Maarten van der Doelen

General discussion and future perspectives

Confirmed ≥50% PSA decreases from baseline occurred in 46% of the patients receiving 177 Lu-PSMA RLT in the VISION trial. This PSA response rate corresponds to the earlier reported ≥50% PSA decline in 45% to 64% of the patients treated with 177 Lu-PSMA RLT, although these trials did not use a confirmed ≥50% PSA decline definition. (6, 7, 14) In patients who are treated with 225 Ac-PSMA TAT, PSA declines ≥50% might be even more frequent (39-88%). (15) In patients receiving PSMA-targeting RLT, HR-QoL evaluation is of particular importance, since the long radiation range of lutetium-177 may lead to fatigue as a result of red bone marrow damage and 225 Ac-PSMA TAT may lead to xerostomia due to destruction of the salivary glands. In large studies, the most commonly reported toxic effects related to PSMA-targeting RLT are xerostomia, nausea and fatigue. Nevertheless, these studies found overall improvements in pain severity and better HR-QoL. (7, 8, 15) The outcomes of the VISION trial pave the way for registration and implementation of PSMA-targeting RLT as new therapeutic option for patients with mCRPC. However, 13 25% of patients show progressive disease to PSMA-targeting RLT on imaging despite visually sufficient PSMA expression on pretherapeutic PSMA-targeting PET/CT. (6, 8, 16) The underlying resistance mechanisms of these tumors have not yet been identified. Biomarkers for early responsemonitoringmight aid in identifying patients who undergo (un)successful PSMA-targeting RLT. However, as such biomarkers are currently lacking, clinical baseline parametersmay be used to identify patientswho need specific attention during follow-up. In a recent multicenter cohort study, a baseline ALP level <220 U/L, the absence of visceral metastases (especially liver metastases) and the number of therapy cycles have been described as predictors of the biochemical response to 177 Lu-PSMA RLT, whereas no correlation was found between the number of bone metastases and PSA response. (6, 17) An older age, low baseline hemoglobin level, pretherapeutic regular need for analgesics and prior taxane-based chemotherapy have been associated with less extensive PSA responses. (18-21) In addition, a high volume of disease on baseline 18 F-FDG PET was associated with worse prognosis in patients receiving 177 Lu-PSMA RLT in a large phase 2 clinical trial. (22) Several studies have quantified the PSMA uptake on baseline 68 Ga-PSMA PET to evaluate PSMA uptake as a potential predictive parameter of response. In these studies, the mean standardized uptake value (SUV) or average of maximal SUV of all metastases were correlated to the absorbed doses of 177 Lu-PSMA RLT, the PSA response and the survival of patients. (22-24)

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