| Summary: | 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 [<sup>18</sup>F]FDG and [<sup>68</sup>Ga]Ga-PSMA-11 PET imaging in this setting. In <i>n</i> = 29 mCRPC patients with worsening disease after a median of four cycles of [<sup>177</sup>Lu]Lu-PSMA-617 RLT, combined [<sup>18</sup>F]FDG and [<sup>68</sup>Ga]Ga-PSMA-11 PET imaging was performed to detect [<sup>18</sup>F]FDG-avid lesions with low or no PSMA expression (mismatch lesions). To evaluate prognostic implication of mismatch, survival analyses regarding presence, location, and [<sup>18</sup>F]FDG PET-derived parameters such as SUV<sub>max</sub>, metabolic tumor volume (MTV<sub>m</sub>), and total lesion glycolysis (TLG<sub>m</sub>) 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 <i>(p</i> = 0.008) shorter than those without (3.3 vs. 6.1 mo). Patients with a high MTV<sub>m</sub> revealed a significantly (<i>p</i> = 0.034) shorter OS of 2.6 mo than patients with low MTV<sub>m</sub> (5.3 mo). Furthermore, patients with hepatic mismatch showed a significantly (<i>p</i> = 0.049) shorter OS than those without (2.9 vs. 5.3 mo). Difference in OS regarding SUV<sub>max</sub> and TLG<sub>m</sub> was not significant. In mCRPC patients with worsening disease during PSMA-RLT, combined [<sup>18</sup>F]FDG and [<sup>68</sup>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.
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