Lutetium and Immunotherapy Combination Produced a Strong Response in Prostate Cancer
In this article
The Lancet Oncology (April 2026). doi: 10.1016/S1470-2045(26)00000-X
Synergy Between Radiation and Immunotherapy: Can combining radioligand therapy with immune checkpoint inhibitors turn “cold” tumors “hot” in metastatic castration-resistant prostate cancer (mCRPC)? The Australian PRINCE study showed that supporting the immunogenic cell death triggered by LuPSMA-617 with pembrolizumab provided promising clinical activity. The response rates achieved, particularly in patients with high PSMA expression, open a new window for immunotherapy in prostate cancer.
The PRINCE Study: Design and Methods
This phase 1b/2 study assessed the combination's safety and efficacy in patients with mCRPC who had received androgen receptor pathway therapy and had high PSMA expression.
- 37 eligible patients with mCRPC (median age: 72).
- 73% of patients had previously received docetaxel.
- High PSMA expression was required in all patients.
- LuPSMA-617: Every 6 weeks, for a maximum of 6 cycles.
- Pembrolizumab: Every 3 weeks, 200 mg (for up to 24 months).
- Co-administration (combination).
- Primary efficacy endpoint: 50% PSA Response Rate.
- Secondary: rPFS, OS, and safety profile.
- Objective response rates (RECIST).
Clinical Analysis and Safety
The combination therapy was consistent with the expected adverse-event profile and showed manageable toxicity.
✅ EFFICACY SUMMARY
A reduction in PSA greater than 90% was observed in 17 patients (46%). These data suggest that the combination may offer more durable responses than studies of LuPSMA alone or pembrolizumab alone, in historical comparisons.
⚠️ SAFETY AND ADVERSE EVENTS
Grade 3 treatment-related adverse events occurred in 35% of patients (increased serum amylase, colitis, and fatigue were most frequent, at 5%). Immune-related adverse events (irAEs) were identified in 30%; these included one case each of rare but serious conditions such as pneumonitis, type 1 diabetes, and myasthenia gravis. No grade 4 or 5 events were observed.
🎓 DROZDOGAN Academy — Commentary and Discussion
Why Does It Matter?
Prostate cancer is traditionally an “immunologically cold” tumor, and PD-1 inhibitors alone have shown limited success in this disease. The core hypothesis of PRINCE is that antigens released as radioligand therapy (LuPSMA) kills tumor cells “train” the immune system for pembrolizumab. The PSA50 response rate of 76% proves that this synergy is real.
Strengths
The long median follow-up of 30 months suggests that responses may be not only deep but also durable. An rPFS exceeding 11 months is particularly notable for a population with advanced mCRPC.
Limitations
The study was single-arm and conducted in a small population. LuPSMA is already known to be a very potent agent; therefore, randomized phase 3 studies, such as EVOLUTION, are needed to clarify exactly how much of the added survival benefit comes from pembrolizumab.
Scientific Sources
- Sandhu S, et al. Lutetium-177–labeled PSMA-617 plus pembrolizumab in mCRPC (PRINCE). The Lancet Oncology 2026.
- Stenger M. LuPSMA-617 and Pembrolizumab in mCRPC. The ASCO Post, April 2026.
This technical review has been updated using current clinical data and institutional announcements, with data as of 16 April 2026.
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