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 [¹⁷⁷Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [¹⁷⁷Lu]Lu-PSMA-I&T. Methods: Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [¹⁷⁷Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [¹⁷⁷Lu]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 [¹⁷⁷Lu]Lu-PSMA-I&T, after the first cycle of [¹⁷⁷Lu]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 [¹⁷⁷Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [¹⁷⁷Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [¹⁷⁷Lu]Lu-PSMA-I&T therapy but showed an immediate response to [¹⁷⁷Lu]Lu-rhPSMA-10.1. The additional treatment with [¹⁷⁷Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients. Conclusions: Patients showing tumour progression while receiving [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [¹⁷⁷Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [¹⁷⁷Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.