Novartis’ radioligand therapy Pluvicto (lutetium vipivotide tetraxetan; [¹⁷⁷Lu]Lu-PSMA-617) has demonstrated a clinically meaningful benefit as first-line treatment in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

This is considered the first Phase III evidence confirming Pluvicto's potential to extend beyond existing castration-resistant prostate cancer (mCRPC) into the first-line (mHSPC) setting.


The findings from the Phase III PSMAddition trial, presented on October 19 at the ESMO 2025 Congress by Professor Scott T. Tagawa of Weill Cornell Medicine (U.S.), confirm the potential for Pluvicto to move earlier in the prostate cancer treatment paradigm.

This study enrolled 1,144 patients with PSMA-positive mHSPC who were either treatment-naive (≤45 days) or had received minimal prior therapy.

Patients were randomized 1:1 to either the combination group (572 patients) receiving Pluvicto + androgen deprivation therapy (ADT) + ARPI, or the ADT + ARPI monotherapy group (572 patients).

Pluvicto was administered at 7.4 GBq every 6 weeks for up to six cycles, with stratification by disease volume (high vs low), age (≥ 70 years), and prior local treatment history of the primary tumor.

The primary endpoint was radiographic progression-free survival (rPFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), safety, and quality of life (QoL).

At a median follow-up of 23.6 months, neither group had reached median rPFS, but the Pluvicto combination group showed a 28% lower risk of disease progression or death. Overall survival (OS) also had not reached its median, but showed an improvement trend in the Pluvicto group.

The objective response rate (ORR) was 85.3% vs 80.8%, and rPFS improvement was consistent across all predefined subgroups.

Safety profile consistent with existing data… No impact on quality of life

Treatment-emergent adverse events (TEAEs) were reported in 98.4% vs 96.6% of patients, with grade ≥ 3 events occurring in 50.7% vs 43.0%, respectively.

The most common AEs were dry mouth (46.5%), fatigue, and nausea, which were mostly mild (Grade 1–2).

Hematologic toxicities (anemia, neutropenia, thrombocytopenia) were more frequent in the combination group but were generally manageable. There were no significant differences between groups in quality of life measures (Fact-P, BPI-SF, etc.).

Professor Tagawa stated, “Combination therapy with Pluvicto plus ADT and ARPI significantly improved radiographic progression-free survival (rPFS) in PSMA-positive mHSPC patients. The effect was consistent across subgroups, safety was consistent with the existing profile, and no deterioration in patient quality of life was observed.”

He further emphasized, “These results provide evidence that an early combination strategy with Pluvicto may offer clinical benefit.”

Professor Ana C. Garrido-Castro (Dana-Farber Cancer Institute/Harvard Medical School), who served as a discussant in the same session, noted, “PSMAddition is the first large-scale Phase III trial demonstrating that PSMA-targeted radiotherapeutics achieve meaningful efficacy even in the hormone-sensitive stage.”

PSMAddition demonstrated that Pluvicto has emerged as a candidate for a new standard of care as a combination therapy in the early stages of prostate cancer using radioligand therapy (RLT). These findings are expected to serve as key evidence supporting future label expansion into the hormone-sensitive setting.