| Summary: | The use of <sup>225</sup>Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with <sup>177</sup>Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [<sup>225</sup>Ac]Ac-PSMA-617 augmented [<sup>177</sup>Lu]Lu-PSMA-617 RLT in <sup>177</sup>Lu-naive mCRPC patients (<i>n</i> = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [<sup>177</sup>Lu]Lu-PSMA-617 RLT, with at least one [<sup>225</sup>Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [<sup>225</sup>Ac]Ac-PSMA-617 augmented [<sup>177</sup>Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.
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