Experience of rescue therapy with [177Lu]Lu-rhPSMA-10.1 in patients with primary or acquired resistance to [177Lu]Lu-PSMA-I&T

Abstract Purpose Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [ 177 Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [ 177 Lu]Lu-PSMA-I&T. Methods Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [ 177 Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [ 177 Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application. Results Despite progression with [ 177 Lu]Lu-PSMA-I&T, after the first cycle of [ 177 Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [ 177 Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [ 177 Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [ 177 Lu]Lu-PSMA-I&T therapy but showed an immediate response to [ 177 Lu]Lu-rhPSMA-10.1. The additional treatment with [ 177 Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients. Conclusions Patients showing tumour progression while receiving [ 177 Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [ 177 Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [ 177 Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance. Graphical Abstract