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Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition)

  • Scott T. Tagawa,
  • Oliver Sartor,
  • Josep Maria Piulats,
  • Fred Saad,
  • Karim Fizazi,
  • Alison H. Reid,
  • Himisha Beltran,
  • Gero Kramer,
  • Hakim Mahammedi,
  • Matthias Eiber,
  • Shilpa Gupta,
  • Daniel E. Castellano Gauna,
  • Ralph Hauke,
  • Hyun Kim,
  • Cheol Kwak,
  • See-Tong Pang,
  • Emmanuel Bouillaud,
  • Angela Zhang,
  • Olga Sakharova,
  • Michael J. Morris

Publication: ESMO25, October 2025

Background

ADT + androgen receptor pathway inhibitor (ARPI) is a standard of care for mHSPC but outcomes remain suboptimal. PSMAddition (NCT04720157) evaluates [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) combined with ADT + ARPI in PSMA+ mHSPC.

Methods

Eligible adults had treatment-naïve/minimally treated (≤45 days) mHSPC and ≥1 PSMA+ metastatic lesion on [68Ga]Ga-PSMA-11 PET/CT. Randomization was 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq q6w, 6 cycles) + ADT + ARPI (177Lu-PSMA-617 arm) or ADT + ARPI (control arm), stratified by disease volume (high/low), age (≥/<70 years) and previous/planned primary tumor treatment (yes/no). Control arm patients with centrally confirmed rPD could cross over to 177Lu-PSMA-617 if eligible. The primary endpoint was rPFS (per centrally assessed PCWG3 RECIST v1.1 or death); secondary endpoints included OS (key), ORR, safety/tolerability and QoL. We report rPFS interim analysis (IA) 2, the first efficacy IA.

Results

1144 patients were randomized (de novo mHSPC, 50.0%; high-volume disease, 68.1%). Baseline characteristics were balanced between arms. At rPFS IA2 (median study follow-up, 23.6 months; 177Lu-PSMA-617 cycles, 6 in 85.6% and ≥4 in 93.1%), the primary endpoint was met, with significantly improved rPFS (Table). There was a positive trend in intent-to-treat OS; ORR favored the 177Lu-PSMA-617 arm (Table). Overall incidence of AEs was slightly higher with addition of 177Lu-PSMA-617 (Table). Dry mouth was the most common AE (all grade 1–2; 177Lu-PSMA-617 vs control arm: 41.0% vs 3.4 % grade 1, 4.8% vs 0.4% grade 2). Grade ≥3 cytopenias were more frequent with added 177Lu-PSMA-617 (14.4% vs 5.0%). Time to worsening in QoL (FACT-P, EQ-5D) did not differ meaningfully between arms.

DCO 13 Jan 2025 177Lu-PSMA-617 + ADT + ARPI ADT + ARPI
Efficacy N = 572 N = 572
rPFSa
Events, n (%) 139 (24.3) 172 (30.1)
Median (95% CI), months NE (NE, NE) NE (29.73, NE)
HR (95% CI), p 0.72 (0.58, 0.90), 0.002
OSb
Events, n (%) 85 (14.9) 99 (17.3)
Median (95% CI), months NE (NE, NE) NE (NE, NE)
HR (95% CI), p 0.84 (0.63, 1.13), 0.125
ORRc, % (95% CI), n 85.3 (79.9, 89.6), 224 80.8 (74.8, 85.8), 213
Safety N = 564 N = 565
Any AE, % 98.4 96.6
Grade ≥3, % 50.7 43.0
Serious, % 31.9 28.7

arPD or death; significance threshold at IA2, 0.009; IF, 74.4%. bIF, 47.3%. cSoft tissue and bone; patients with measurable disease at baseline. CI, confidence interval; DCO, data cut off; IA, interim analysis; IF, information fraction; NE, not estimable.

Conclusions

Combining 177Lu-PSMA-617 with ADT + ARPI significantly improved rPFS in this first phase 3 trial of radioligand therapy in mHSPC. Safety findings were consistent with the known profile and QoL was not adversely affected.

Clinical trial identification

NCT04720157.