{"entity":{"id":"opp-grpr-psma-negative-prostate","kind":"opportunity","name":"GRPR imaging when the PSMA scan is negative","aka":["GRPR PET","bombesin receptor imaging"],"tldr":"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.","summary":"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.\n\nGRPR 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.\n\nThat 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.","asOf":"2026-09-23","links":[{"label":"68Ga-RM2 phase 2/3, Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38423030/"},{"label":"68Ga-RM2 against PSMA tracers head to head, J Nucl Med 2021","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8612333/"},{"label":"177Lu-RM2 first-in-human dosimetry in PSMA-insufficient patients","url":"https://pubmed.ncbi.nlm.nih.gov/31482426/"},{"label":"NCT03872778: NeoRay, 177Lu-NeoB","url":"https://clinicaltrials.gov/study/NCT03872778"},{"label":"GRPR distribution in cancer, J Nucl Med 2020","url":"https://jnm.snmjournals.org/content/61/6/792"}],"tags":["unmet need first","prostate","PSMA-negative","second-look imaging"],"related":["ga-68","lu-177"],"indications":["prostate-mcrpc","prostate-bcr"],"sections":[],"technologies":["psma-pet","pet-ct","radioligand-therapy","peptide-drug-conjugate"],"targets":["grpr","psma"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"lens":"unmet-need-first","unmetNeed":"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.","useCase":"A prostate multidisciplinary team would order a GRPR scan as a second look after a negative or discordant PSMA PET in a man whose PSA says the disease is there, and as the selection test before GRPR-directed radioligand therapy in a patient who has exhausted PSMA-directed options.","hypothesis":"In the subgroup defined by a negative or low-uptake PSMA PET, GRPR imaging will identify disease that PSMA imaging missed at a rate high enough to change management, even though in unselected patients it detects fewer lesions than PSMA imaging does.","rationale":"GRPR overexpression has been reported in 63 to 100% of prostate cancers, and the receptor is inversely related to PSMA in part of the disease, which is why the first patients treated with 177Lu-RM2 were chosen for insufficient PSMA expression. The imaging agent has the largest dataset of any non-PSMA prostate tracer, including a completed phase 2/3 trial, and the therapeutic pair exists with a defined phase 2 dose. The lesion-level studies that look unfavourable to GRPR were all run in unselected patients, which is the wrong population for this hypothesis.","test":"A prospective study enrolling only men with a negative or equivocal PSMA PET and biochemical or clinical evidence of disease, imaging them with a GRPR tracer, with histology or subsequent conventional imaging as the truth standard, and reporting the proportion in whom a management-changing lesion was found. Enrolment on the PSMA-negative criterion is the whole design; the existing unselected head-to-heads have already answered the other question.","maturity":"being-tested-at-scale","verdict":"standalone-and-companion","mostAdvanced":"68Ga-RM2 for imaging, with a completed phase 2/3 trial (NCT02624518, 100 patients analysed) published in Lancet Oncology 2024; on the therapy side 177Lu-NeoB from Advanced Accelerator Applications, phase 1 complete in NeoRay (NCT03872778) with a maximum tolerated dose of 9.25 GBq.","dueDiligence":[{"domain":"target-biology","state":"strong","why":"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.","source":"Frontiers in Oncology 2023 review","url":"https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1199432/full","weighted":true},{"domain":"clinical-evidence","state":"strong","why":"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.","source":"Duan et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38423030/","weighted":true},{"domain":"diagnostic-performance","state":"moderate","why":"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.","source":"Baratto et al., J Nucl Med 2021","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8612333/","weighted":true},{"domain":"safety-dosimetry","state":"strong","why":"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.","source":"Kurth et al., EJNMMI 2020","url":"https://pubmed.ncbi.nlm.nih.gov/31482426/"},{"domain":"regulatory-path","state":"moderate","why":"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.","source":"FDA approval package, NETSPOT","url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208547Orig1s000Approv.pdf"}],"flags":[{"category":"technical","flag":"green","why":"Gallium-68 labelled antagonist peptides with same-day imaging and a published clean safety record; the chemistry is not the problem here."},{"category":"unmet-need","flag":"green","why":"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."},{"category":"ip","flag":"amber","why":"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."},{"category":"commercial","flag":"amber","why":"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."},{"category":"isotope","flag":"green","why":"Gallium-68 for imaging and lutetium-177 for therapy; both established supply chains."},{"category":"competition","flag":"amber","why":"Novartis through Advanced Accelerator Applications holds the most advanced therapy and its companion tracer, so the therapeutic pairing is largely taken."}],"competition":[{"name":"Stanford University","what":"68Ga-RM2, completed phase 2/3 imaging trial in biochemical recurrence, 100 patients analysed, published in Lancet Oncology 2024.","stage":"phase 2/3 complete","url":"https://clinicaltrials.gov/study/NCT02624518"},{"name":"Advanced Accelerator Applications (Novartis)","what":"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.","stage":"phase 1/2a","url":"https://clinicaltrials.gov/study/NCT03872778"},{"name":"Rostock University Medical Center","what":"177Lu-RM2 and 177Lu-AMTG first-in-human dosimetry, four patients treated after screening 35 with 68Ga-RM2 PET/CT.","stage":"first-in-human","url":"https://pubmed.ncbi.nlm.nih.gov/31482426/"}],"differentiation":"The percentage of PSMA-negative tumour area on immunohistochemistry is reported as an independent prognostic factor but is not a clinical decision tool, and no ctDNA or blood test identifies a GRPR-positive compartment. Imaging is the only way to establish target expression at every lesion at once, which is exactly what a patient with a discordant PSMA scan needs.","metrics":[{"label":"68Ga-RM2 PET-MRI positive rate against MRI alone in biochemical recurrence","value":"69% against 40% of 100 patients","source":"Duan et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38423030/"},{"label":"Extra lesions found by each tracer in 50 patients imaged with both","value":"PSMA 36 lesions in 13 patients; RM2 7 lesions in 4 patients","source":"Baratto et al., J Nucl Med 2021","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8612333/"},{"label":"Primary prostate cancers negative on PSMA PET despite high PSA","value":"around 10%","source":"Published review","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7255040/"},{"label":"Maximum tolerated dose of 177Lu-NeoB in phase 1","value":"9.25 GBq","source":"Phase 1 NeoRay report","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12866383/"}],"risks":["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."],"watch":["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."]},"route":"/opportunities/opp-grpr-psma-negative-prostate/","neighbours":{"isotope":[{"id":"ga-68","kind":"isotope","name":"Gallium-68","route":"/isotopes/ga-68/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}],"indication":[{"id":"prostate-bcr","kind":"indication","name":"Biochemical recurrence of prostate cancer","route":"/indications/prostate-bcr/"},{"id":"prostate-mcrpc","kind":"indication","name":"Metastatic castration-resistant prostate cancer","route":"/indications/prostate-mcrpc/"}],"technology":[{"id":"peptide-drug-conjugate","kind":"technology","name":"Peptide-drug & small-molecule-drug conjugates","route":"/technologies/peptide-drug-conjugate/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"},{"id":"psma-pet","kind":"technology","name":"PSMA PET","route":"/technologies/psma-pet/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"}],"target":[{"id":"grpr","kind":"target","name":"GRPR (gastrin-releasing peptide receptor)","route":"/targets/grpr/"},{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}]}}