Maarten van der Doelen

Chapter 8

617 ( 177 Lu-PSMA) RLT was provided on a compassionate use basis for mCRPC patients with no other treatment options. Large retrospective series, followed by prospective phase 2 and 3 trials on 177 Lu-PSMA RLT have been published. (6-8) However, data on 225 Ac-PSMA TAT are rather scarce. (9, 10) Therefore, we conducted an observational cohort study to assess the efficacy of 225 Ac-PSMA TAT in advanced mCRPC patients, as described in chapter 2 of this thesis. In addition, we evaluated the safety and toxicity of this treatment and its impact on health-related quality of life (HR-QoL). In total, thirteen mCRPC patients underwent 225 Ac-PSMA TAT after prior taxane-based chemotherapy and androgen-receptor targeting therapies. Two (15%) patients had progressed on previous 177 Lu-PSMA RLT. Patients received a median of three 225 Ac-PSMA TAT cycles. Nine (69%) patients achieved ≥50% PSA decrease and six (46%) patients showed ≥90% PSA decline. All evaluable patients demonstrated >90% total tumor volume reduction as determined by the whole-body tumor volume measurements on Gallium-68 labeled PSMA-11 ( 68 Ga-PSMA) PET/CT scans. Grade 3-4 toxicity was not observed. However, all patients reported (irreversible) grade 1-2 dry mouth symptoms (xerostomia) as a result of radiation-induced inflammation of the salivary glands. Patients reported clinically relevant decrease of pain complaints, improved physical and role functioning and large improvement of fatigue and dyspnea. Although limited by its observational nature and small sample size, the results of this study show the high potential of 225 Ac-PSMA TAT in heavily pretreated mCRPC patients. Recently, the randomized phase 3 VISION trial reported prolonged imaging-based progression-free survival and overall survival (OS) in patients receiving 177 Lu-PSMA RLT plus standard care when compared to standard care alone (mainly androgen-receptor targeting therapies). (8) In this trial, a complete and partial radiological response according to RECIST version 1.1 criteria was noted in 9.2% and 41.8% of the patients receiving 177 Lu-PSMA RLT, respectively. Although 68 Ga-PSMA PET/CT has been described as useful molecular imaging-derived biomarker for monitoring response to 177 Lu-PSMA RLT, theVISION trial protocol didnotmandate 68 Ga-PSMAPET/CT scanningduring follow up. (11-13) In our study on 225 Ac-PSMATAT, we found that the combination of 68 Ga-PSMA PET plus high-dose CT was useful for the response evaluation of individual solid lesions as well as whole-body tumor volume measurements. High-dose CT scanning enables the effect evaluation of target lesions according to RECIST version 1.1 criteria, whereas PSMA-targeting PET scanning facilitates quantitative measurements of the tumor volume over time. Therefore, 68 Ga-PSMA PET plus high-dose CT might become the new standard for the effect evaluation of PSMA-targeting RLT.

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