Refining the clinical utility of [177Lu]Lu/[225Ac]Ac-PSMA tandem RLT in patients with metastatic castration resistant prostate cancer

Abstract Purpose This study aimed to evaluate the efficacy and safety of Lutetium-177/Actinium-225 prostate-specific membrane antigen tandem radioligand therapy ([ 177 Lu]Lu/[ 225 Ac]Ac-PSMA tandem RLT) and to explore clinical and imaging-based predictors of treatment response to support individualized patient selection. Methods This retrospective, single-center study included 23 patients with mCRPC who underwent Fluor-18 ([ 18 F]F)-PSMA-1007 positron emission tomography/computed tomography (PET/CT) and subsequent tandem RLT. Whole-body tumor segmentation on PET/CT and standard laboratory values were acquired before treatment initiation. Primary endpoint was partial response (PR), defined as either a decline in prostate specific antigen of ≥ 50% (according to prostate cancer clinical trial working group) or PET-based response according to Response Evaluation Criteria on PSMA PET/CT. Safety assessment included renal and hematological side effects following common terminology criteria of adverse events version 5. Results Following two cycles of tandem RLT, 11 patients (48%) achieved a PR. The treatment was generally tolerated well. Grade 3 events included renal impairment in two (9%) and grade 3 anemia in five (22%) patients, while no Grade 4/5 events occurred. Patients with increased PSMA expression on pretherapeutic PET (defined by the average mean standardized uptake value of all tumor lesions [SUV mean ]) had a higher response rate (86%; 6 out of 7) compared to those with decreased SUV mean (31%; 5 out of 16). In Cox regression analysis, SUV mean was significantly associated with PR with a hazard ratio of 1.34 (95% CI, 1.01–1.77; P = 0.042). PSMA-tumor volume ( P = 0.036) and total lesion-PSMA ( P = 0.041) were also significant predictors, whereas none of the clinical parameters showed predictive value. Kaplan-Meier analysis further confirmed SUV mean as the strongest PR ( P = 0.003). Conclusion [ 177 Lu]Lu/[ 225 Ac]Ac-PSMA tandem RLT may offer a safe, effective treatment option. Assessment of PSMA expression on pretherapeutic PET predicts response, supporting its use in guiding personalized treatment.