# Adding a checkpoint inhibitor to PSMA radioligand therapy

Source: https://nuclide.cc/ideas/idea-rlt-plus-checkpoint-inhibitor/  
Nuclide record `idea-rlt-plus-checkpoint-inhibitor` (Idea). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

Radiation from a targeted radioactive treatment can spill tumour debris that alerts the immune system. Giving an immunotherapy drug at the same time, to stop the immune system being switched off, is being tested to see if it makes the radioactive treatment work better.

## Summary

Radiation-induced cell death can expose tumour antigens and trigger immune responses, but immune checkpoints such as PD-1 can suppress that response. The PRINCE trial (NCT03658447, Peter MacCallum Cancer Centre) tested whether adding the PD-1 inhibitor pembrolizumab to 177Lu-PSMA-617 could improve outcomes in metastatic castration-resistant prostate cancer, a disease in which checkpoint inhibitors alone have limited activity. In this single-arm phase 1b/2 study of 37 patients, up to six cycles of 177Lu-PSMA-617 were given with pembrolizumab every three weeks for up to 24 months. The trial reported a PSA50 response rate of 76% and PSA90 of 46%, notably higher than the roughly 46% (VISION) and 66% (TheraP) PSA50 rates reported with 177Lu-PSMA-617 alone in other trials, and median radiographic progression-free survival of 11.2 months with median overall survival of 17.8 months.

The combination was not free of added toxicity: 35% of patients experienced grade 3 treatment-related adverse events, including grade 3 immune-related events in 30% of patients (colitis, myasthenia gravis, acute kidney injury, oral mucositis among them), and 14% of patients discontinued pembrolizumab because of immune-related toxicity, though all patients were able to continue 177Lu-PSMA-617. Because PRINCE was single-arm with no concurrent comparator, the reported PSA response rates cannot be directly attributed to the addition of pembrolizumab rather than to differences in patient selection between trials. A second combination trial, testing the CTLA-4-directed antibody ONC-392 alongside 177Lu-PSMA-617 (NCT05682443), is exploring an alternative checkpoint target in the same disease setting.

## Fields

- Kind: Idea
- Last checked: 2026-09-22
- Tags: combination therapy; immunotherapy; prostate
- Hypothesis: Combining lutetium-177-PSMA-617 with the PD-1 inhibitor pembrolizumab will produce a higher PSA response rate in metastatic castration-resistant prostate cancer than radioligand therapy alone, by exposing radiation-released tumour antigens to an immune system no longer blocked by PD-1 signalling.
- Rationale: The single-arm PRINCE trial (37 patients) reported a PSA50 response rate of 76% and PSA90 of 46%, higher than the 46% (VISION) and 66% (TheraP) PSA50 rates reported for 177Lu-PSMA-617 monotherapy in other trials, but with no concurrent comparator arm the apparent improvement could reflect differences in patient selection rather than a true treatment effect. The trial also documented a meaningful immune-related toxicity burden, with 30% of patients experiencing grade 3 immune-related adverse events and 14% discontinuing pembrolizumab.
- Proposed test: A randomised phase 2 or 3 trial directly comparing 177Lu-PSMA-617 plus pembrolizumab against 177Lu-PSMA-617 alone in PSMA-positive metastatic castration-resistant prostate cancer, powered on PSA50 response rate or radiographic progression-free survival, roughly 150-250 patients, to confirm or refute the single-arm PRINCE signal and quantify the added immune-related toxicity against any efficacy gain.
- Maturity: early-clinical
- Actor: research

## Sources

- 177Lu-PSMA-617 in combination with pembrolizumab for treatment of mCRPC (PRINCE): phase 1b/2 study (PubMed, 2026): https://pubmed.ncbi.nlm.nih.gov/41926961/
- PRINCE trial 12-month follow-up results (ASCO abstract, 2025): https://www.asco.org/abstracts-presentations/ABSTRACT383277
- Lu-PSMA-617/Pembrolizumab Shows Early Efficacy in Metastatic CRPC (Cancer Network, summary of Lancet Oncology publication): https://www.cancernetwork.com/view/lu-psma-617-pembrolizumab-shows-early-efficacy-in-metastatic-crpc
- PRINCE study (ClinicalTrials.gov, NCT03658447): https://clinicaltrials.gov/study/NCT03658447

## Connected records

- drugs: [Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/), [Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/)
- people: [Shahneen Sandhu](https://nuclide.cc/people/sandhu-shahneen/)
- indications: [Metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-mcrpc/)
- trials: [TheraP (ANZUP 1603)](https://nuclide.cc/trials/therap/), [VISION](https://nuclide.cc/trials/vision/)
- isotopes: [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)

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