) decrease and >90% total tumor volume reduction on Gallium-68 labeled PSMA-11 ( 68 Ga-PSMA) PET/CT scans in all evaluable patients. High grade toxicity was not observed. However, all patients reported dry mouth symptoms (xerostomia) as a result of radiation-induced inflammation of the salivary glands. The outcomes of this study, together with the available evidence from other patient cohort studies, suggest that 225 Ac-PSMA TAT is efficacious and safe for the treatment of mCRPC patients. A general introduction and outline of the thesis is presented in chapter 1 .

9

231