Clinical trialPhase 3Prostate cancer

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

Lancet · 2024468 patients

Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. Lancet. 2024. 404:1227-1239

A newer report of this study has been published: Final overall survival and safety analyses of the phase III PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer (2025)

Study type: Clinical trial
Study name: PSMAfore
Phase: Phase 3
Design: Randomised, open-label, controlled trial (74 centres in Europe and North America)
Sample size: 468 patients
Source: Lancet · 2024
Trial registration: NCT04689828

In plain words

This study looked at whether lutetium-177-PSMA radioligand treatment could be used earlier, that is, before chemotherapy. In men whose cancer had grown on a newer hormone drug, lutetium kept the disease under control for almost twice as long as switching to another hormone drug, and it caused fewer severe side effects.

Key results

9.30 vs 5.55 months

Radiographic progression-free survival (primary analysis)

HR 0.41; 95% CI 0.29–0.56; p<0.0001

11.60 vs 5.59 months

Radiographic progression-free survival (updated analysis)

HR 0.49; 95% CI 0.39–0.61

36% vs 48%

Grade 3 to 5 adverse events

Lutetium vs ARPI change

Drugs in this study:Abiraterone (Zytiga)Enzalutamide (Xtandi)

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 (234 patients)

¹⁷⁷Lu-PSMA-617 at an activity of 7.4 GBq (200 mCi) ±10% IV every 6 weeks for 6 cycles (median cumulative dose 42.39 GBq). Blood counts and biochemistry weekly in cycle 1 and in weeks 1, 3 and 5 of cycles 2 to 6.

2ARPI change (234 patients)

Switch to continuous oral abiraterone or enzalutamide per the drug label; crossover to ¹⁷⁷Lu-PSMA-617 allowed after centrally confirmed radiographic progression.

Source of the regimen details: Full text of the final report (PMC12399216) and ClinicalTrials.gov NCT04689828

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

468 patients aged 18 or older with progressive mCRPC that was PSMA-positive on ⁶⁸Ga-PSMA-11 PET-CT (at least one metastatic lesion with uptake greater than liver parenchyma and no exclusionary PSMA-negative lesions; central reading), ECOG performance status 0 or 1, testosterone below 50 ng/dL, who had progressed only once on a second-generation ARPI (abiraterone, enzalutamide, darolutamide or apalutamide; most recent therapy), without prior taxane (except up to 6 cycles of neoadjuvant/adjuvant treatment more than 12 months earlier) and candidates for an ARPI change.

Endpoints

Primary outcome: radiographic progression-free survival in the intention-to-treat population. Secondary outcome: safety (and overall survival and other outcomes).

Safety and side effects

Grade 3 to 5 adverse events were less frequent with lutetium (36% versus 48%); grade 5 deaths in 2% of each group (none treatment-related in the lutetium group; one treatment-related in the ARPI-change group).

Clinical significance and place in guidelines

In March 2025, based on PSMAfore, the FDA extended the use of ¹⁷⁷Lu-PSMA-617 to patients with PSMA-positive mCRPC after an ARPI who are candidates for delaying chemotherapy. An overall survival benefit has not yet been shown because of extensive crossover.

Limitations

The control arm (ARPI change) has limited efficacy and may be a weak comparator; 57% crossover makes overall survival difficult to interpret; open-label design.

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.