News|Articles|June 2, 2026

Lutetium Lu 177 Vipivotide Tetraxetan Triplet Shows Consistent rPFS Benefit Across Disease Volume and mHSPC Status Subgroups

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Key Takeaways

Prespecified subgrouping used CHAARTED conventional-imaging criteria for disease volume and initial stage IVB status to define de novo versus recurrent metastatic hormone-sensitive disease.
Radiographic PFS benefit with the triplet regimen was consistent in high volume (HR 0.72) and low volume (HR 0.73) disease, despite wider confidence intervals in low volume.
De novo and recurrent presentations demonstrated similar rPFS hazard ratios (both 0.74), supporting broad applicability of PSMA-targeted radioligand intensification in mHSPC.
Safety findings were uniform across subgroups, with higher grade ≥3 AEs, cytopenias, and dry mouth on lutetium; discontinuation due to AEs remained 6%–9% and renal events were uncommon.

PSMAddition subgroup data show lutetium PSMA-617 triplet yields consistent rPFS, PSA, and mCRPC benefits regardless of disease volume or mHSPC status.

Adding lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) produced consistent radiographic progression-free survival (rPFS) benefit across high and low disease volume and de novo and recurrent disease subgroups in patients with prostate-maturation antigen (PSMA)–positive metastatic hormone-sensitive prostate cancer (mHSPC), according to subgroup analyses from the phase 3 PSMAddition trial (NCT04720157) presented at the 2026 ASCO Annual Meeting.¹

Across all 4 prespecified and exploratory subgroups, the HRs for rPFS with lutetium Lu 177 vipivotide tetraxetan plus ADT/ARPI vs ADT/ARPI alone ranged from 0.72 to 0.74, closely tracking the overall population HR of 0.72 (95% CI, 0.58-0.90, P = .002) reported at the second interim analysis. Secondary efficacy end points including time to PSA progression, time to metastatic castration-resistant prostate cancer (mCRPC), and investigator-assessed PFS followed similar patterns. Safety profiles were likewise consistent within each treatment arm across subgroups.

PSMAddition Subgroup Analysis Key Findings

rPFS HR of 0.72-0.74 with lutetium Lu 177 vipivotide tetraxetan plus ADT/ARPI vs ADT/ARPI across all 4 subgroups, consistent with the overall population HR of 0.72.

Time to PSA progression benefit was numerically strongest in the recurrent mHSPC subgroup (HR, 0.35, 95% CI, 0.21-0.60) and low disease volume subgroup (HR, 0.29, 95% CI, 0.08-1.05).

Time to mCRPC benefit was most pronounced in de novo patients (HR, 0.61, 95% CI, 0.47-0.80) versus recurrent patients (HR, 0.75, 95% CI, 0.56-1.00).

How were the subgroups defined, and what were the overall PSMAddition results?

PSMAddition enrolled treatment-naive or minimally treated patients with mHSPC confirmed by conventional imaging who had at least 1 PSMA-positive lesion on ⁶⁸Ga-PSMA-11 PET/CT and were candidates for ADT plus an ARPI.^1,2 Patients were randomly assigned to 6 cycles of lutetium Lu 177 vipivotide tetraxetan (7.4 GBq ±10% every 6 weeks) plus ADT/ARPI or ADT/ARPI alone. Crossover was permitted upon blinded independent central review-confirmed radiographic progression. The trial enrolled 1144 patients (572 per arm) with a median study follow-up of 23.6 months (range, 17.7-42.8).

Disease volume subgroups were defined per CHAARTED criteria using conventional imaging: high volume required the presence of visceral metastases and/or at least 4 bone lesions with at least 1 beyond the vertebral bodies and pelvis, all other patients were classified as low volume. mHSPC status subgroups were defined as de novo (stage IVB at initial diagnosis) or recurrent (below stage IVB at initial diagnosis). Baseline characteristics were generally balanced between treatment arms within each subgroup.

The primary end point was rPFS. Overall survival (OS) represented the key secondary end point.

What did the subgroup efficacy data show?

For rPFS, the primary end point, the HR for lutetium Lu 177 vipivotide tetraxetan plus ADT/ARPI versus ADT/ARPI was 0.72 (95% CI, 0.56-0.92) in the high disease volume subgroup and 0.73 (95% CI, 0.42-1.27) in the low disease volume subgroup. In the mHSPC status analysis, HRs were 0.74 (95% CI, 0.54-1.01) in de novo patients and 0.74 (95% CI, 0.53-1.04) in recurrent patients.

Benefits extended to additional secondary end points. For time to PSA progression, the overall HR was 0.42 (95% CI, 0.30-0.59), with consistent directionality across subgroups. The HR for time to PSA progression was 0.43 (95% CI, 0.31-0.62) in high volume, 0.29 (95% CI, 0.08-1.05) in low volume, 0.51 (95% CI, 0.32-0.79) in de novo, and 0.35 (95% CI, 0.21-0.60) in recurrent disease. Time to mCRPC followed a similar pattern, with an overall HR of 0.70 (95% CI, 0.58-0.84), HRs ranged from 0.61 to 0.87 across the 4 subgroups.

What was the safety profile across subgroups?

The on-treatment adverse event (AE) profile of lutetium Lu 177 vipivotide tetraxetan plus ADT/ARPI was consistent across disease volume and mHSPC status subgroups. Any-grade AEs occurred in 98% or more of patients in the lutetium Lu 177 vipivotide tetraxetan arm across all subgroups. Grade 3 or higher AEs were observed in 47% to 53% of patients in the triplet arm vs 39% to 46% in the control arm across subgroups. Serious AEs occurred in 29% to 33% of patients receiving lutetium Lu 177 vipivotide tetraxetan across subgroups. Discontinuation of lutetium Lu 177 vipivotide tetraxetan due to AEs ranged from 6% to 9% across the 4 subgroups.

Safety topics of special interest showed consistent patterns across subgroups. Cytopenias occurred in 41% to 47% of patients in the lutetium Lu 177 vipivotide tetraxetan arm vs 18% to 22% in the control arm. Dry mouth was observed in 43% to 51% of patients in the triplet arm vs 3% to 5% in controls. Rates of renal events and second primary malignancies were low and generally similar between arms and across subgroups.

Disclosures: Saad received honoraria from Abbvie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen Oncology, Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, Sanofi, Sumitomo Dainippon Pharma Oncology, and Tolmar. He holds consulting or advisory roles with Abbvie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca/MedImmune, Bayer, GlaxoSmithKline, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, Sanofi, Sumitomo Dainippon Pharma Oncology, and Tolmar. He received research funding from Abbvie (Inst), Advanced Accelerator Applications (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Janssen Oncology (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Point Therapeutics (Inst), and Sanofi (Inst).

References

Saad F, Tagawa ST, Sartor O, et al. Subgroup analyses by disease volume and
de novo/recurrent mHSPC in the PSMAddition study of [¹⁷⁷Lu]Lu-PSMA-617. J Clin Oncol. 2026;44(suppl 16):5020. doi:10.1200/JCO.2026.44.16_suppl.5020
An international prospective open-label, randomized, phase III study comparing 177Lu-PSMA-617 in combination with standard of care (SoC), versus SoC alone, in adult male patients with metastatic hormone sensitive prostate cancer (mHSPC) (PSMAddition). ClinicalTrials.gov. Updated May 27, 2026. Accessed June 2, 2026. https://clinicaltrials.gov/study/NCT04720157