EVOLUTION Trial Ipilimumab And Nivolumab Plus 177Lu‑PSMA‑617 in mCRPC

Phase II EVOLUTION is a randomized study testing whether adding ipilimumab and nivolumab to 177Lu‑PSMA‑617 improves outcomes versus 177Lu‑PSMA‑617 alone in men with metastatic castration‑resistant prostate cancer (mCRPC). Early data presented in 2025 indicate that at 12 months, 33% of patients on the combination were free of progression versus 17% on 177Lu‑PSMA‑617 alone, signaling a potentially meaningful benefit that warrants continued follow‑up.​

The therapeutic logic behind EVOLUTION is to transform a typically “immune‑cold” prostate cancer into an “immune‑responsive” disease by pairing targeted beta‑radiation from 177Lu‑PSMA‑617 with dual checkpoint blockade, thereby coupling immunogenic cell death and antigen release with CTLA‑4/PD‑1 pathway inhibition to amplify antitumor immunity. Radioligand therapy can modulate the tumor microenvironment, promote dendritic cell activation, and broaden T‑cell repertoires, while ipilimumab and nivolumab can sustain and expand these responses, a rationale supported by preclinical and early clinical observations across radiotherapy–ICI combinations and PSMA‑directed theranostics.​

The trial, led by ANZUP with national partners, closed to recruitment and enrolled 93 patients in Australia, with further follow‑up ongoing to assess durability, survival, and translational correlatives.​

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