Maarten van der Doelen

Chapter 8

Furthermore, when radium-223 is initiated later in the treatment paradigm, less patients will be able to complete six injections as a result of their advanced disease stage with inherent symptoms, poorer performance status and reduced hematological function. (49, 118) Additionally, later timing of radium-223 may also have impact on the OS and HR-QoL benefits of radium-223. (119) Therefore, in my opinion, radium-223 therapy should be initiated early in the mCRPC treatment paradigm, when patients have good performance status and are asymptomatic or minimally symptomatic. The standard combination with bone protective agents should be mandatory for mCRPC patients with bone metastases, especially when they are treated with radium-223. Positioning of actinium-225 labeled PSMA-617 targeted alpha-radionuclide therapy After the positive outcomes of the randomized phase 3 VISION trial on 177 Lu-PSMA RLT, the positioning of PSMA-targeting RLT within the treatment paradigm of mCRPC is a hot topic. (8) As with other agents in mCRPC, the therapeutic outcome of patients receiving PSMA-targeting RLT is highly dependent of the number of prior therapies. In a retrospective German multicenter analysis, chemotherapy-naïve mCRPC patients who received 177 Lu-PSMA RLT had a significantly longer OS than patients with a history of chemotherapy. (80) Furthermore, randomized phase 2 and 3 trials have demonstrated that 177 Lu-PSMA RLT was non-inferior to taxane-based chemotherapy and more frequently resulted in PSA responses. (120, 121) Likewise, biochemical and radiological responses in a cohort of chemotherapy-naïve mCRPC patients who were treated with 225 Ac-PSMATAT were alsomore pronouncedwhen compared to a cohort of more heavily pretreated patients. (122) In addition, a swimmer plot analysis in a cohort of patients who underwent 225 Ac-PSMA TAT suggested that the OS benefit of 225 Ac-PSMA TAT was larger than from other (registered) systemic therapies. (10) These findings suggest that PSMA-targeting RLT might be more effective when applied earlier in the disease course of metastatic prostate cancer patients and might be more effective than other systemic agents. The efficacy of 177 Lu-PSMA RLT in mHSPC patients with low-volume disease (≤10 metastases) after prior treatment of localized prostate cancer was recently described in a prospective pilot study including ten patients, with half of the patients having ≥50% PSA decline and one patient showing complete response. (123) The results of this study support the initiation of clinical trials on 177 Lu PSMA RLT in mHSPC patients with oligometastases. (124) Head-to-headprospective randomized studies, such as the recentTheraP trial evaluating 177 Lu-PSMA RLT versus cabazitaxel, are essential to define the place of PSMA-targeting RLT within the treatment landscape of metastatic prostate cancer. (120)

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