Phase 1 Trial: 177Lu-DGUL Plus Pembrolizumab (Keytruda) in mCRPC

A pivotal clinical trial is underway to evaluate the safety and efficacy of combining Lutetium (177Lu) DGUL radioligand therapy with pembrolizumab (Keytruda) for treating metastatic castration-resistant prostate cancer in patients who have progressed after androgen receptor-targeted therapies but have not yet received chemotherapy. The study enrolls men with prostate-specific membrane antigen (PSMA)-positive tumors, with disease progression confirmed by imaging and lab criteria. Participants receive either the radioligand alone administered four times at six-week intervals or the combination with pembrolizumab given up to 18 times on the same schedule.

Dubbed  KEYNOTE-G28, the trial launched as Korea’s first-ever radioligand-immunotherapy combo, pitting the duo against DGUL alone to gauge safety, tumor shrinkage, and survival gains.​

At its core, 177Lu-DGUL homes in on prostate-specific membrane antigen overexpressed on cancer cells, delivering targeted beta radiation to shred tumor DNA while sparing healthy tissue thanks to a compact thiourea linker that cuts kidney exposure compared to rivals like Pluvicto. this agent agent shone in phase 2 monotherapy, posting a 35.9% tumor response rate by standard scans and 81% by PET criteria, with nearly 9% complete remissions (numbers edging out Pluvicto’s VISION trial benchmarks). Pembrolizumab, the PD-1 blocker sold as Keytruda, unleashes T-cells against tumors but falters solo in prostate cancer, yielding just 5% responses in unselected patients; prior UCSF work with similar 177Lu-PSMA-617 showed a single radiation priming dose sparked 56% responses when followed by Keytruda maintenance.​

Safety drives primary goals via adverse event tracking and dose-limiting toxicities through six-month follow-up, while secondary measures span radiographic progression-free survival, one-year overall survival, PSA drops over 50%, quality-of-life scores via EORTC questionnaires, and detailed dosimetry of radiation uptake in tumors versus organs. Exclusions bar prior checkpoint inhibitors, active autoimmune issues, or brain metastases needing steroids.​

Radiation from lutetium-177 triggers immunogenic cell death, pumping out danger signals that rally immune cells and boost PD-L1, priming tumors for pembrolizumab’s T-cell boost, as validated in UCSF’s Lancet Oncology publication where sequential dosing beat concurrent use. DGUL, with its tumor-favoring biodistribution, may amplify this synergy while dodging Pluvicto’s salivary and kidney woes.

Clinical trial.