Pre-therapeutic comparative dosimetry of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA-I&T in patients with metastatic castration resistant prostate cancer (mCRPC)

Introduction: Radiohybrid prostate-specific membrane antigen (rhPSMA)-ligands allow for labelling with ¹⁸F and radiometals for endoradiotherapy. rhPSMA-7.3 is designated as lead compound with promising preclinical data for ¹⁷⁷Lu-rhPSMA-7.3 indicating higher tumor uptake compared with ¹⁷⁷Lu-PSMA-I&T. In this retrospective analysis we compared pre-therapeutic clinical dosimetry of both PSMA-ligands. Methods: Six mCRPC patients underwent both ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA-I&T pre-therapeutic dosimetry. Whole-body scintigraphy was performed at 1h, 4h, 24h, 48h and 7d post injection. Regions of interest (ROI) covering the whole body, organs, bone marrow and tumor lesions per patient were drawn. Absorbed doses for individual patients and pre-therapeutic applications were calculated using OLINDA/EXM. To facilitate comparison of both ligands we introduced the therapeutic index (TI) defined as ratio of mean pre-therapeutic doses to tumor lesions over relevant organs-at-risk. Results: Mean whole-body pre-therapeutic effective doses were 0.12±0.07 vs. 0.05±0.03 Sv/GBq and mean absorbed organ doses were e.g. 1.65±0.28 vs. 0.73±0.18 Gy/GBq for the kidneys; 0.19±0.09 vs. 0.07±0.03 Gy/GBq for the liver and 2.35±0.78 vs. 0.80±0.41 Gy/GBq for the parotid, for the bone marrow 0.67±0.62 vs. 0.30±0.27 Gy/GBq for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. Tumor lesions received a mean absorbed doses of 6.44±6.44 vs. 2.64±2.24 Gy/GBq for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. The mean TI(kidney) and TI(bone_marrow) were 3.7±2.2 vs. 3.6±2.2 and 15.2±10.2 vs. 15.1±10.2, for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. Conclusion: Pre-therapeutic clinical dosimetry confirmed preclinical results with 2-3 times higher mean absorbed doses for tumors of ¹⁷⁷Lu-rhPSMA-7.3 compared to ¹⁷⁷Lu-PSMA-I&T. Absorbed doses to normal organs also tended to be higher for ¹⁷⁷Lu-rhPSMA-7.3 resulting overall in a similar average TI for both radiopharmaceuticals with considerable inter-patient variability. ¹⁷⁷Lu-rhPSMA-7.3 holds promise for similar therapeutic efficacy as ¹⁷⁷Lu-PSMA-I&T at lower amounts of injected activity simplifying radiation safety measurements (especially for large patient numbers and/or dose escalation regimes).