Safety Analyses of the Phase 3 VISION Trial of [177Lu]lu-Psma-617 in Patients with Metastatic Castration-resistant Prostate Cancer.

Background and objective: [Lu-177]Lu-PSMA-617 (Lu-177-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of Lu-177-PSMA-617 and the impact of longer observation time for patients receiving Lu-177-PSMA-617 plus SoC. Methods: VISION was an international, open-label study. Patients were randomised 2:1 to receive Lu-177-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received <= 4 cycles versus 5-6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs. Key findings and limitations: The any-grade TEAE incidence was similar in cycles 1-4 and cycles 5-6. TEAE frequency was similar across all cycles of Lu-177-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with Lu-177-PSMA-617 remained higher in the Lu-177-PSMA-617 arm. Conclusions and clinical implications: Longer exposure to Lu-177-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of Lu-177-PSMA-617 in this setting and the use of up to 6 cycles of Lu-177-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy. Patient summary: For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called Lu-177-PSMA-617 from four to six had no additional adverse side effects.