177Lu-PSMA-617 Enhances PSA Responses in PSMA+ mHSPC

Findings from the phase 3 PSMAddition trial (NCT04720157) shared at the 2026 AUA Annual Meeting showed that PSA responses were more frequent and deeper when Lu 177 vipivotide tetraxetan (Pluvicto; 177Lu-PSMA-617) was added to androgen-deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) vs ADT/ARPI alone in patients with PSMA–positive metastatic hormone-sensitive prostate cancer (mHSPC).¹

The results showed that PSA levels declined substantially from baseline in the majority of patients across both treatment arms. Among the 557 patients in the lutetium Lu 177 vipivotide tetraxetan arm with a baseline and at least 1 post-baseline PSA measurement, the best PSA change from baseline was a decrease in 98.2% of patients. Among the 553 evaluable patients in the ADT plus ARPI control arm, the best PSA change from baseline was a decrease in 98.7% of patients.

The rate of patients achieving a confirmed 90% or greater decrease in PSA from baseline (PSA90) was also nominally higher in the lutetium Lu 177 vipivotide tetraxetan arm (n = 561) than in the control arm (n = 554) at all time points evaluated, at 89.5% (95% CI, 86.6%-91.9%) vs 85.6% (95% CI, 82.4%-88.4%), respectively. At week 12, PSA90 response rates were 83.8% (n = 414/494; 95% CI, 80.3%-86.9%) vs 78.1% (n = 350/448; 95% CI, 74.0%-81.9%), respectively. At week 24, respective rates were 87.4% (n = 396/453; 95% CI, 84.0%-90.3%) vs 81.9% (n = 343/419; 95% CI, 77.8%-85.4%). At week 48, respective rates were 84.7% (n = 310/ 366; 95% CI, 80.6%-88.2%) vs 80.5% (n = 317/394; 95% CI, 76.2%-84.3%).

Moreover, the addition of lutetium Lu 177 vipivotide tetraxetan to ADT and an ARPI was associated with a 58% reduction in the risk of PSA progression compared with ADT plus ARPI alone (HR, 0.42; 95% CI, 0.30-0.59). PSA progression events occurred in 8.7% of patients in the lutetium Lu 177 vipivotide tetraxetan arm vs 18.7% of patients in the control arm, with 91.3% and 81.3% of patients censored, respectively. The median time to PSA progression was not reached in either treatment arm (95% CI, not evaluable [NE]-NE).

“Combining [lutetium Lu 177 vipivotide tetraxetan] with ADT plus ARPI increased the frequency and depth of PSA responses, in addition to the rapid and substantial decline in PSA levels with ADT plus ARPI alone,” lead presenter Fred Saad, CQ, MD, FRCS, FCAHS, and colleagues wrote in their presentation.

Saad is a professor and chairman of the Department of Surgery; holds the Raymond Garneau Chair in Prostate Cancer Research; and is the director of GU Oncology and the Molecular Oncology Research Laboratory in Prostate Cancer at the Université de Montréal in Canada.

Clinical Context

PSMAddition represents the first phase 3 investigation of targeted radioligand therapy in the mHSPC setting. Findings from the second interim analysis of PSMAddition presented at the 2025 ESMO Congress showed that the study met its primary end point of improved radiographic progression-free survival (rPFS) with lutetium Lu 177 vipivotide tetraxetan plus ADT and an ARPI (n = 572), with a median rPFS that was not reached (NR; 95% CI, NE-NE) vs NR (95% CI, 29.7-NE) with an ARPI plus ADT alone (n = 572; HR, 0.72; 95% CI, 0.58-0.90; P = .002).²

Safety outcomes were consistent with the known profile of lutetium Lu 177 vipivotide tetraxetan, although adverse effects reported during treatment were more frequent in the lutetium Lu 177 vipivotide tetraxetan arm than in the control arm.

Because PSA is a sensitive biomarker for monitoring disease progression and evaluating treatment response, PSA-related end points were analyzed as part of the PSMAddition trial's second interim analysis, Saad explained.¹

Design of PSMAddition

PSMAddition enrolled eligible male patients with mHSPC diagnosed by conventional imaging who had at least one PSMA-positive metastatic lesion confirmed on [⁶⁸Ga]Ga-PSMA-11 PET/CT, were untreated or minimally treated, had an ECOG performance status of 0 to 2, and were appropriate candidates for ADT plus ARPI.

Of the 1,529 patients screened, 1,420 underwent [⁶⁸Ga]]Ga-PSMA-11 PET/CT imaging; 86.8% of those patients were PSMA-positive. Eligible patients were randomly assigned 1:1 to receive either lutetium Lu 177 vipivotide tetraxetan at 7.4 GBq ± 10% for 6 cycles every 6 weeks plus ADT and an ARPI (n = 572) or ADT plus ARPI alone (n = 572). Of note, crossover was permitted upon radiographic progressive disease (rPD).

The study’s primary end point was rPFS, with overall survival serving as a key secondary end point. PSA-related end points reported in this analysis included the following prespecified and post hoc measures:

• Prespecified
  • PSA90 response rate
  • Time to PSA progression
  • Proportion of patients with a PSA level below 0.2 ng/mL at weeks 12, 24, and 48
• Post hoc
  • Proportion of patients with a PSA level below 0.02 ng/mL at weeks 12, 24, and 48
  • Best percentage change from baseline in PSA

The median study follow-up was 23.6 months (range, 17.7-42.8) and the data cutoff was January 13, 2025.

Baseline Patient Characteristics

Baseline characteristics were well balanced between arms. In the overall patient population (n = 1144), the median age was 68.0 years (range, 36-91), with 43.0% of patients aged 70 years or older. The majority of patients had an ECOG performance status of 0 (70.3%). Bone metastases were present in 91.2% of patients, and soft tissue involvement was present in 59.4%. The median baseline PSA was 11.91 ng/mL (interquartile range, 3.01–50.34). Additional baseline characteristics included:

• Gleason score 8–10 (grade group 4-5): 69.5% of patients
• High tumor volume per CHAARTED criteria: 68.1% of patients
• De novo mHSPC (stage IVb per AJCC 8th edition): 50.0% of patients
• Liver involvement: 14.6% of patients
• Lung or liver involvement: 10% of patients combined (lung, 2.8%; liver, 14.6%)

Deep PSA Suppression

A greater proportion of patients in the lutetium Lu 177 vipivotide tetraxetan arm achieved very low PSA levels at each time point evaluated, both for the prespecified threshold of less than 0.2 ng/mL and the post hoc threshold of less than 0.02 ng/mL.

For PSA levels less than 0.2 ng/mL, cumulative rates up to week 12 were 47.6% (n = 23/494; 95% CI, 43.1%-52.1%) with lutetium Lu 177 vipivotide tetraxetan vs 37.7% (n = 169/448; 95% CI, 33.2%-42.4%) in the control arm. Rates up to week 24 were 73.7% (n = 334/453; 95% CI, 69.4%-77.7%) vs 59.7% (n = 250/419; 95% CI, 54.8%-64.4%), respectively. By week 48, 87.4% (n = 320/366; 95% CI, 83.6%-90.6%) of patients in the lutetium Lu 177 vipivotide tetraxetan arm had achieved a PSA level below 0.2 ng/mL vs 74.9% (n = 295/394; 95% CI, 70.3%-79.1%) of patients in the control arm.

For the more stringent post hoc threshold of PSA less than 0.02 ng/mL, cumulative rates up to week 12 were 17.6% (n = 87/494; 95% CI, 14.4%-21.3%) with lutetium Lu 177 vipivotide tetraxetan vs 9.2% (n = 41/448; 95% CI, 6.6%-12.2%) in the control arm. Rates up to week 24 were 45.4% (n = 206/453; 95% CI, 40.8%-50.2%) vs 33.2% (n = 139/419; 95% CI, 28.7%-37.9%), and up to week 48 were 65.3% (n = 239/366; 95% CI, 60.2%-70.2%) vs 46.7% (n = 184/394; 95% CI, 41.7%-51.8%), respectively.

Disclosures: Saad reported consulting and advisory fees from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca/MedImmune, Bayer, GSK, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, Sumitomo Dainippon Pharma Oncology, and Tolmar; honoraria from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, GSK, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, Sanofi, Sumitomo Dainippon Pharma Oncology, and Tolmar; and research funding from AbbVie, Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Merck, Novartis, Pfizer, POINT Therapeutics, and Sanofi.

References

1. Saad F, Tagawa ST, Sartor O, et al. Prostate-specific antigen endpoints in the phase 3 PSMAddition study of [177Lu]Lu-PSMA-617 combined with ADT and ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. Presented at: 2026 American Urological Association Annual Meeting; May 15-18, 2026; Washington, DC. Abstract PD23-02.

2. Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Ann Oncol. 2025;35(2):S1627-S1628. doi: 10.1016/j.annonc.2025.09.101