GRPR imaging when the PSMA scan is negative
Prostate cancer imaging and treatment both rely on one protein, PSMA. In a minority of men the tumour does not carry it, and for those men a negative scan is a dead end. A second receptor, GRPR, is the best-studied alternative, and the honest reading of the head-to-head studies is that it finds fewer lesions overall but different ones.
Overview
PSMA has become the single axis of prostate cancer molecular imaging and radioligand therapy, which means the patient whose tumour does not express it has nowhere to go. The published estimates of how large that group is vary by how it is measured: around 5 to 10% of primary tumours are PSMA-negative on immunohistochemistry and around 10% are negative on PSMA PET despite a high PSA, while a commentary puts the figure at 15 to 25% of metastatic castration-resistant patients whose tumours do not significantly express PSMA.
GRPR is the most clinically mature alternative. 68Ga-RM2 has a completed phase 2/3 imaging trial published in Lancet Oncology in 2024: of 209 men screened, 100 were analysed, and RM2 PET-MRI was positive in 69% against 40% for MRI alone, with no grade 1 or worse events. But the head-to-head studies are not a story of superiority. At Stanford, in 50 patients imaged with both, PSMA-directed tracers found 36 extra lesions in 13 patients while RM2 found 7 extra in 4 patients. In a Chilean mCRPC cohort of 17 patients referred for radioligand therapy, PSMA detected 23% more lesions, though in 4 of 17 the two distributions were comparable. A Bordeaux study found the two discordant in 18.8% of lesions, with RM2 better at low-ISUP tumours and PSMA better at clinically significant ones.
That is the shape of the real opportunity: not a replacement for PSMA PET but a second-look agent for the specific patient in whom PSMA imaging has failed, and a selection test for GRPR-directed therapy. 177Lu-NeoB from Advanced Accelerator Applications has completed phase 1 in NeoRay with a maximum tolerated dose of 9.25 GBq in 17 patients, and 177Lu-RM2 has first-in-human dosimetry in 4 mCRPC patients selected precisely because they had insufficient PSMA expression.
When a man with clinically obvious prostate cancer has a negative or low-uptake PSMA PET, nothing tells his clinician whether the disease is genuinely small-volume, PSMA-negative but targetable through another receptor, or dedifferentiated and beyond either.
- In unselected patients GRPR imaging detects fewer lesions than PSMA imaging, so the agent only makes sense in a narrow, test-defined subgroup and must be trialled that way.
- There is no agreed definition of a PSMA-negative scan, so the enrolment criterion for the pivotal study has to be constructed before the study can run.
- The most advanced therapeutic pairing sits inside Novartis, which limits partnering options for an independent imaging agent.
- Any trial that enrols on PSMA-negativity rather than on known measurable disease, which would be the first real test of this hypothesis.
- Phase 2a efficacy from NeoRay in the prostate cohort, which determines whether a companion diagnostic has a therapy to serve.
- Whether the 15 to 25% mCRPC figure is ever established by a primary dataset rather than commentary; the size of the opportunity turns on it.
The five domains of a radiopharmaceutical due-diligence review, adapted from the Fryback-Thornbury hierarchy of diagnostic efficacy. Each carries the state of the public evidence and the fact behind it, not a score out of five: a single total hides the reason and stops telling candidates apart. Domains marked as carrying most weight are the ones that decide the case at this asset's stage.
GRPR overexpression has been reported in 63 to 100% of prostate cancers, and preclinical work found high 177Lu-NeoB binding in PSMA-negative castration-resistant samples, which is the inverse relationship the whole case depends on.
A completed phase 2/3 imaging trial of 100 analysed patients published in Lancet Oncology, plus three published head-to-head comparisons against PSMA tracers and a phase 1 therapy dataset.
68Ga-RM2 PET-MRI was positive in 69% of patients against 40% for MRI alone, but against PSMA tracers it detected fewer lesions: 7 extra in 4 patients versus 36 extra in 13 patients across 50 men imaged with both.
No grade 1 or worse events were reported in the 100-patient imaging trial; on the therapy side mean absorbed dose was 1.08 plus or minus 0.44 Gy/GBq in the pancreas and 6.20 plus or minus 3.00 Gy/GBq in tumour lesions, with no side effects observed in four treated patients.
Receptor-targeted PET has an accepted non-inferiority route: NETSPOT was approved in June 2016 on non-inferiority of performance characteristics against OctreoScan, without an advisory committee. No GRPR imaging agent has been filed anywhere.
Red, amber or green on each review category, each with its reason, so an obvious no-go takes seconds rather than a meeting.
Gallium-68 labelled antagonist peptides with same-day imaging and a published clean safety record; the chemistry is not the problem here.
A PSMA-negative scan currently ends the pathway, and the population is somewhere between 10% on PET and a reported 15 to 25% of metastatic castration-resistant disease.
RM2 originated at Bayer and is developed academically at Stanford; NeoB belongs to Advanced Accelerator Applications; a new entrant would need its own antagonist scaffold.
Standalone as a second-look scan and a companion for GRPR therapy, but the addressable group is defined by another test's failure, which makes volume a function of PSMA PET throughput.
Gallium-68 for imaging and lutetium-177 for therapy; both established supply chains.
Novartis through Advanced Accelerator Applications holds the most advanced therapy and its companion tracer, so the therapeutic pairing is largely taken.
- Stanford Universityphase 2/3 complete
68Ga-RM2, completed phase 2/3 imaging trial in biochemical recurrence, 100 patients analysed, published in Lancet Oncology 2024.
https://clinicaltrials.gov/study/NCT02624518 - Advanced Accelerator Applications (Novartis)phase 1/2a
177Lu-NeoB with its 68Ga-NeoB companion; NeoRay phase 1 complete, maximum tolerated dose 9.25 GBq, 35-patient target enrolment across 18 sites in 6 countries.
https://clinicaltrials.gov/study/NCT03872778 - Rostock University Medical Centerfirst-in-human
177Lu-RM2 and 177Lu-AMTG first-in-human dosimetry, four patients treated after screening 35 with 68Ga-RM2 PET/CT.
https://pubmed.ncbi.nlm.nih.gov/31482426/
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