lutetium (177Lu) vipivotide tetraxetan
177Lu-PSMA-617, LuPSMA, lutetium Lu 177 vipivotide tetraxetan, PSMA-617 (unlabelled ligand)
Lutetium-177 PSMA-617 is a targeted radioligand therapy for metastatic castration-resistant prostate cancer. Despite frequently being grouped with peptide radiopharmaceuticals, it is not a peptide: its targeting element is a small-molecule glutamate-urea-lysine motif that occupies the active site of the PSMA enzyme. It is the first radioligand therapy shown in a randomised phase 3 trial to prolong overall survival in prostate cancer.
Mechanism
Prostate-specific membrane antigen, more accurately glutamate carboxypeptidase II or folate hydrolase 1 (FOLH1), is a type II transmembrane zinc metallopeptidase. It is expressed at low levels in normal prostate epithelium, proximal renal tubules, salivary glands and small intestine, but is overexpressed roughly a hundred to a thousand-fold in prostate adenocarcinoma, with expression rising as tumours dedifferentiate and become castration-resistant, precisely the opposite of the usual pattern where targets are lost with progression. It is therefore an unusually good target in advanced disease.
PSMA-617 is a small-molecule inhibitor built in three parts. The pharmacophore is a glutamate-urea-lysine (Glu-urea-Lys) motif, in which the urea carbonyl coordinates the active-site zinc ions and the glutamate occupies the S1' glutamate recognition pocket. This is a transition-state mimic of the enzyme's natural substrates, not a peptide binding a receptor. A linker containing 2-naphthyl-L-alanine and trans-4-(aminomethyl)cyclohexanecarboxylic acid engages a hydrophobic accessory pocket and the arene-binding site at the entrance funnel, and this linker chemistry is what raised affinity and, more importantly, tumour retention to the level needed for therapy. The third part is the macrocyclic DOTA chelator holding lutetium-177. On binding, PSMA internalises the whole complex by clathrin-mediated endocytosis and routes it to endosomes, where the charged radiometal is trapped. Lutetium-177 then emits beta-minus particles (Emax 498 keV, mean tissue range around 0.67 mm) that break tumour DNA, and gamma photons at 113 and 208 keV that permit post-treatment imaging and dosimetry.
What the research shows
The VISION trial randomised 831 patients with PSMA-positive metastatic castration-resistant prostate cancer, all previously treated with at least one androgen receptor pathway inhibitor and one or two taxane regimens, 2:1 to lutetium-177 PSMA-617 plus standard care or standard care alone. Median overall survival was 15.3 versus 11.3 months (HR 0.62) and median radiographic progression-free survival 8.7 versus 3.4 months (HR 0.40), the first randomised phase 3 demonstration of a survival benefit from radioligand therapy in prostate cancer. PSMAfore then moved the treatment earlier, randomising 468 taxane-naive patients to lutetium-177 PSMA-617 or a switch to a different androgen receptor pathway inhibitor, with median radiographic progression-free survival of 12.02 versus 5.59 months (HR 0.43).
The randomised phase 2 TheraP trial is where the picture becomes more nuanced, and it deserves emphasis. TheraP compared lutetium-177 PSMA-617 directly against cabazitaxel chemotherapy in 200 men. On the primary endpoint the radioligand won clearly: PSA response of 50% or more occurred in 66% versus 37%. Grade 3-4 adverse events were also less frequent (33% versus 53%). But the secondary overall survival analysis, published in 2024, found median overall survival of 19.5 months with lutetium-177 PSMA-617 and 19.1 months with cabazitaxel, essentially identical. In other words, when compared against effective chemotherapy rather than against a control arm with limited options, the radioligand produced better biochemical responses and fewer side effects but did not extend life further. PSMAfore's overall survival data have likewise been confounded by high crossover from the control arm. The fair summary is that lutetium-177 PSMA-617 is an effective, comparatively well-tolerated treatment with a proven survival benefit against standard care in the post-taxane setting, and a proven progression benefit earlier, but it is not demonstrably better than cabazitaxel for survival.
Evidence assessment
High-quality evidence
A randomised phase 3 trial (VISION) with a statistically significant overall survival benefit, a second phase 3 trial in an earlier line (PSMAfore) meeting its progression-free survival endpoint, a randomised phase 2 comparison against active chemotherapy (TheraP), and full marketing authorisation in the US, EU and UK. All four citations verified against PubMed. The tier reflects that evidence base; the honest caveats about the size of the survival gain and the null overall survival result in TheraP are given below.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer Preclinical only
Median overall survival 15.3 versus 11.3 months (HR 0.62) and radiographic progression-free survival 8.7 versus 3.4 months (HR 0.40) versus standard care alone. First phase 3 survival benefit for radioligand therapy in prostate cancer.
[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial Preclinical only
PSA response of 50% or more in 66% versus 37% favouring the radioligand, with fewer grade 3-4 adverse events (33% versus 53%). Direct comparison against active chemotherapy rather than a weak control.
Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial Preclinical only
Median overall survival 19.5 versus 19.1 months, no difference between the radioligand and cabazitaxel despite the large advantage in PSA response. An important null result that tempers claims of superiority over chemotherapy.
177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial Preclinical only
Median radiographic progression-free survival 12.02 versus 5.59 months (HR 0.43). Overall survival data were confounded by extensive crossover from the control arm. Supported the 2025 US indication expansion.
Safety
Fatigue is the commonest complaint. Xerostomia and dry eye follow directly from PSMA expression in salivary and lacrimal glands, which take up the radioligand; salivary toxicity is generally milder with lutetium-177 than with alpha-emitting actinium-225 constructs but can be persistent. Bone marrow suppression (anaemia, thrombocytopenia, lymphopenia and neutropenia) is common and occasionally severe, particularly in patients with extensive marrow involvement or prior myelosuppressive therapy. Nausea, vomiting, decreased appetite, constipation and diarrhoea occur frequently. Renal effects reflect physiological PSMA expression in the proximal tubule; renal function is monitored, and adequate hydration is standard. Myelodysplastic syndrome and acute leukaemia have been reported uncommonly. Radiation protection precautions apply for a period after each administration, covering close contact, sleeping arrangements and toilet hygiene, and patients receive specific instructions from the treating centre. Male fertility may be impaired.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | EU marketing authorisation granted 9 December 2022, in combination with androgen deprivation therapy with or without androgen receptor pathway inhibition, for adults with progressive PSMA-positive metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Licensed in Great Britain by the MHRA; access is through specialist nuclear medicine and oncology centres. The European indication is narrower than the current US one. |
| United States | FDA approved 23 March 2022 for PSMA-positive metastatic castration-resistant prostate cancer in patients previously treated with an androgen receptor pathway inhibitor and taxane-based chemotherapy. The indication was expanded in March 2025 on the basis of the PSMAfore trial; the current labelled indication covers adults with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibitor therapy and are either considered appropriate to delay taxane-based chemotherapy or have received prior taxane-based chemotherapy. Patient selection requires a positive PSMA PET scan. |
| WADA (sport) | Not on the WADA Prohibited List. It is a targeted radiotherapeutic with no anabolic, hormonal or masking properties. |
Questions
No, despite frequently being described as one. Its targeting element is a glutamate-urea-lysine small molecule that mimics the transition state of the PSMA enzyme's natural substrate. The glutamate and lysine are joined by a urea bridge, not a peptide bond, and the molecule inhibits an enzyme rather than binding a peptide receptor. Contrast this with lutetium-177 dotatate, which genuinely is a peptide.
Better tolerated and better at producing PSA responses, but not proven better for survival. The TheraP trial compared it head to head with cabazitaxel: PSA response was 66% versus 37% in favour of the radioligand, but median overall survival was 19.5 versus 19.1 months, effectively identical.
PSMA is expressed physiologically in the salivary and lacrimal glands, so they take up some of the radioligand along with the tumour. Xerostomia and dry eye are among the most characteristic side effects. They are generally milder with lutetium-177 than with alpha-emitting actinium-225 versions of the same ligand.
Because the therapy only reaches tumours that express the target. A PSMA PET scan, typically with gallium-68 gozetotide or a fluorine-18 agent, confirms that the disease is PSMA-avid and identifies patients whose tumours would not take up the therapeutic radioligand. A meaningful minority of screened patients are excluded on this basis.
It is the international nonproprietary name assigned to the ligand: 'vipivotide' designates the PSMA-targeting portion and 'tetraxetan' is the standard INN stem for the DOTA chelator. Together with the radionuclide prefix, lutetium (177Lu) vipivotide tetraxetan is the full generic name for what the literature calls 177Lu-PSMA-617.