Unfortunately, I can confidently say that none of these therapeutics will work for everyone with metastatic castration-resistant prostate cancer. Not surprisingly, approximately 15-25% of metastatic castration-resistant prostate cancer patients have tumors that do not significantly express PSMA. As a result, PSMA is not an ideal imaging or therapeutic target for such patients. The next obvious question is, “What is the molecular makeup of these non- or low-PSMA expressing tumors?” Some have likely undergone neuroendocrine transformation or are at least somewhere on the spectrum of a variant prostate cancer. It is also hypothesized that these might be biologically more aggressive prostate cancers.
Gastrin-releasing peptide receptor (GRPR) is a cell membrane receptor overexpressed in various cancers, including prostate cancer. GRPR is a G protein-coupled receptor that has a role in cell growth, proliferation, angiogenesis, and migration.2 The most well-recognized ligand of GRPR is bombesin, and when bombesin binds, both the PI3K/AKT and the MAPK signaling pathways are activated. In prostate cancer, the expression of GRPR has some slightly confusing results. For example, a positive correlation between GRPR expression and Gleason score has been reported.3 Another study found an inverse correlation between GRPR expression with Gleason score, PSA, and tumor size, implying a positive correlation with lower-risk tumors.4 A positive association between GRPR expression and relapse and more advanced-stage disease remains.5
The well-known heterogeneity of imaging and therapeutic targets in prostate cancer renders rationale to evaluate GRPR and PSMA PET imaging simultaneously. Several recent prospective, single-center trials compared 68Ga-PSMA-617 with 68Ga-RM2 (GRPR antagonist) PET/CT imaging before radical prostatectomy. They found PSMA PET imaging to have higher detection for higher-grade tumors, while GRPR PET imaging had higher detection for lower-grade tumors.6,7 For biochemically recurrent prostate cancer, a couple of studies point towards similar detection rates between 68Ga-RM2 compared with 68Ga-PSMA-11 or 18F-DCFPyL PET. However, distinct distributions were noted, emphasizing the heterogeneity of target expression.8,9
This expression heterogeneity lends some promise that GRPR expression may be upregulated in a subset of low or absent PSMA-expressing prostate cancers. The only way to confirm this hypothesis is to add to the small amount of clinical trial data that exists by performing more trials with men with metastatic castration-resistant prostate cancer, using both PSMA and GRPR imaging modalities simultaneously. Another approach is to target patients with known PSMA PET-negative metastases and image them with a GRPR-targeting complex. As we look forward to the next obvious step of GRPR-directed radioligand therapy, it becomes important to recognize one of the challenges of PSMA-directed radioligand therapy is the high expression of PSMA on salivary glands, leading to xerostomia as a key toxicity. Meanwhile, GRPR lacks expression on salivary and lacrimal glands, and imaging GRPR also offers low hepatobiliary radiotracer clearance as a couple of potential advantages moving forward.10
Please see below for some actively accruing trials focused on imaging GRPR in patients with prostate cancer. Many of the trials below are already performing imaging followed by a radioligand therapy complement for those patients with GRPR-expressing tumors. Although GRPR-targeted radioligand therapy may be complementary to PSMA-targeted agents, it would be even more exciting, and it could fulfill an unmet need if GRPR can be significantly identified. Therapeutic targeting can be efficacious in PSMA-low or -negative prostate cancer patients.
Clinical Trials Imaging GRPR in Patients with Prostate Cancer
• 64Cu-SAR Bobesin in PSMA negative prostate cancer (NCT05613842)
• COMBAT – 64Cu-SAR-BBN and 67Cu-SAR-BBN identification and treatment for castration-resistant prostate cancer patients ineligible for 177Lu-PSMA-617 (NCT05633160)
• NeoRay - 177Lu-NeoB in patients with advanced solid tumors with 68Ga-NeoB uptake (NCT03872778)
• 99mTc-RM26 for both prostate and breast cancer (NCT04746638)
• 212Pb-DOTAM-GRPR1 for patients recurrent or metastatic GRPR-expressing tumors (NCT03809013)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA
References:
- Sartor O, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med (2021) 385:1091-103.
- Baratto L, et al. Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors. Mol Imaging Biol (2018) 20:501-9.
- Beer M, et al. Profiling gastrin-releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. Prostate (2012): 72:318-25.
- Faviana P, et al. Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen? Front Oncol. (2021): 11: 650249.
- Schollhammer R, et al. Comparison of 68Ga-PSMA-617 PET/CT and 68Ga-RM2 PET/CT in Patients with Localized Prostate Cancer Who Are Candidates for Radical Prostatectomy: A Prospective, Single-Arm, Single-Center, Phase II Study. J Nucl Med 2023; 64:379-85.
- Gao X, et al. Eur J Nucl Med Mol Imaging 2023; 50:2177-87.
- Baratto L, et al. PSMA- and GRPR-Targeted PET: Results from 50 Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med 2021; 62:1545-9.
- Iagaru A, et al. J Clin Oncol 34, no. 2_suppl (January 10, 2016) 331-331.
- Iagaru A. J Nucl Med 2017; 58:1883-4.