Subgroup analyses by disease volume and de novo /recurrent mHSPC in the PSMAddition study of [ 177 Lu]Lu-PSMA-617.

5020 Background: In the phase 3 PSMAddition study (NCT04720157), combining [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) with ADT + ARPI significantly improved rPFS in patients with PSMA+ mHSPC vs ADT + ARPI at rPFS interim analysis (data cut off Jan 13, 2025), with a HR of 0.72 (95% CI 0.58, 0.90; p = 0.002). Methods: Patients had treatment-naive/minimally treated mHSPC diagnosed by CT/MRI/bone scan and ≥1 PSMA+ metastatic lesion on [ 68 Ga]Ga-PSMA-11 PET/CT. Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq ± 10% q6w, 6 cycles) + ADT + ARPI ( 177 Lu-PSMA-617 arm) or ADT + ARPI (control arm). The primary endpoint of rPFS (centrally assessed rPD per PCWG3/RECIST v1.1 or death) and selected secondary efficacy, safety, and patient-reported outcomes (PROs) were assessed in subgroups of high/low disease volume (DV) per CHAARTED criteria (locally assessed by CT/MRI/bone scan; prespecified) and de novo /recurrent mHSPC (AJCC stage ≥/ post hoc ) . Results: Of 572 patients randomized to the 177 Lu-PSMA-617 arm and 572 to the control arm, 68.0% and 68.2% had high DV, and 52.1% and 47.9% had de novo mHSPC. Efficacy and PRO HRs for the 177 Lu-PSMA-617 arm vs control arm were generally similar in the overall population and DV and mHSPC subgroups (rPFS HR 0.72–0.74; time to PSA progression HR 0.29–0.51) (Table). Incidences of AEs, grade ≥3 AEs, serious AEs, and selected safety topics of interest (cytopenias, dry mouth) were similar across subgroups within each treatment arm. Conclusions: In patients with PSMA+ mHSPC, combining 177 Lu-PSMA-617 with ADT + ARPI improved rPFS vs ADT + ARPI across high/low DV and de novo /recurrent mHSPC subgroups. Other efficacy outcomes, PROs, and the safety profile were generally consistent across subgroups. Clinical trial information: NCT04720157 . Efficacy and PROs. HR (95% CI) for 177 Lu-PSMA-617 arm vs control arm OverallN = 1144 High DVn = 779 Low DVn = 365 De novo mHSPCn = 572 Recurrent mHSPCn = 523 rPFS a 0.72 (0.58, 0.90) 0.72 (0.56, 0.92) 0.73 (0.42, 1.27) 0.74 (0.54, 1.01) 0.74 (0.53, 1.04) PFS per investigator b 0.64 (0.51, 0.79) 0.61 (0.48, 0.78) 0.80 (0.46, 1.37) 0.65 (0.48, 0.88) 0.64 (0.46, 0.89) Time to: PSA progression 0.42 (0.30, 0.59) 0.43 (0.31, 0.62) 0.29 (0.08, 1.05) 0.51 (0.32, 0.79) 0.35 (0.21, 0.60) Symptomatic skeletal event 0.89 (0.62, 1.26) 0.93 (0.64, 1.37) 0.67 (0.27, 1.66) 0.97 (0.60, 1.57) 0.82 (0.48, 1.40) mCRPC 0.70 (0.58, 0.84) 0.67 (0.54, 0.82) 0.87 (0.55, 1.37) 0.61 (0.47, 0.80) 0.75 (0.56, 1.00) BPI-SF pain intensity worsening c 1.02 (0.87, 1.18) 0.98 (0.82, 1.18) 1.09 (0.83, 1.44) 1.06 (0.85, 1.31) 0.97 (0.78, 1.22) FACT-P total score worsening