Clinical trialPhase 3Prostate cancer

Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

N Engl J Med · 2021831 patients

Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. N Engl J Med. 2021. 385:1091-1103

Study type: Clinical trial
Study name: VISION
Phase: Phase 3
Design: International open-label randomised trial (2:1 ratio)
Sample size: 831 patients
Source: N Engl J Med · 2021
Trial registration: NCT03511664

In plain words

Lutetium-177-PSMA is a "guided medicine": a molecule that sticks to the PSMA protein on prostate cancer cells and delivers radiation straight to them. In men whose disease had grown despite newer hormone therapy and chemotherapy, this treatment extended life by about 4 months on average and delayed the growth of the disease.

Key results

8.7 vs 3.4 months

Imaging-based progression-free survival

HR 0.40; 99.2% CI 0.29 to 0.57; P<0.001

15.3 vs 11.3 months

Overall survival

HR 0.62; 95% CI 0.52 to 0.74; P<0.001

52.7% vs 38.0%

Grade 3 or higher adverse events

No adverse effect on quality of life

Dose and schedule cards

Lutetium-177–PSMA-617 (VISION, PSMAfore, PSMAddition)

PSMA-positive disease on PSMA PET: mCRPC after an ARPI, either after a taxane (VISION) or to postpone a taxane (PSMAfore); and, per the FDA label, with an ARPI in ARPI-naive or ARPI-sensitive metastatic disease (PSMAddition)Each drug’s schedule in the tableOn the page “Prostate cancer” · PSMA-positive disease: radioligand therapy

Drug	Dose	Route	Schedule
177Lu-PSMA-617 (lutetium-177 vipivotide tetraxetan)	7.4 GBq (200 mCi)	IV	Every 6 weeks
ADT (± ARPI in ARPI-sensitive disease)	Per each drug’s label	—	Continuous

Cycle schedule: Lutetium-177–PSMA-617 every 6 weeks; ADT (± ARPI) continuous
Duration: 6 doses, or until progression or unacceptable toxicity

Per the FDA label and the trials. Patient selection by PSMA PET (centrally read in the trials). Only one 20% dose reduction, to 5.9 GBq (160 mCi), is allowed, and re-escalation is not permitted; if a second reduction is needed, discontinue; if a treatment delay due to an adverse reaction lasts more than 4 weeks, consider permanent discontinuation. Complete blood count and creatinine/creatinine clearance before and during treatment; withhold for creatinine clearance below 30 mL/min. The patient should drink plenty of water and urinate frequently before and after the infusion. Dry mouth is the most common adverse reaction. To be administered only by a physician licensed to use radiopharmaceuticals.

On the page “Prostate cancer” · PSMA-positive disease: radioligand therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lutetium-177-PSMA-617 + protocol-permitted standard care

¹⁷⁷Lu-PSMA-617 at an activity of 7.4 GBq (±10%) IV every 6 weeks (±1 week) for four to a maximum of six cycles (two additional cycles after assessment of response, residual disease and tolerability after cycle four), with protocol-permitted standard care (no chemotherapy, immunotherapy, radium-223 or investigational drugs).

2Protocol-permitted standard care alone

Best supportive/standard care at the investigator's choice, with the same restrictions (for example ARPI, corticosteroids, palliative radiotherapy).

Source of the regimen details: Published abstract and full text (PMC8446332); ClinicalTrials.gov NCT03511664

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

831 patients aged 18 years or older with progressive mCRPC that was PSMA-positive on ⁶⁸Ga-PSMA-11 PET-CT (central reading), ECOG performance status 0 to 2, life expectancy over 6 months and testosterone below 50 ng/dL, who had received at least one ARPI (enzalutamide and/or abiraterone) and 1 or 2 taxane regimens (each regimen at least 2 cycles; one regimen was enough if the patient was unsuitable for a second taxane).

Endpoints

Alternate primary endpoints: imaging-based progression-free survival and overall survival. Key secondary endpoints: objective response, disease control and time to symptomatic skeletal events.

Safety and side effects

Grade 3 or higher adverse events 52.7% versus 38.0%; quality of life was not adversely affected. With lutetium: fatigue 43.1% (grade 3 or higher 5.9%), dry mouth 38.8% (no grade 3), nausea 35.3%, anaemia 31.8% (grade 3 or higher 12.9% versus 4.9%). Adverse events leading to dose reduction, interruption or discontinuation were infrequent.

Clinical significance and place in guidelines

VISION led to FDA and EMA approval (2022) of ¹⁷⁷Lu-PSMA-617 (Pluvicto) in PSMA-positive mCRPC after an ARPI and a taxane, and brought radioligand therapy into the EAU, ESMO and NCCN guidelines.

Limitations

Open-label design; the control group was not allowed chemotherapy (such as cabazitaxel) or radium-223; early dropout of control patients at the start of the study led to a protocol amendment; PSMA PET is needed to select patients.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.