Lutetium-PSMA in prostate cancer: the VISION trial
Table of contents
A 71-year-old retired man has metastatic castration-resistant prostate cancer. He took abiraterone for almost 2 years and then had 6 cycles of docetaxel. Now the PSA is rising again, the hip pain has worsened and the CT scan shows new bone and lymph node lesions. The blood count shows hemoglobin of 10.2 g/dL and platelets of 140,000, and the estimated creatinine clearance is 55 mL/min. The family has heard about a radiation treatment that seeks out cancer cells and asks whether it can cure. The scene is fictional and was written for teaching.
This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is lutetium-177-PSMA-617, sold as Pluvicto, tested in the VISION trial. The focus is choosing well who receives it: the PSMA PET, the previous treatments and the bone marrow and kidney reserve. It does not replace your service's protocol or the decision of the oncology and nuclear medicine team. If you play the case of the day on NEXO, you will recognize the challenge: an effective treatment only helps those who have the target and can withstand the toxicity.
Key points
- Lutetium-PSMA delivers beta radiation to cells that express PSMA, and that is why selection starts with the PSMA PET.
- In VISION, in men already treated with an androgen receptor inhibitor and a taxane, median survival was 15.3 versus 11.3 months.
- No study has shown that the treatment cures; the goal is to prolong life and control the disease.
- The bone marrow and the kidney are the organs that most limit the treatment, and the label directs suspending or reducing the dose according to toxicity.
- The FDA approved its use on 03/23/2022 and expanded the indication in 2025 and 2026; at the EMA, the authorization is dated 12/09/2022.
Why this is a reasoning scenario
Prostate cancer that progresses after hormone blockade and chemotherapy has few options and a guarded prognosis (Sartor et al., 2021). Lutetium-PSMA arrived in this scenario with the promise of targeted radiation, which spares much of the normal tissue in patients selected by imaging (Sartor et al., 2021). The family in the scene heard that promise and wants to know whether it is a cure. Answering honestly is part of the reasoning.
The treatment is a good exercise because three questions come before the prescription. Does the tumor have the target? Has the patient already been through the treatments the trial required? Can the bone marrow and the kidney withstand it? The post on signs, symptoms and history helps you not miss the anemia and the pain that change the conversation, and the post on clinical decision-making reminds you that the PSMA PET is the test that decides.
What the scene teaches
The scene trains six habits. The first is to order the PSMA PET before promising the treatment. The second is to check the sequence of previous treatments. The third is to measure the bone marrow reserve. The fourth is to measure kidney function. The fifth is to explain the radiation precautions at home. The sixth is to state clearly that the goal is not a cure.
What is not at stake
The text does not discuss the initial treatment of localized prostate cancer or salvage radiotherapy after prostatectomy, which are topics of other texts in the series. Nor does it compare all possible treatments after docetaxel. The post on diagnostic uncertainty helps when the PET leaves doubt about a lesion.
What lutetium-PSMA is
PSMA is a membrane protein highly expressed in prostate cancer cells (Kuo et al., 2024). Lutetium-PSMA is a PSMA-targeted ligand that delivers beta radiation to the cells that express it and to the surrounding tissue (Kuo et al., 2024). The maximum tissue penetration of lutetium-177 is about 2 mm, and the mean is 0.67 mm (Pluvicto label, 07/2026). The same molecule that serves as the target for therapy serves as the target for imaging, which is why nuclear medicine calls this theranostics (Kratochwil et al., 2023).
Where the radiation goes. In the VISION dosimetry subanalysis, with 29 patients, the organs with the highest absorbed dose were the lacrimal glands, the salivary glands, the large intestine, the kidneys and the bladder wall (Pluvicto label from 07/2026). This explains dry mouth, one of the most common adverse effects, and the attention to the kidney (Pluvicto label from 07/2026). The label advises drinking plenty of fluids and urinating often to reduce the dose in the bladder (Pluvicto label from 07/2026).
Dose
The label indicates 7.4 GBq, or 200 mCi, intravenously every 6 weeks, for 6 doses, or until disease progression or unacceptable toxicity (Pluvicto label from 07/2026). The patient must keep the gonadotropin-releasing hormone analog or have already undergone bilateral orchiectomy (Pluvicto label from 07/2026). Treatment must be given by professionals trained in the safe use of radiopharmaceuticals (Pluvicto label from 07/2026).
Who is a candidate: PSMA PET
How VISION defined the target
In VISION, the tumor had to be PSMA positive on gallium-68-PSMA-11 PET, read centrally (Sartor and colleagues, 2021). There had to be at least one metastasis with PSMA uptake and no PSMA-negative lesion meeting the exclusion criteria (Sartor and colleagues, 2021). A lesion was considered negative when uptake was equal to or lower than that of the liver, in a lymph node of at least 2.5 cm in the short axis, in an organ of at least 1 cm or in bone with a soft tissue component of at least 1 cm (Pluvicto label from 07/2026).
How many were left out
Of the patients who underwent PET, 126, or 12.6 percent, did not meet the imaging criteria, because they had no positive lesion or had at least one negative lesion that excluded them (Sartor and colleagues, 2021). This shows that PET is not a bureaucratic detail: about 1 in 8 would not have had the necessary target (Sartor and colleagues, 2021).
The more uptake, the better
In a secondary analysis of VISION with 826 patients, mean PSMA uptake in the tumor was strongly linked to better results with lutetium-PSMA (Kuo and colleagues, 2024). Each 1-unit increase in this whole-body uptake was associated with 10 percent lower risk of death (Kuo and colleagues, 2024). A larger volume of PSMA-positive tumor, in turn, was associated with worse survival (Kuo and colleagues, 2024). The European and North American guideline notes that lesions that are positive on FDG PET but negative for PSMA predict a worse response (Kratochwil and colleagues, 2023).
The post about differential diagnosis helps you think about what it means when a lesion grows without taking up PSMA.
Who is a candidate: treatments, marrow and kidney
Previous treatments in VISION
All had received at least one androgen receptor inhibitor and 1 or 2 taxane chemotherapy regimens (Pluvicto label from 07/2026). All had at least one prior taxane, and 41 percent had received two (Pluvicto label from 07/2026). Half, 51 percent, had received one androgen receptor inhibitor, 41 percent two, and 8 percent three or more (Pluvicto label from 07/2026).
The control arm
The permitted standard care could not include cytotoxic chemotherapy, radium-223, immunotherapy or investigational drugs, due to lack of safety data with the combination (Sartor and colleagues, 2021). A published critique argues that this control, without chemotherapy, may have favored the experimental arm (Schnog and colleagues, 2024). In a comparison with the TheraP study, in which lutetium-PSMA was compared with cabazitaxel, the hazard ratio for death was 0.98, with an interval of 0.71 to 1.36 (Soon and colleagues, 2024).
Before the taxane
In PSMAfore, patients had progressed once on an androgen receptor inhibitor and had not yet received a taxane for metastatic disease (Pluvicto label of 07/2026). That scenario is discussed further on. For the retiree in the scene, who has already had abiraterone and docetaxel, the scenario is the VISION one. The post on interprofessional clinical reasoning shows why oncology and nuclear medicine need to decide together.
Marrow
In VISION, adequate marrow and organ function was required, performance status from 0 to 2 and life expectancy of at least 6 months (Sartor et al., 2021). The European and North American guideline cites as limits leukocytes below 2,500 per microliter, neutrophils below 1,500 and platelets below 75,000 (Kratochwil et al., 2023). In selected cases, such as extensive marrow infiltration, the guideline allows treatment with strict blood count monitoring, because the cytopenia caused by the tumor may improve (Kratochwil et al., 2023).
In the label, in VISION, there was grade 3 or 4 drop in hemoglobin in 15 percent, in platelets in 9 percent, in leukocytes in 7 percent and in neutrophils in 4.5 percent (Pluvicto label of 07/2026). Grade 3 or higher pancytopenia occurred in 1.1 percent, with two deaths, and there were deaths from bleeding linked to the platelet drop, from sepsis with neutropenia and from marrow failure (Pluvicto label of 07/2026).
Kidney
The guideline cites as limits a filtration rate below 30 mL/min and creatinine above twice the upper limit (Kratochwil et al., 2023). Experience with filtration between 30 and 50 mL/min is still limited (Kratochwil et al., 2023). In VISION, grade 3 or 4 acute kidney injury occurred in 3.4 percent (Pluvicto label of 07/2026). The label calls for creatinine and calculated clearance before and during treatment (Pluvicto label of 07/2026).
Other treatments
The guideline advises suspending large-field radiotherapy, chemotherapy and bone-seeking radiopharmaceuticals for at least 4 weeks, because of the effect on the marrow (Kratochwil et al., 2023). For older or frail patients, a 2026 review argues for detailed assessment before starting and monitoring as a continuous process (Bauckneht et al., 2026).
The table summarizes when the label requires suspending or reducing the dose.
| Situation | Label action | Source |
|---|---|---|
| Grade 2 blood count drop | Suspend until grade 1 or baseline | (Pluvicto label of 07/2026) |
| Grade 3 or higher blood count drop | Suspend and reduce to 5.9 GBq | (Pluvicto label of 07/2026) |
| Confirmed creatinine clearance below 30 mL/min | Suspend until it improves | (Pluvicto label of 07/2026) |
| Grade 3 dry mouth | Suspend and reduce to 5.9 GBq | (Pluvicto label of 07/2026) |
| Delay longer than 4 weeks due to adverse effect | Suspend for good | (Pluvicto label of 07/2026) |
The label does not list a contraindication (Pluvicto label of 07/2026). That does not mean everyone can receive it: the limits come from the studies and the guidelines (Kratochwil et al., 2023). The post on the diagnostic pause helps to check the blood count and the kidney before each dose.
The assessment before each dose can follow the points below.
- Complete blood count.
- Creatinine and clearance calculated by actual weight.
- Dry mouth and dry eyes.
- Nausea, fatigue and hydration.
- Pain and signs of spinal cord compression.
What VISION showed
Design
VISION was a phase 3, open-label study conducted at 84 centers in North America and Europe (Sartor et al., 2021). Between June 2018 and October 2019, 831 patients were randomized in a 2 to 1 ratio, 551 to lutetium-PSMA with standard care and 280 to standard care (Sartor et al., 2021). The primary outcomes were overall survival and imaging-based progression-free survival (Sartor et al., 2021).
Results
Median overall survival was 15.3 months with lutetium-PSMA and 11.3 months with standard care, with a hazard ratio of 0.62 and an interval of 0.52 to 0.74 (Sartor et al., 2021). Median imaging-based progression-free survival was 8.7 versus 3.4 months, with a hazard ratio of 0.40 (Sartor et al., 2021). Partial response occurred in 41.8 percent versus 3 percent of those with measurable disease (Sartor et al., 2021). Time to worsening of quality of life and pain also favored lutetium-PSMA, with hazard ratios of 0.54 and 0.52 (Fizazi et al., 2023).
PSA and progression
In the lutetium-PSMA arm, 15 percent of those who had a PSA rise at week 6 had a decline at week 12 (Armstrong et al., 2024). In the same database, imaging-based progression-free survival correlated strongly with overall survival (Morris et al., 2024). These data help avoid abandoning treatment because of a single PSA, but they do not replace imaging and clinical assessment.
Limitations
The authors acknowledge that the lack of placebo and double blinding is a common limitation of studies with radiopharmaceuticals (Sartor et al., 2021). Another limitation was the promotion of imaging-based progression-free survival to primary endpoint by amendment, after discussion with the FDA (Sartor et al., 2021). The label notes that the interpretation of progression-free survival was limited by the early withdrawal of many patients from the control arm (Pluvicto label of 07/2026).
It is not a cure
None of the studies cited here showed a cure with lutetium-PSMA. The VISION gain was about 4 months in median survival (Sartor et al., 2021) (Schnog et al., 2024). For the family in the scene, the honest answer is that the treatment can prolong life and relieve pain, with no established curative intent.
After VISION: PSMAfore and PSMAddition
PSMAfore
PSMAfore randomized 468 patients who had progressed on an androgen receptor inhibitor and had not yet received a taxane, between June 2021 and October 2022 (Morris et al., 2024). They received lutetium-PSMA or a switch to another inhibitor (Morris et al., 2024). Median imaging-based progression-free survival was 9.30 versus 5.55 months, with a hazard ratio of 0.41 (Morris et al., 2024).
In the final analysis, median overall survival was 24.48 versus 23.13 months, with a hazard ratio of 0.91 and an interval of 0.72 to 1.14, with no significant difference (Fizazi et al., 2025). A large part of the control arm went on to receive lutetium-PSMA after progression, and the analysis adjusted for this crossover estimated a hazard ratio of 0.59 (Fizazi et al., 2025). The authors conclude that the crossover confounded the survival analysis (Fizazi et al., 2025). One critique notes that switching one inhibitor for another is not the best control after failure of the first (Schnog et al., 2024).
PSMAddition
According to the label, PSMAddition randomized 1144 patients with metastatic prostate cancer still sensitive to hormonal blockade to lutetium-PSMA plus an androgen receptor inhibitor or the inhibitor alone (Pluvicto label of 07/2026). The hazard ratio for imaging progression or death was 0.72, with an interval of 0.58 to 0.90 (Pluvicto label of 07/2026). The overall survival data were still immature (Pluvicto label of 07/2026).
Safety at home
After each dose, the label advises limiting close contact, to less than about 90 cm, for 2 days with adults and for 7 days with children and pregnant women (Pluvicto label of 07/2026). It also advises avoiding sexual intercourse for 7 days and sleeping in a separate room for 3 days, 7 days if there are children and 15 days if there is a pregnant woman (Pluvicto label of 07/2026). Men with a partner who can become pregnant should use contraception during treatment and for 14 weeks after the last dose (Pluvicto label of 07/2026). The total dose can cause temporary or permanent infertility (Pluvicto label of 07/2026).
The post about clinical deterioration in the ward helps recognize the patient with bleeding or fever during the drop in blood counts.
Regulatory situation: FDA and EMA
FDA
Pluvicto has NDA 215833 at the FDA, with original approval on 03/23/2022 (Drugs@FDA, NDA 215833) (FDA 2022 approval letter). On 03/28/2025, supplements S-021 and S-024 revised the indication to include those who have not yet received a taxane (Drugs@FDA, NDA 215833). On 07/31/2026, supplement S-037 added the indication with an androgen receptor inhibitor in metastatic hormone-sensitive cancer (Drugs@FDA, NDA 215833). The current label was revised in 07/2026 (Pluvicto label from 07/2026).
EMA
At the EMA, the committee for medicinal products for human use issued a positive opinion on 10/13/2022, and the authorization was issued on 12/09/2022 (Pluvicto page at the EMA). In the query of 10/24/2026, the indication listed on the EMA page is for patients already treated with an androgen receptor inhibitor and taxane chemotherapy (Pluvicto page at the EMA). Therefore, the most recent FDA indications should not be taken as valid in Europe without checking the current text.
How NEXO helps train this reasoning
In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. Lutetium-PSMA is a good exercise because the decision depends on an imaging test, the treatment history and two blood tests. The post on case-based learning explains why this format makes knowledge stick.
Three exercises with cases
Change the PET. Say what changes if a 3 cm lesion in the liver did not take up PSMA.
Change the marrow. Say what you would do if platelets fell to 60,000 before the third dose.
Change the kidney. Say what changes if creatinine clearance fell from 55 to 28 mL/min.
The post on simulated consultations helps train the conversation with the family about the goal of treatment.
The limits of use of the game are described on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information on curation and on creators, and institutions can learn about the proposal on the partnerships page.
Frequently asked questions
Does lutetium-PSMA cure prostate cancer?
No curative intent has been established. In VISION, it extended median survival by about 4 months (Sartor et al., 2021).
Who can receive it?
Those with PSMA-positive metastatic cancer on PET who meet the criteria of the indication and of marrow and kidney reserve (Pluvicto label from 07/2026) (Kratochwil et al., 2023).
What is the dose?
7.4 GBq every 6 weeks, for 6 doses (Pluvicto label from 07/2026).
What are the most common side effects?
Fatigue, dry mouth, nausea and a drop in blood counts (Pluvicto label from 07/2026).
Does the patient become radioactive?
For a few days, they need to limit close contact, especially with children and pregnant women (Pluvicto label from 07/2026).
Final checklist
- I ordered the PSMA PET and checked for negative lesions.
- I checked the previous androgen receptor inhibitor and taxane.
- I checked the blood count.
- I checked creatinine and clearance.
- I maintained hormone blockade.
- I explained the radiation precautions at home.
- I gave guidance on contraception and infertility.
- I stated clearly that the goal is not a cure.
Want to practice reasoning with progressive clues? Play the case of the day.
References
- Armstrong AJ, Sartor O, de Bono J, et al. Association of Declining Prostate-specific Antigen Levels with Clinical Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Receiving [(177)Lu]Lu-PSMA-617 in the Phase 3 VISION Trial. Eur Urol. 2024. PMID 39242323.
- Bauckneht M, Borsellino N, Colloca GF, et al. Frailty and [(177)Lu]Lu-PSMA-617 therapy: tools and strategies for older men with metastatic castration-resistant prostate cancer. Theranostics. 2026. PMID 42707638.
- European Medicines Agency. Pluvicto | European Medicines Agency (EMA). Accessed on 10/24/2026. Official source.
- Fizazi K, Chi KN, Shore ND, et al. Final overall survival and safety analyses of the phase III PSMAfore trial of [(177)Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2025. PMID 40680993.
- Fizazi K, Herrmann K, Krause BJ, et al. Health-related quality of life and pain outcomes with [(177)Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023. PMID 37269841.
- Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. NDA 215833, Pluvicto. Accessed on 24/10/2026. Official source.
- Food and Drug Administration. NDA 215833. NDA APPROVAL. Approval letter of 23/03/2022. Official source.
- Kratochwil C, Fendler WP, Eiber M, et al. Joint EANM/SNMMI procedure guideline for the use of (177)Lu-labeled PSMA-targeted radioligand-therapy ((177)Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2023. PMID 37246997.
- Kuo PH, Morris MJ, Hesterman J, et al. Quantitative (68)Ga-PSMA-11 PET and Clinical Outcomes in Metastatic Castration-resistant Prostate Cancer Following (177)Lu-PSMA-617 (VISION Trial). Radiology. 2024. PMID 39162634.
- Morris MJ, Castellano D, Herrmann K, et al. (177)Lu-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. Lancet. 2024. PMID 39293462.
- Morris MJ, de Bono J, Nagarajah J, et al. Correlation analyses of radiographic progression-free survival with clinical and health-related quality of life outcomes in metastatic castration-resistant prostate cancer: Analysis of the phase 3 VISION trial. Cancer. 2024. PMID 39031642.
- Novartis. PLUVICTO® (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use. Prescribing information revised in 07/2026. Official source.
- Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021. PMID 34161051.
- Schnog JB, Duits AJ, Samson MJ. Design issues with lutetium-177 PSMA-617 registration studies that bias the outcome of the experimental arm reflect an increasing misalignment of contemporary oncology trials with true patient benefit. BJC Rep. 2024. PMID 39516569.
- Soon YY, Marschner IC, Schou M, et al. Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer. JAMA Netw Open. 2024. PMID 39287944.