Health-related quality of life, pain, and symptomatic skeletal events in the phase 3 PSMAddition study of [ ¹⁷⁷ Lu]Lu-PSMA-617 ( ¹⁷⁷ Lu-PSMA-617) combined with ADT and ARPI in patients with PSMA-positive mHSPC.

18 Background: In PSMAddition (NCT04720157), combining 177 Lu-PSMA-617 with ADT + ARPI significantly improved rPFS, vs ADT + ARPI, in patients with PSMA+ mHSPC (HR 0.72; 95% CI 0.58, 0.90; p = 0.002) at interim analysis 2 (IA2). We present health-related quality of life (HRQoL), pain and symptomatic skeletal events (SSE) results at rPFS IA2 (data cutoff, Jan 13, 2025). Methods: Eligible patients had treatment-naive/minimally treated (≤45 days pre-consent) mHSPC 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 to ADT + ARPI alone (control arm). The primary endpoint was rPFS (BIRC-confirmed rPD by PCWG3/RECIST v1.1 or death). Safety and tolerability were secondary endpoints. Secondary endpoints also included time to worsening (TTW) in patient-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as composites of score worsening by prespecified thresholds, clinical progression, or death; and composite time to SSE (TTSSE) or death. Post hoc non-composite analyses excluded death and clinical progression. Results: 1144 patients were randomized. Median study treatment exposure was 20.6 months in the 177 Lu-PSMA-617 arm and 19.94 months in the control arm. Overall incidences of grade ≥3 AEs and serious AEs were 50.7% and 26.6%, respectively, in the 177 Lu-PSMA-617 arm and 43.0% and 22.8% in the control arm. HRs for TTW in all FACT-P, EQ-5D-5L, and BPI-SF scales/subscales were >1.0 but <1.2, and all 95% CIs included 1.0 (Table) ( 177 Lu-PSMA-617 arm vs control arm). Post hoc results were similar. The HR for TTSSE was 0.89 (95% CI 0.62, 1.26); medians were not reached. Post hoc results were similar. Conclusions: Combining 177 Lu-PSMA-617 with ADT + ARPI improved rPFS, with a trend toward prolonged TTSSE, vs ADT + ARPI, in patients with PSMA+ mHSPC. The frequency of AEs was slightly increased, but there were no clinically significant differences in TTW in HRQoL and pain. Clinical trial information: NCT04720157 . Pre-specified composite TTW, months – median (95% CI) 177 Lu-PSMA-617 arm (n = 572) Control arm (n = 572) HR (95% CI) FACT-P Total score 11.33 (8.84, 14.03) 17.12 (13.80, 19.91) 1.14 (0.98, 1.33) Physical well-being 9.20 (7.72, 11.79) 14.49 (11.47, 19.35) 1.16 (0.99, 1.35) Emotional well-being 22.67 (17.08, 27.89) 23.29 (20.04, 28.16) 1.05 (0.88, 1.24) Functional well-being 8.80 (7.43, 11.47) 11.14 (8.31, 13.83) 1.01 (0.87, 1.17) Social/family well-being 8.77 (7.39, 11.24) 11.50 (8.54, 16.46) 1.05 (0.91, 1.22) EQ-5D-5L Utility score 11.10 (8.84, 14.06) 15.67 (11.76, 19.12) 1.13 (0.97, 1.31) BPI-SF Pain intensity 11.53 (8.77, 14.09) 13.83 (11.10, 16.79) 1.02 (0.87, 1.18) Pain interference 13.44 (11.33, 17.64) 17.45 (14.03, 23.75) 1.12 (0.95, 1.31) Worst pain intensity 11.14 (8.57, 12.65) 11.99 (9.23, 16.36) 1.01 (0.87, 1.18)