Value of Combined PET Imaging with [(18)F]FDG and [(68)Ga]Ga-PSMA-11 in mCRPC Patients with Worsening Disease during [(177)Lu]Lu-PSMA-617 RLT

SIMPLE SUMMARY: Prostate-specific membrane antigen (PSMA) is regularly overexpressed in prostate cancer cells. Radioligand therapy (RLT) targeting PSMA has shown impressive results in recent years in treatment of metastatic castration-resistant prostate cancer (mCRPC). In some patients, however, the disease worsens during PSMA-RLT. A proportion of these patients develop a type of metastasis that has intense glucose metabolism but missing or low PSMA expression; these metastases are referred to as ‘mismatch metastases’. We found that combined PET imaging using the radiolabeled glucose analog [(18)F]FDG and the PSMA radioligand [(68)Ga]Ga-PSMA-11 is essential to identify patients with mismatch findings, which are associated with significantly worse outcome, especially if the mismatch is located in the liver or of high volume. Consequently, additional treatments or change to another treatment modality appears necessary. ABSTRACT: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC), some patients show worsening disease during PSMA-RLT. We investigated the value of combined [(18)F]FDG and [(68)Ga]Ga-PSMA-11 PET imaging in this setting. In n = 29 mCRPC patients with worsening disease after a median of four cycles of [(177)Lu]Lu-PSMA-617 RLT, combined [(18)F]FDG and [(68)Ga]Ga-PSMA-11 PET imaging was performed to detect [(18)F]FDG-avid lesions with low or no PSMA expression (mismatch lesions). To evaluate prognostic implication of mismatch, survival analyses regarding presence, location, and [(18)F]FDG PET-derived parameters such as SUV(max), metabolic tumor volume (MTV(m)), and total lesion glycolysis (TLG(m)) of mismatch findings were performed. Seventeen patients (59%) showed at least one mismatch metastasis. From the time point of combined PET imaging, the median overall survival (OS) of patients with mismatch findings was significantly (p = 0.008) shorter than those without (3.3 vs. 6.1 mo). Patients with a high MTV(m) revealed a significantly (p = 0.034) shorter OS of 2.6 mo than patients with low MTV(m) (5.3 mo). Furthermore, patients with hepatic mismatch showed a significantly (p = 0.049) shorter OS than those without (2.9 vs. 5.3 mo). Difference in OS regarding SUV(max) and TLG(m) was not significant. In mCRPC patients with worsening disease during PSMA-RLT, combined [(18)F]FDG and [(68)Ga]Ga-PSMA-11 PET imaging is essential to identify mismatch findings, as these are associated with poor outcomes requiring a change in therapy management.