Response to 225Ac-PSMA-I&T after failure of long-term 177Lu-PSMA RLT in mCRPC.

Radioligand therapy (RLT) using 177Lu-PSMA ligands is highly effective in metastatic castration-resistant prostate cancer (mCRPC); however, failure of 177Lu-PSMA RLT remains challenging as RLT already represents last-line treatment.

The α-emitter 225Ac provides higher biological effectiveness compared with 177Lu [1]. Several centers reported remarkable response after PSMA-targeted alpha therapy (TAT) using 225Ac-PSMA-617 after failure of 177Lu-PSMA RLT [2, 3]. Here we present encouraging response to TAT in a patient with advanced mCRPC showing progression after long-term 177Lu-PSMA RLT (10 cycles). PSA values are provided under the date of each PSMA-PET MIP image (A–B using 68Ga-PSMA-11 and E–H using 18F-PSMA-1007). The patient was referred for RLT after radical prostatectomy and radiotherapy in 2005, and anti-hormonal therapy started in 2013 due to biochemical progression. Further progression was observed in February 2017 (A) after 2nd-line anti-hormonal therapy from 2015 to 2016, 223Ra-Dichloride in 2016, and docetaxel chemotherapy from 2016 to 2017. Two cycles of 177Lu-PSMA-617 were highly effective (B). PSA was still decreasing after two additional 177Lu-PSMA-617 cycles despite increasing PSMA-ligand uptake in PSMA-PET (C). Maintenance therapy using 177Lu-PSMA-617 was continued until January 2019 with further response (D and E); however, disease progression occurred after watchful waiting and two cycles of 177Lu-PSMA-I&T (F and G). The patient then received two cycles of 225Ac-PSMA-I&T and showed encouraging response (H). The main TAT-related side effect was grade 2 xerostomia (grade 2), which was already preexisting after 10 cycles of RLT. No TAT-related grade 3/4 hematological side effects were noted. Further cycles are planned but were suspended due to the COVID-19 crisis upon patient’s request.

Different approaches including tandem therapy with 177Lu or de-escalating doses during consolidation have been proposed for TAT as a trade-off between therapeutic efficacy and tolerable side effects [2, 4], and further studies investigating 225Ac-PSMA remain highly important for prostate cancer theranostics.