Clinical trialPhase 3Prostate cancer

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

Ann Oncol · 2025468 patients

Fizazi K, Chi KN, Shore ND, Herrmann K, de Bono JS, Castellano D, et al. Ann Oncol. 2025. 36:1319-1330

Study type: Clinical trial
Study name: PSMAfore
Phase: Phase 3
Design: International, randomised, open-label trial (1:1) with crossover allowed
Sample size: 468 patients
Source: Ann Oncol · 2025
Trial registration: NCT04689828

In plain words

In men whose prostate cancer had grown after a newer hormone tablet and who had not yet had chemotherapy, lutetium-177-PSMA radioligand treatment kept the disease under control for longer. In the final analysis, there was no clear difference in how long the two groups lived (about 24 vs 23 months), probably because most patients in the comparison group later received the same treatment. Dry mouth was the most common side effect.

Key results

24.48 vs 23.13 months

Median overall survival (intention to treat)

HR 0.91 (0.72–1.14); P=0.20

0.59

Crossover-adjusted overall survival hazard ratio

0.38–0.91

141 of 234 patients (60.3%)

Crossover from the ARPI-change group

59.5%

Dry mouth with lutetium

Grade 3 or higher: 2 of 227

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

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

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 paper (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

Radiographic progression-free survival (primary), overall survival (key secondary) and safety.

Safety and side effects

Exposure-adjusted incidence of grade 3 or higher adverse events was 60.8 versus 85.1, and of serious adverse events 32.5 versus 49.9, per 100 patient-years of treatment. Dry mouth occurred in 59.5% and anaemia in 27.3% of the lutetium group.

Clinical significance and place in guidelines

Overall survival did not improve in the intention-to-treat analysis; the place of lutetium-177-PSMA-617 before a taxane therefore rests on the progression-free survival benefit and better safety. ESMO 2026 considers it a recommendable option for PSMA-positive patients after an ARPI who are not immediate candidates for docetaxel [I, B].

Limitations

The open-label design and extensive crossover make overall survival difficult to interpret; the comparator (ARPI change) is a treatment of low efficacy.

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.