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

Abstract

Background and objective: [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-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 ¹⁷⁷Lu-PSMA-617 and the impact of longer observation time for patients receiving ¹⁷⁷Lu-PSMA-617 plus SoC.

Methods: VISION was an international, open-label study. Patients were randomised 2:1 to receive ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-PSMA-617 remained higher in the ¹⁷⁷Lu-PSMA-617 arm.

Conclusions and clinical implications: Longer exposure to ¹⁷⁷Lu-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 ¹⁷⁷Lu-PSMA-617 in this setting and the use of up to 6 cycles of ¹⁷⁷Lu-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 ¹⁷⁷Lu-PSMA-617 from four to six had no additional adverse side effects.

Keywords: (177)Lu-PSMA-617; Metastatic castration-resistant prostate cancer; Radioligand therapy; Treatment exposure; Treatment-emergent adverse events.

Fig. 1 –

Time to first occurrence of any-grade safety events of interest. Analyses were for the 734 patients who received at least one dose of randomised treatment. Second primary malignancies are not shown owing to their low incidence. n/N = number of events/number of patients in treatment arm; PSMA = prostate-specific membrane antigen.

Fig. 2 –

Unadjusted and exposure-adjusted incidence of (A,B) dry mouth, dry eye, and acute myelosuppression events, (C,D) fatigue and gastrointestinal events, and (E,F) musculoskeletal, renal, and liver events, and dyspnoea. Analyses were for the 734 patients who received at least one dose of randomised treatment. ALT = alanine aminotransferase; PSMA = prostate-specific membrane antigen; PTY = patient-treatment years.