Effects of androgen receptor signaling inhibitors on absorbed doses in mCRPC patients undergoing [177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T therapy: dosimetry results

Background Androgen receptor signaling inhibitors (ARSi) have significantly improved clinical outcomes in men with prostate cancer (PCa). Preliminary data suggest the potential for ARSi to enhance PSMA expression in patients with mCRPC. In this analysis, we present preliminary dosimetry results from mCRPC patients treated with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T radioligand therapy (RLT) in combination with ARSi compared to a Control Group of patients receiving [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T monotherapy. Methods This retrospective analysis was performed at a single center, including 50 patients diagnosed with mCRPC who underwent their first cycle of [ 177 Lu]Lu-PSMA-617 (n = 37) or [ 177 Lu]Lu-PSMA-I&T (n = 13) RLT ± concomitant ARSi treatment (abiraterone or enzalutamide). Patients were divided into a Combination Group (RLT + ARSi, n = 25) and a Control Group (RLT only, n = 25). Quantitative SPECT imaging was performed at 3 time points: 24 h (+ CT), 48 h, and 72 h post-administration of the initial cycle of RLT. Tumor lesions were segmented using the 24 h SPECT images, while organs-at-risk (kidney, spleen, liver) were delineated on the corresponding CT. Absorbed doses were calculated by applying a mono-exponential curve fit, incorporating local density scaling. Dosimetry results were evaluated separately for each radioligand. Results Overall, 148 tumor lesions were included in this analysis (median 3 lesions per patient). The median tumor absorbed dose was comparable between the Combination Group and the Control Group: [ 177 Lu]Lu-PSMA-617 (2.1 ± 4.0 Gy/GBq vs 1.5 ± 1.7 Gy/GBq, p = 0.24) and [ 177 Lu]Lu-PSMA-I&T (1.2 ± 1.2 Gy/GBq vs 1.2 ± 3.5 Gy/GBq, p = 0.21). Furthermore, the median absorbed dose in organs-at-risk was comparable between the two groups in [ 177 Lu]Lu-PSMA-617: Kidneys: 0.28 ± 0.11 Gy/GBq vs 0.27 ± 0.13 Gy/GBq, p = 0.90; Spleen: 0.05 ± 0.05 Gy/GBq vs 0.06 ± 0.05 Gy/GBq, p = 0.75; Liver: 0.08 ± 0.03 Gy/GBq vs 0.07 ± 0.04 Gy/GBq, p = 0.75). A statistically significant difference was noted in kidneys and liver for [ 177 Lu]Lu-PSMA-I&T: Kidneys: 0.21 ± 0.10 Gy/GBq vs 0.30 ± 0.08 Gy/GBq, p = 0.01; Spleen: 0.02 ± 0.02 Gy/GBq vs 0.04 ± 0.03 Gy/GBq, p = 0.20; Liver: 0.02 ± 0.01 Gy/GBq vs 0.04 ± 0.01 Gy/GBq, p = 0.01. Conclusion In this pilot cohort, concomitant ARSi therapy did not significantly enhance tumor absorbed doses in patients receiving [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T RLT. Further prospective studies with larger patient numbers are needed to evaluate the impact of concomitant ARSi treatment on the absorbed doses in mCRPC tumor lesions.