Total Tumor Volume on ¹⁸F-PSMA-1007 PET as Additional Imaging Biomarker in mCRPC Patients Undergoing PSMA-Targeted Alpha Therapy with ²²⁵Ac-PSMA-I&T

Background: PSMA-based alpha therapy using ²²⁵Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of ¹⁷⁷Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during ²²⁵Ac-PSMA-I&T RLT. Methods: mCRPC patients undergoing RLT with ²²⁵Ac-PSMA-I&T with available ¹⁸F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of ²²⁵Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST. Results: 13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to ²²⁵Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (<i>p</i> > 0.05 each). Between short-term survivors (STS, <10 months OS) and long-term survivors (LTS, ≥10 months OS), TTV and PSA were comparable (<i>p</i> = 0.592 & <i>p</i> = 0.286, respectively), whereas AP was significantly lower in the LTS (<i>p</i> = 0.029). A total of 7/13 patients completed two cycles and underwent a follow-up ¹⁸F-PSMA-1007 PET/CT. Among these patients, there was a significant decrease in TTV (median 835 vs. 201 mL, <i>p</i> = 0.028) and PSA (median 687 ng/dL vs. 178 ng/dL, <i>p</i> = 0.018) after two cycles of ²²⁵Ac-PSMA RLT. Here, percentage changes of TTV after two cycles showed no direct correlation to all other clinical parameters (<i>p</i> > 0.05 each). In two patients, new PET-avid lesions were detected on ¹⁸F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable. Conclusion: PET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to ²²⁵Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of ¹⁷⁷Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of ²²⁵Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.