Lutetium Lu-177 Vipivotide Tetraxetan

A radioligand in which the small-molecule PSMA inhibitor PSMA-617 carries the beta emitter lutetium-177 into prostate-specific membrane antigen-positive prostate cancer cells, FDA approved since 2022 for metastatic prostate cancer and extended to earlier disease settings in 2025 and 2026.

Also referenced as: Pluvicto, 177Lu-PSMA-617, lutetium PSMA-617, Lu-PSMA-617, AAA617

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What is Lutetium Lu-177 Vipivotide Tetraxetan?

Lutetium Lu-177 vipivotide tetraxetan is a radioligand therapy for prostate cancer: the prostate-specific membrane antigen (PSMA) inhibitor PSMA-617 linked through the chelator DOTA to the radioactive metal lutetium-177. It is not a peptide. The targeting portion is a glutamate-urea-lysine small molecule, a peptidomimetic in which two amino acids are joined by a urea bridge rather than a peptide bond, extended by a linker built from 2-naphthyl-L-alanine and a cyclohexane carboxylic acid unit. The molecule was designed at the German Cancer Research Center and Heidelberg University Hospital and was assembled by solid-phase peptide chemistry, and it is usually discussed alongside true peptide radiopharmaceuticals because it shares their chelator, radionuclide and receptor-targeting design (Benešová et al., Journal of Nuclear Medicine, 2015). Vipivotide tetraxetan is the international nonproprietary name for unlabeled PSMA-617; the complete radiolabeled drug has the molecular formula C49H68(177Lu)N9O16 and a molecular mass of about 1,216 g/mol (FDA label, Description section).

Marketed as Pluvicto by Novartis, it was the first PSMA-targeted radioligand approved by the FDA, on March 23, 2022, and sits in the same therapeutic family as Lutetium Lu-177 Dotatate, which pairs the same radionuclide and chelator with a genuine somatostatin-analog peptide. It is not a research-market product; it is a radiopharmaceutical manufactured to order and handled only under radiation licenses.

How it works

The molecule separates into two jobs: the ligand finds PSMA-expressing cells and the radionuclide irradiates them.

• PSMA binding and internalization. PSMA is a transmembrane glutamate carboxypeptidase overexpressed on most prostate adenocarcinoma cells, with expression that generally rises as the disease becomes castration-resistant and metastatic. The glutamate-urea-lysine pharmacophore of PSMA-617 occupies the enzyme’s active site with sub-nanomolar to low-nanomolar affinity (Ki 0.37 nM in an enzymatic assay and 2.34 nM on LNCaP cells), and the receptor-ligand complex is efficiently taken into the cell, concentrating the radiometal in the tumor. The naphthyl-containing linker was selected to improve tumor uptake and speed kidney clearance relative to earlier PSMA ligands (Benešová et al., Journal of Nuclear Medicine, 2015).
• Beta-particle DNA damage. Lutetium-177 decays with a physical half-life of 6.647 days, emitting beta-minus particles with a maximum energy of 498 keV. The radiation deposits its energy in the PSMA-expressing cell and its immediate neighbors, producing DNA double-strand breaks that lead to cell death in target cells and in nearby cells that may express less PSMA (FDA label, Mechanism of Action and Description sections). The antitumor effect comes from the radiation, not from any pharmacologic action of the ligand.
• Gamma photons for imaging. Lutetium-177 also emits gamma photons at 208 keV and 113 keV that a gamma camera can detect, so uptake after treatment can be imaged and absorbed doses estimated from the same administration (FDA label, Description section).
• Normal-tissue uptake and toxicity. Immunohistochemistry finds PSMA in the proximal renal tubules and the duodenal mucosa as well as the prostate (Silver et al., Clinical Cancer Research, 1997), and PSMA imaging shows intense uptake in the salivary and lacrimal glands, where the mechanism is only partly explained by PSMA expression. Dry mouth is the most frequent adverse event in the PSMAfore and PSMAddition trials and among the most frequent in VISION, and renal and hematologic toxicity follow from kidney clearance and marrow exposure rather than from an off-target drug effect (Sartor et al., New England Journal of Medicine, 2021; Tagawa et al., Lancet, 2026).

Because the drug only works where PSMA is present, every approved indication requires patients to be selected by PSMA positron emission tomography with gallium Ga 68 gozetotide (PSMA-11) or another approved PSMA imaging agent.

Research status

Lutetium Lu-177 vipivotide tetraxetan has one of the largest randomized evidence bases of any radiopharmaceutical: three positive Phase 3 trials spanning late to early metastatic disease, plus an academic Phase 2 comparison against chemotherapy.

Early clinical experience. After the 2015 preclinical report, Heidelberg investigators published the first treated patients (Kratochwil et al., Journal of Nuclear Medicine, 2016, 57(8):1170-1176) and a German multicenter retrospective series of 145 patients with metastatic castration-resistant prostate cancer (mCRPC) reported a biochemical response rate of 45% with grade 3-4 anemia in 10% of patients (Rahbar et al., Journal of Nuclear Medicine, 2017, 58(1):85-90). Novartis acquired the program in 2018.

TheraP (NCT03392428). The Australian and New Zealand Urogenital and Prostate Cancer Trials Group randomized 200 men with mCRPC progressing after docetaxel to 177Lu-PSMA-617 or cabazitaxel (Hofman et al., Lancet, 2021, 397(10276):797-804). PSA responses of at least 50% occurred in 66% versus 37% of patients, and grade 3-4 adverse events were less frequent with the radioligand (33% versus 53%). With mature follow-up, however, overall survival did not differ between the arms (restricted mean survival 19.1 versus 19.6 months at 36 months, p = 0.77), with crossover in both directions (Hofman et al., Lancet Oncology, 2024, 25(1):99-107). TheraP also required a negative FDG-PET screen for PSMA-negative disease, a selection step not used in the sponsor’s trials.

VISION (NCT03511664). Sartor et al. (New England Journal of Medicine, 2021, 385(12):1091-1103) randomized 831 patients with PSMA-positive mCRPC previously treated with at least one androgen receptor pathway inhibitor (ARPI) and one or two taxane regimens, 2:1, to 177Lu-PSMA-617 plus protocol-permitted standard care or standard care alone. Median imaging-based progression-free survival was 8.7 versus 3.4 months (hazard ratio 0.40) and median overall survival 15.3 versus 11.3 months (hazard ratio 0.62, p < 0.001). Grade 3 or higher adverse events were more common with the radioligand (52.7% versus 38.0%). Health-related quality of life and pain outcomes favored the treatment arm (Fizazi et al., Lancet Oncology, 2023, 24(6):597-610). VISION is the only trial to date in which the drug has shown a statistically significant overall survival benefit, and it supported the original FDA approval; the FDA’s own review is summarized in Fallah et al., Clinical Cancer Research, 2023, 29(9):1651-1657.

PSMAfore (NCT04689828). Morris et al. (Lancet, 2024, 404(10459):1227-1239) moved the drug before chemotherapy: 468 taxane-naive patients with PSMA-positive mCRPC who had progressed on one ARPI were randomized 1:1 to 177Lu-PSMA-617 or a switch to abiraterone or enzalutamide. Median radiographic progression-free survival was 9.30 versus 5.55 months at the primary analysis (hazard ratio 0.41, p < 0.0001) and 11.60 versus 5.59 months at the updated analysis. Grade 3-5 adverse events were less frequent with the radioligand (36% versus 48%). The final overall survival analysis was not statistically significant, with median survival of 24.5 versus 23.1 months (hazard ratio 0.91, 95% confidence interval 0.72 to 1.14); 60% of control patients had crossed over to 177Lu-PSMA-617 after progression (Fizazi et al., Annals of Oncology, 2025, 36(11):1319-1330). The FDA accepted the progression-free survival benefit and expanded the indication on March 28, 2025.

PSMAddition (NCT04720157). Tagawa et al. (Lancet, 2026, 408(10557):793-807) reported the second interim analysis of 1,144 patients with PSMA-positive metastatic androgen pathway modulator-naive or -sensitive prostate cancer (the population traditionally called metastatic hormone-sensitive prostate cancer), enrolled at 169 sites in 20 countries between June 15, 2021 and July 25, 2023 and randomized 1:1 to 177Lu-PSMA-617 plus androgen deprivation therapy and an ARPI, or androgen deprivation therapy plus an ARPI alone. At a data cutoff of January 13, 2025, radiographic progression or death had occurred in 24% versus 30% of patients (hazard ratio 0.72, 95% confidence interval 0.58 to 0.90, p = 0.0021), and median radiographic progression-free survival had not been reached in either arm. Grade 3 or worse adverse events occurred in 51% versus 43% of patients, and dry mouth in 46% versus 4%, all grade 1 or 2. Overall survival was immature at the analysis. The FDA approved this indication on July 31, 2026, under Project Orbis with the UK MHRA, and the trial remains ongoing with an estimated completion in February 2027.

Regulatory record. The FDA approved Pluvicto on March 23, 2022 for PSMA-positive mCRPC after ARPI therapy and taxane chemotherapy, with the imaging agent gallium Ga 68 gozetotide (Locametz) approved the same day as the companion diagnostic. The European Commission authorized the drug on December 13, 2022. The US indication was extended to taxane-naive mCRPC on March 28, 2025 and to metastatic androgen pathway modulation-naive or -sensitive disease, in combination with an ARPI, on July 31, 2026; the current prescribing information is dated July 2026.

Active work. ClinicalTrials.gov lists dozens of open studies as of November 2026, including trials in oligometastatic hormone-sensitive disease, biochemical recurrence and the neoadjuvant setting, dosimetry-guided and retreatment protocols, and combinations with PARP inhibitors, immune checkpoint inhibitors and radiosensitizers. The same PSMA-617 ligand labeled with the alpha emitter actinium-225 (225Ac-PSMA-617) is a separate investigational product that is not approved anywhere.

Common dosage forms

• Pluvicto. A sterile solution for intravenous use in a single-dose 30 mL vial, 1,000 MBq/mL at calibration.
• No other presentation. No oral, pen or other presentation exists, and the unlabeled vipivotide tetraxetan ligand is not a drug product on its own.

Key considerations

• Regulatory status. The FDA Approved status reflects the March 23, 2022 approval of Pluvicto for PSMA-positive metastatic castration-resistant prostate cancer after ARPI and taxane therapy. The indication was extended to taxane-naive mCRPC in March 2025 and to metastatic androgen pathway modulation-naive or -sensitive disease with an ARPI in July 2026, and every indication requires PSMA PET-based patient selection.
• Progression versus survival. Only VISION has shown a statistically significant overall survival benefit; PSMAfore’s final survival analysis was not significant, PSMAddition’s survival data were immature at approval, and TheraP found no survival difference against cabazitaxel. High crossover rates confound those comparisons, but the earlier-line approvals rest on delayed radiographic progression rather than on proven longer life.
• Toxicity signals. Grade 3-4 decreased hemoglobin occurred in 15% and decreased platelets in 9% of VISION patients, grade 3-4 acute kidney injury in 1.3% to 3.4% across the three Phase 3 trials, and dry mouth from salivary-gland uptake in 39% to 61% of treated patients. Cumulative radiation exposure adds long-term cancer and fertility risk.
• Not a peptide, and not interchangeable with its relatives. PSMA-617 is a glutamate-urea-lysine peptidomimetic, so results obtained with peptide radioligands such as lutetium Lu-177 dotatate do not transfer to it, and vice versa. Gallium Ga 68 gozetotide (PSMA-11) is the imaging agent used to select patients, not a treatment; PSMA-I&T and 225Ac-PSMA-617 are different investigational ligands or isotopes with their own evidence.
• Naming. Pluvicto, 177Lu-PSMA-617, lutetium Lu 177 vipivotide tetraxetan and AAA617 all describe the same drug, while PSMA-617 and vipivotide tetraxetan alone refer to the unlabeled ligand. The July 2026 label renames the populations metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) and modulation-resistant (mAPMR) prostate cancer; each new term refers to the same population as the one it replaced.