PET-derived total tumor volume in the course of 225Ac-PSMA radioligand therapy in advanced mCRPC

Introduction: PSMA-based alpha therapy using ²²⁵Ac-PSMA-I&T provides treatment of metastatic castration-resistant prostate cancer (mCRPC), even after failure of ¹⁷⁷Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcome and plays an increasing role in mCRPC patients. Hence, we aimed to assess the TTV and changes during treatment with ²²⁵Ac-PSMA-RLT in direct comparison to clinical parameters. 

Methods: mCRPC patients with ¹⁸F-PSMA-1007 PET/CT prior to ²²⁵Ac-PSMA were included. Image derived, clinical and biochemistry parameters like PSA were assessed prior to and during ²²⁵Ac-PSMA. Patients were classified as early dropout group (≤ 2 cycles, ineligible for follow-up or further treatment) and completion group (≥2 cycles and completed follow-up including PET). TTV and further clinical parameters were directly compared between groups. In the completion group, changes of the TTV and clinical parameters after two cycles were assessed. 

Results: 13 mCRPC patients were included. 7 patients were in the completion, 6 in the dropout group. Baseline clinical parameters including PSA and TTV were comparable between groups (median PSA: 313.5 vs. 102.0 ng/mL; p=0.181; median TTV 815.9 vs. 939.0 ml; p=0.945). Overall, pretherapeutic PSA and TTV were not directly correlated (r=-0.022; p=0.943). 

In the completion group, there was a median PSA decline of -32.8% (-67.3% – -14.2%) and a median TTV decline of -62.4% (-97.8% – +2.6%), which was statistically comparable (p=0.128). Again, the percentage declines of PSA and TTV were not directly correlated (r=0.107, p=0.819). In two patients, new PSMA-avid lesions occurred during treatment; however, TTV (i.e. -64.5% / 2.6 %) and PSA (i.e. -32.8% / -25.2%) were significantly decreasing or stable (in TTV) in these cases. The 4- / 8- / 12-month survival rates were 100% / 85.7% / 42.9% in the completion and 66.7% / 16.7% / 16.7% in the dropout group, respectively.

Conclusions: Acquisition of TTV during ²²⁵Ac-PSMA RLT is feasible and can guide response evaluation. In patients completing at least 2 cycles and follow-up PET, a decrease of TTV was present in all but one patient. Patients with decreasing or stable TTV after 2 cycles showed good clinical outcome data, even in case of extensive initial TTV prior to ²²⁵Ac-PSMA RLT or new PSMA-avid lesions during therapy. TTV was not directly correlated with PSA and might represent an additional imaging biomarker in the light of ²²⁵Ac-PSMA RLT.