key papersKey paper

PSMAfore: 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor in taxane-naive mCRPC

In men with advanced prostate cancer who had not yet had chemotherapy but whose disease had grown on one hormone-blocking drug, switching to the radioactive PSMA treatment kept the cancer under control for longer than switching to a different hormone drug.

PSMAfore was a phase 3, randomised, controlled, open-label trial at 74 sites in Europe and North America. Taxane-naive men with PSMA-positive metastatic castration-resistant prostate cancer who had progressed once on an androgen receptor pathway inhibitor (ARPI) were randomised 1:1 to 177Lu-PSMA-617 (7.4 GBq every 6 weeks for six cycles) or a change of ARPI (abiraterone or enzalutamide). Crossover to 177Lu-PSMA-617 was permitted after confirmed radiographic progression on ARPI change. The primary endpoint was radiographic progression-free survival (rPFS).

Of 468 randomised men, updated analysis (median follow-up ~24 months) showed median rPFS of 11.6 months with 177Lu-PSMA-617 versus 5.6 months with ARPI change (HR 0.49, 95% CI 0.39-0.61). The final overall survival analysis (Ann Oncol 2025) found no significant intention-to-treat difference (24.5 vs 23.1 months, HR 0.91, p=0.20), heavily confounded by a 60% crossover rate from the control arm; a crossover-adjusted analysis suggested benefit (HR 0.59). Grade 3+ and serious adverse events were less frequent with 177Lu-PSMA-617 than with ARPI change.

PSMAfore moved PSMA radioligand therapy earlier in the treatment sequence - before chemotherapy - and was the evidentiary basis, alongside VISION, for regulators to consider extending 177Lu-PSMA-617 use to the pre-taxane setting.

Randomised controlled trialChanged practice468 participants276 citations

Authors

Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, et al.

Published

Lancet, 2024

Full text

doi:10.1016/S0140-6736(24)01653-2 PubMed 39293462

Findings

Updated analysis: median rPFS 11.6 months (177Lu-PSMA-617) vs 5.6 months (ARPI change); HR 0.49 (95% CI 0.39-0.61).
Primary analysis: median rPFS 9.3 months vs 5.55 months; HR 0.41 (95% CI 0.29-0.56), p<0.0001.
Final overall survival (intention to treat): 24.48 vs 23.13 months, HR 0.91 (95% CI 0.72-1.14), p=0.20; crossover-adjusted HR 0.59 (95% CI 0.38-0.91).
60.3% of men assigned to ARPI change crossed over to 177Lu-PSMA-617 after progression.
Grade 3+ treatment-emergent adverse events: 60.8 per 100 patient-treatment years (177Lu-PSMA-617) vs 85.1 (ARPI change).

What it means

For men who still have a working hormone treatment option but whose cancer is progressing, offering the PSMA radioligand therapy sooner - before chemotherapy - delayed disease progression, though it did not clearly extend how long men lived once the very high rate of patients switching over is accounted for.

Caveats

Open-label design and high crossover from control to experimental arm make the overall-survival comparison unreliable by intention to treat.
Crossover-adjusted survival analyses rely on modelling assumptions rather than randomisation.
Trial excluded men who had already had a taxane, so results do not generalise to post-chemotherapy patients (that population is VISION and TheraP).