Phase 2/3 Trial For 68Ga-DOTA-RM2: GRPR-Targeted PET Could Open the Door to a New Theranostic Platform

PSMA has transformed prostate cancer imaging and radioligand therapy, but it is not the only useful target on prostate cancer cells. A new pivotal trial, SPARROW, is now testing 68Ga-DOTA-RM2, a PET tracer that targets the gastrin-releasing peptide receptor, or GRPR, in men with prostate cancer.

The study is designed to determine how accurately GRPR-PET can detect disease compared with pathology. The phase 2 portion will optimise imaging conditions, while the larger phase 3 portion will enrol around 400 men with high-risk or suspected metastatic prostate cancer who are undergoing prostatectomy and pelvic lymph-node dissection. This allows the PET findings to be checked directly against tissue removed at surgery.

The important point is that GRPR is a different biological target from PSMA. That could make GRPR-PET useful in tumours where PSMA expression is low, heterogeneous or otherwise suboptimal. Rather than replacing PSMA-PET, the more realistic possibility is that GRPR could become a complementary imaging target.

But the bigger story may be the ligand itself. RM2 is a DOTA-based GRPR-targeting molecule, and DOTA can bind different radiometals. In imaging, RM2 is labelled with gallium-68, but the same targeting concept has already been tested with lutetium-177, turning the molecule from an imaging tracer into a therapeutic radioligand.
That is the basis of a theranostic strategy: first use PET to identify patients whose tumours express the target, then use the same or a closely related ligand to deliver a therapeutic isotope directly to those cancer cells. This is essentially the same logic that helped PSMA evolve from an imaging target into a treatment platform.
Small human studies with 177Lu-RM2 have already shown that GRPR-positive prostate cancer lesions can receive potentially therapeutic radiation doses. Other GRPR ligands are also being developed to improve stability and tumour retention, suggesting that the field is already looking beyond imaging alone.

There are important caveats, changing the isotope also changes dosimetry, safety and pharmacology, so the transition from PET tracer to radioligand therapy still requires proper clinical development.
Still, if GRPR-PET performs well, the implications could go beyond better imaging.

Clinical trial.