Maarten van der Doelen

General discussion and future perspectives

In 2013, targeted alpha-radionuclide therapy (TAT) with radium-223 was registered as a new life-prolonging therapeutic option for patients with symptomatic bone metastatic castration-resistant prostate cancer (mCRCPC) based on the outcomes of the phase 3 Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. (1) Actinium-225 labeled prostate-specific membrane antigen-617 (PSMA-617, 225 Ac-PSMA) radioligand therapy (RLT) is a promising TAT for patients with mCRPC. The overall aim of this thesis was to evaluate radium-223 therapy and 225 Ac-PSMA TAT in patients with mCRPC in daily clinical practice 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. In this chapter, themain outcomes, limitations and implications of the studies presented in this thesis will be discussed. In the final part of this chapter, remaining challenges with regard to TAT in metastatic prostate cancer are described and my vision on future research on this subject is shared. The efficacy of systemic therapies for metastatic prostate cancer can be evaluated with several outcomemeasures.With regard to clinical response, outcomes such as reduction of pain, delay in the occurrence of skeletal-related events and improvement of quality of life are important. Decreases in prostate-specific antigen (PSA) and alkaline phosphatase (ALP) are used to describe the biochemical response to therapies in prostate cancer patients. For radiological response evaluation, quantification of antitumor effect on imaging with computer tomography (CT), bone scintigraphy, magnetic resonance imaging (MRI) or positron-emission tomography (PET) is desirable. Newer response outcomes include immunological and molecular response measurements. Ideally, the recommendations for trial endpoints defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) are followed when designing new studies. (2) Effect evaluation of actinium-225 labeled PSMA-617 targeted alpha radionuclide therapy Treatmentwith 225 Ac-PSMATATwasdescribed for thefirst time in2016. (3)The therapeutic concept of RLTusingPSMA-targetingmonoclonal antibodiesor smallmolecule inhibitors was described earlier in mCRPC patients. (4, 5) In Germany, Lutetium-177 labeled PSMA- PART I: EFFECT EVALUATION OF TARGETED ALPHA RADIONUCLIDE THERAPIES

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