Background
International, open-label, randomized phase 3 superiority trial (169 sites, 20 countries); N=1144. Treatment-naive or minimally treated metastatic androgen pathway modulator-naive/sensitive (hormone-sensitive) prostate cancer with ≥1 PSMA-positive lesion on centrally read 68Ga-PSMA-11 PET; 50% de novo metastatic, 68% high-volume. 177Lu-PSMA-617 is a PSMA-targeted radioligand delivering β-particle radiation to PSMA-expressing cells.
Results
Interventions and follow up: Arm A: 177Lu-PSMA-617 7.4 GBq (200 mCi) IV q6w × up to 6 cycles + ADT + ARPI (investigator's choice)
Arm B: ADT + ARPI alone; crossover to 177Lu-PSMA-617 permitted at centrally confirmed radiographic progression
Primary endpoint: rPFS (blinded central review, PCWG3-modified RECIST 1.1)
mFollow up: 19.6 mo (rPFS follow-up; median 23.6 mo from randomization to cutoff; second interim analysis)
Results: rPFS: median NR vs NR; events 24% vs 30%; HR 0.72, 95% CI 0.58–0.90, P=.0021 — primary endpoint met
OS: NR (immature at this interim analysis)
Arm B: ADT + ARPI alone; crossover to 177Lu-PSMA-617 permitted at centrally confirmed radiographic progression
Primary endpoint: rPFS (blinded central review, PCWG3-modified RECIST 1.1)
mFollow up: 19.6 mo (rPFS follow-up; median 23.6 mo from randomization to cutoff; second interim analysis)
Results: rPFS: median NR vs NR; events 24% vs 30%; HR 0.72, 95% CI 0.58–0.90, P=.0021 — primary endpoint met
OS: NR (immature at this interim analysis)
Adverse events
Grade ≥3 (any): 51% vs 43%
Serious AEs: 32% vs 29% (3% attributed to 177Lu-PSMA-617)
Dry mouth: 46% vs 4% (all grade 1–2)
Other: cytopenias and GI disturbances more frequent in the 177Lu-PSMA-617 arm; no unexpected safety findings
Serious AEs: 32% vs 29% (3% attributed to 177Lu-PSMA-617)
Dry mouth: 46% vs 4% (all grade 1–2)
Other: cytopenias and GI disturbances more frequent in the 177Lu-PSMA-617 arm; no unexpected safety findings
Conclusions
Adding 177Lu-PSMA-617 to ADT + ARPI significantly prolonged rPFS in PSMA-positive metastatic hormone-sensitive prostate cancer — the first phase 3 win for PSMA radioligand therapy in the hormone-sensitive setting. Toxicity was higher but manageable, with no new safety signals.
Key Limitations
Open-label design; rPFS is a surrogate with medians not reached and OS immature (crossover at progression will dilute future OS readouts). Control arm was ADT + ARPI doublet — no docetaxel triplet comparator for high-volume disease (ARASENS/PEACE-1 setting). Requires PSMA-PET screening and radioligand infrastructure; ARPI choice was heterogeneous by investigator.
Clinical Context
177Lu-PSMA-617 (Pluvicto) is FDA-approved for PSMA-positive mCRPC after ARPI (VISION), with 2025 expansion to the pre-taxane mCRPC setting (PSMAfore); it is not yet approved in hormone-sensitive disease, and PSMAddition is expected to support regulatory filing in mHSPC. Current NCCN/ESMO standard for 1L metastatic hormone-sensitive disease is ADT + ARPI ± docetaxel; positioning of radioligand intensification will hinge on OS maturation and PSMA-PET–based patient selection.