Diagnostic performance of gastrin-releasing peptide receptor-targeted positron-emission tomography in biochemically recurrent prostate cancer—a systematic review and meta-analysis
Original Article

Diagnostic performance of gastrin-releasing peptide receptor-targeted positron-emission tomography in biochemically recurrent prostate cancer—a systematic review and meta-analysis

Hexiao Huang1#, Yanyou Huang2#, Zhichao Xie1, Rong Tian1, Guohua Shen1

1Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, China; 2Department of Vascular Surgery, West China Hospital of Sichuan University, Chengdu, China

Contributions: (I) Conception and design: Y Huang, H Huang; (II) Administrative support: G Shen, R Tian; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Y Huang, H Huang, Z Xie; (V) Data analysis and interpretation: Y Huang, H Huang, Z Xie; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Guohua Shen, MD, PhD. Department of Nuclear Medicine, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, China. Email: shengh1990@126.com.

Background: Gastrin-releasing peptide receptor (GRPR)-targeting radiopharmaceuticals are being developed for diagnostic and therapeutic applications in prostate cancer. This systematic review and meta-analysis aimed to synthesize available evidence regarding the diagnostic performance of GRPR-targeted positron-emission tomography (PET) in biochemically recurrent prostate cancer.

Methods: A comprehensive literature search was performed using appropriate keywords search strings formulated with Boolean syntax in the PubMed, Embase and Cochrane Library. Articles related to GRPR-targeted PET in biochemically recurrent prostate cancer were included, covering publications available up to May 1, 2025. A meta-analysis with a random-effects model was used to estimate overall and subgroup-specific pooled detection rate (DR). The literature quality was determined by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. A sensitivity analysis using leave-one-out method was performed to evaluate the potential bias.

Results: Out of 469 articles, 212 underwent full-text screening and 6 articles with 278 patients were finally included. The overall DR of GRPR-targeted PET for biochemical recurrence (BCR) was 0.68 [95% confidence interval (CI): 0.6–0.75]. Four studies reported the pooled DRs stratified by serum prostate-specific antigen (PSA) levels: 0.38 (95% CI: 0.25–0.51) for PSA <0.5 ng/mL stratum, 0.69 (95% CI: 0.53–0.85) for PSA 0.5 to <1.0 ng/mL stratum, 0.61 (95% CI: 0.43–0.79) for PSA 1.0 to <2.0 ng/mL stratum, 0.75 (95% CI: 0.58–0.91) for PSA 2.0 to <5.0 ng/mL stratum, 0.72 (95% CI: 0.60–0.84) for PSA ≥5.0 ng/mL stratum, respectively.

Conclusions: In the present meta-analysis, GRPR-targeted PET has comparable and promising diagnostic utility for BCR of prostate cancer compared to prostate-specific membrane antigen (PSMA) and conventional imaging. Nevertheless, the limited sample sizes of existing studies warrant large-sample prospective trials comparing GRPR-targeted PET with first-line modalities to validate its clinical diagnostic and therapeutic value.

Keywords: Gastrin-releasing peptide receptor (GRPR); positron-emission tomography (PET); prostate cancer; biochemical recurrence (BCR)

Submitted Aug 20, 2025. Accepted for publication Nov 14, 2025. Published online Dec 31, 2025.

doi: 10.21037/qims-2025-1809

Introduction

Among men, prostate cancer is the most frequently diagnosed cancer in over 50% of countries worldwide (1), representing 15% of all cancer cases and ranking as the fifth leading cause of cancer-related mortality (2). After initial treatment with radical prostatectomy or radiotherapy, the risk of recurrence is over 50% in patients with the high disease risk features (1). According to the recommendations of the RTOG-ASTRO Phoenix Consensus Conference (2), biochemical recurrence (BCR) in prostate cancer is defined according to treatment modality: a postoperative status characterized by two consecutive prostate-specific antigen (PSA) values exceeding 0.2 ng/mL following radical prostatectomy, or a post-radiotherapy status requiring a PSA elevation ≥2 ng/mL above the nadir level after external beam radiation therapy (EBRT), regardless of concurrent hormonal therapy (3). For these BCR patients, early and accurate localization of recurrent sites is critical for guiding subsequent treatment and management.

Recently, prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) imaging has revolutionized prostate cancer diagnosis, targeted biopsy, staging, restaging, and treatment monitoring (4,5). Notably, this molecular imaging has demonstrated superior diagnostic performance for detecting recurrent disease, even at low PSA levels in which conventional imaging often yields false-negative results. In this context, PSMA PET has been increasingly incorporated into major clinical guidelines as a recommend imaging modality for the localizing BCR in prostate cancer (6,7). However, approximately 5–10% of prostate cancers (e.g., the ductal prostatic cancer) present with low PSMA expression and may be missed by single PSMA imaging, highlighting the necessity of complementary imaging targets (8,9).

Alternatively designated as bombesin receptor subtype 2, gastrin-releasing peptide receptor (GRPR) is a G protein-coupled receptor within the bombesin receptor family. This molecular target enables dual diagnostic-therapeutic applications through specifically engineered radioconjugates, which serve as precision tools for both PET imaging and targeted radionuclide therapy (10). Clinically significant GRPR overexpression has been documented across multiple malignancies, including breast, prostate, and gastrointestinal cancers (11,12). GRPR-targeted radiopharmaceuticals with different binding sites, including but not limited to [68Ga]Ga-SB3 (13,14), [68Ga]Ga-NeoB (15,16), [68Ga]Ga-RM2 (17-21), [68Ga]Ga-RM26 (22-24) and [64Cu]Cu-SAR-BBN (25,26), have indicated promising results in pilot studies, phase I, II or III clinical trials on prostate cancer (27).

While existing meta-analyses focused on GRPR-targeted PET applications in primary prostate cancer (28), a critical knowledge gap persists regarding its diagnostic utility in BCR of prostate cancer. Thus, we conducted this systematic review and meta-analysis to quantitatively evaluate the detection efficacy of GRPR-targeted PET in BCR patients, to establish evidence-based performance metrics for clinical deployment. We present this article in accordance with the PRISMA-DTA reporting checklist (29,30) (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1809/rc).

Methods

Search strategy

This meta-analysis has registered on PROSPERO (No. CRD420251063695). The PubMed, Embase, and Cochrane Library databases were the bibliographic databases to a comprehensive literature search related to the review question, covering publications available up to May 1, 2025. Search terms and keywords were as follow: (“Gastrin-Releasing Peptide Receptor” OR “GRPR” OR “bombesin”) AND (“Positron-Emission Tomography” OR “PET”) AND (“Prostatic Neoplasms” OR “Prostate Cancer” OR “Prostate Tumor” OR “Prostate Carcinoma” OR “Prostatic Adenocarcinoma” OR “Prostate Malignancy” OR “Prostate Neoplasia” OR “PCa”). Two reviewers independently carried out the screening of titles and abstracts, and a thorough screening of the full texts for potential eligibility. Discrepancies were resolved by a third reviewer, based on a consensus majority rule.

Screening and selection

Original publications regarding GRPR-targeted PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) in patients with BCR of prostate cancer were included. Eligible publications dated through May 1, 2025 were considered, with no limitations imposed on publication year or country. Exclusion criteria comprised: (I) irrelevant to the research focus; (II) secondary publications including reviews, meta-analyses, editorials, comments, letters, news and conference proceedings; (III) case reports or small case series (<5 recurrent prostate cancer cases); (IV) overlapping populations; (V) non-English articles.

Data extraction and quality assessment

The following data from included studies was independently extracted into a standard form by two reviewers: (I) study characteristics (authors, year of publication, country, study design, sample size); (II) patients characteristics (inclusion and exclusion criteria, mean age, Gleason scores, serum PSA levels, follow-up time); (III) imaging protocol details (radiotracer name, administered activity); (IV) overall diagnostic performance of GRPR-targeted PET, PSA-stratified detection rates (DRs) (PSA levels: <0.5, 0.5 to <1.0, 1.0 to <2.0, 2.0 to <5.0, and ≥5.0 ng/mL), and DRs of PSMA-targeted PET and multiparametric MRI (mpMRI) as comparison; (V) other information (PET-positive lesion criteria, standardized uptake value (SUV), reference standard for lesion validation, metastatic patterns). Any disagreements were resolved by a third reviewer.

Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the overall quality of studies by two reviewers (31). This tool comprises four domains: patient selection, index test, reference standard, and flow and timing. All domains are assessed for risk of bias, while the first three domains are also evaluated for applicability concerns.

Statistical analysis

All statistical analyses were performed using STATA 18.0 (Stata Corp, College Station, Texas, USA, 2023) in this study. Heterogeneity was assessed using Cochran’s Q test and the I2 statistic, with significant heterogeneity defined as a P value <0.05 for the Q test and an I2>50% (32,33). Pooled estimates of diagnostic sensitivity and specificity, along with their 95% confidence intervals (CIs), were visualized using forest plots based on a random-effects model. The same model was applied to generate subgroup forest plots stratified by PSA levels. Additionally, Deek’s funnel plots were created to assess potential publication bias (34).

Results

Study characteristics

A total of 469 articles were identified after initial search, including 78 from PubMed, 384 from Embase, and 7 from Cochrane Library. After rigorous screening, six articles comprising 278 patients were included in the final meta-analysis (Figure 1) (16,18,26,35-37). All these 6 studies are prospective, including 4 monocentric studies (16,18,26,37) and 2 multicentric studies (35,36). Regarding radiotracers, [68Ga]Ga-RM2 was employed in 4 studies (18,35-37), [68Ga]Ga-NeoB in 1 study (16) and [64Cu]Cu-SAR-BBN in 1 study (26). In addition to GRPR-targeted tracers, 4 studies employed PSMA-targeted tracers for comparison {[68Ga]Ga-PSMA-11 (35,36), [68Ga]Ga-PSMA-R2 (16) and [18F]DCFPyL (35)}. The characteristics of the included articles are detailed in Table 1.

Figure 1 PRISMA flowchart of the study selection process.

Table 1

Characteristics of included studies

Authors Year Country Study design Sample size Age (years) Baseline PSA (ng/mL) Follow-up time (month) Scanner modality GRPR radiotracer Dose of radiotracer Uptake time (min) Other radiotracers for comparison Interval between different radiotracers (d) Criteria for PET-positive lesion Lesion validation
Duan et al. (18) 2024 USA P mono 100 69 [63–73]‡ 1.41 [0.46–5.13]‡ 49.3 [36.7–59.2]‡ PET/MRI [68Ga]Ga-RM2 140.6 [137.7–144.3] MBq‡ 47 [45–52]‡ NA NA mPROMISE Composited reference standard
Ghezzo et al. (36) 2023 Italy P multi 44 70.1 [62.8–74.6]‡ 0.54 [0.38–2.18]‡ 22.8 [16.8–29.1]‡ PET/MRI [68Ga]Ga-RM2 2.00±0.31 MBq/kg† 51±12† [68Ga]Ga-PSMA-11 2 [2–16]‡ Focal uptake above background Composited reference standard
Duan et al. (16) 2024 USA P mono 27 67.8±8.8 [49.0–82.0]† 3.5±3.9 [0.3–13.5]† 24.8±3.9 [17.2–31.7]† PET/MRI [68Ga]Ga-NeoB 198.1±25.5 [145.1–245.6] MBq† 49.7±7.2 [43–77]† [68Ga]Ga-PSMA-R2 11.0±15.2 [1–72]† Focal uptake above background Composited reference standard
Baratto et al. (35) 2021 USA P multi 50 64.9±7 [52.0–81.0]† 4.2±5 [0.1–21.5]† NA PET/MRI [68Ga]Ga-RM2 114.3±7.4 [111–155.4] MBq† 52.7±11 [39–100]† [68Ga]Ga-PSMA-11, [18F]DCFPyL 15.8±17.7 [1–60]† Focal uptake above background NR
Minamimoto et al. (37) 2017 USA P mono 32 68.7±6.4 [59.0–83.0]† 10.1±21.3 [0.3–119.0]† 17.1±5.2 [3–25]† PET/MRI [68Ga]Ga-RM2 140.6±7.4 [133.2–151.7] MBq† 50.5±6.8 [40–69]† NA NA Focal uptake above background NR
Li et al. (26) 2024 Australia P mono 25 69 [62–76]‡ 0.69 [0.28–2.45]‡ 10 [9–12]‡ PET/CT [64Cu]Cu-SAR-BBN 200 MBq† 61 [60–67]‡ [68Ga]Ga-PSMA-11 34 [21–77]‡ Focal uptake above background Composited reference standard

†, data presented with mean ± standard deviation [range]; ‡, data presented with median [interquartile range]. Composited reference standard, histopathology, follow-up imaging and PSA response. CT, computed tomography; GRPR, gastrin-releasing peptide receptor; mPROMISE, modified Prostate Cancer Molecular Imaging Standardized Evaluation; mono, monocentric; MRI, magnetic resonance imaging; multi, multicentric; NA, not available; NR, not reported; P, prospective; PET, positron-emission tomography; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen.

Quality assessment

The results of quality assessment were presented in Figure 2 and Figure S1. In one investigation (35), the risk of bias was deemed unclear for two domains: (I) patient selection, due to unreported inclusion/exclusion criteria; and (II) index test, as the authors did not confirm whether PET imaging interpretation was performed blinded to the reference standard results. Two studies (35,37) had unclear risk of bias for reference standard and flow and timing because the reference standard was not reported in their studies. In all studies, there was a low concern for applicability for patient selection and index test. However, regarding applicability for reference standard, 2 studies (35,37) had unclear concerns as no reference standard was mentioned.

Figure 2 QUADAS-2 assessment of included studies for risk of bias and applicability concerns. QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies-2.

Overall DR and subgroup analyses

Across 6 included studies, GRPR-targeted PET demonstrated a pooled DR of 0.68 (95% CI: 0.61–0.75; range, 0.44–0.75) for recurrent prostate cancer (Figure 3). For patients with PSA <0.5 ng/mL, the pooled DR was 0.38 (95% CI: 0.25–0.51), which increased to 0.69 (95% CI: 0.53–0.85), 0.61 (95% CI: 0.43–0.79), 0.75 (95% CI: 0.58–0.91), and 0.72 (95% CI: 0.60–0.84) for 0.5 to <1.0, 1.0 to <2.0, 2.0 to <5.0 and ≥5.0 ng/mL PSA subgroups, respectively (Figure 4; Figure S2).

Figure 3 Forest plot showing the overall pooled DR of GRPR-targeted PET in BCR of prostate cancer. BCR, biochemical recurrence; CI, confidence interval; DR, detection rate; GRPR, gastrin-releasing peptide receptor; PET, positron-emission tomography.
Figure 4 Bar chart showing DRs of overall and subgroup stratified by serum PSA levels (ng/mL). DR, detection rate; PSA, prostate-specific antigen.

Comparison of GRPR and PSMA/mpMRI

Across 3 comparative studies (16,35,36), the pooled DRs for GRPR- and PSMA-targeted PET were 0.71 (95% CI: 0.63–0.79) and 0.72 (95% CI: 0.60–0.84), respectively (Figure 5). In 2 head-to-head studies for GRPR-targeted PET comparing with mpMRI (18,37), GRPR-targeted PET demonstrated higher pooled DR compared to mpMRI: 0.70 (95% CI: 0.62–0.78) versus 0.39 (95% CI: 0.31–0.48), respectively (Figure 5).

Figure 5 Forest plots showing comparison of GRPR and PSMA, and GRPR and mpMRI. (A) DR of GRPR-targeted PET comparing with PSMA; (B) DR of GRPR-targeted PET comparing with mpMRI; (C) DR of PSMA-targeted PET; (D) DR of mpMRI. CI, confidence interval; DR, detection rate; GRPR, gastrin-releasing peptide receptor; mpMRI, multiparametric magnetic resonance imaging; PET, positron-emission tomography; PSMA, prostate-specific membrane antigen.

Heterogeneity and publication bias

No significant heterogeneity (I2=32.14%, Cochran’s Q 7.37, P=0.19) was observed for the overall pooled DR. Subgroup analyses of pooled DRs stratified by serum PSA levels demonstrated no significant statistical heterogeneity. In addition, Deek’s funnel plot asymmetry tests revealed no evidence of publication bias in the overall analysis or PSA-stratified subgroups (Figure 6; Figure S3).

Figure 6 Publication bias assessment using Deek’s funnel plot. CI, confidence interval.

Discussion

Despite significant preclinical progress in developing GRPR-targeted radiopharmaceuticals for prostate cancer, their clinical translation remains limited. This translational gap largely results from on-target toxicity associated with GRPR agonists, causing dose-limiting gastrointestinal adverse events like nausea and diarrhea (38,39). However, next-generation GRPR antagonists {e.g., [68Ga]Ga-RM2, [68Ga]Ga-NeoB} circumvent these toxicity issues and demonstrate promising diagnostic performance (40). In addition, recent advancements reported the easy formulation in cold kits for radiolabeling at room temperature, such as [68Ga]Ga-labeled GRPR antagonists with Dar derivatives or NOTA as chelating agents demonstrating high radiochemical purity and stability, providing the possibility of the widespread use of GRPR-targeted radiopharmaceuticals (41,42). This meta-analysis therefore aims to comprehensively evaluate the diagnostic utility of GRPR antagonist PET imaging specifically for detecting BCR of prostate cancer.

In this meta-analysis, GRPR-targeted PET achieved a pooled DR of 0.68 (95% CI: 0.61–0.75) for biochemically recurrent prostate cancer, indicating this new method may offer superior diagnostic accuracy compared to conventional imaging modalities and potentially rival the performance of currently prevalent PSMA-targeted PET approaches. Head-to-head comparisons across 3 studies (16,35,36) reported comparable DRs of GRPR- and PSMA-targeted PET [0.71 (95% CI: 0.63–0.79) and 0.72 (95% CI: 0.60–0.84), respectively], indicating GRPR may provide complementary value to existing PSMA-based imaging approaches. According to clinical studies on PSMA, up to 10% of prostate cancer lack PSMA expression (9,43,44), indicating that a single radiotracer is insufficient to ensure comprehensive detection of prostate cancer. This inherent limitation may account for the observed potential of GRPR in the included studies to serve as an alternative radiotracer. In addition, in comparison to mpMRI, GRPR-targeted PET demonstrated better performance on both lesion-based detection (143 vs. 96 positive lesions) and patient-based detection [0.70 (95% CI: 0.62–0.78) vs. 0.39 (95% CI: 0.31–0.48)] (18,37), highlighting its exceptional potential with higher DR of metastases of prostate cancer. What is more, radiotracer uptake or activity is not limited by anatomical contrast, making PET more sensitive to small lesion in prostate cancer (45).

Regarding subgroup analysis stratified by serum PSA levels, the pooled DR of GRPR-targeted PET improved from 0.38 (95% CI: 0.25–0.51) for PSA <0.5 ng/mL to 0.69 (95% CI: 0.53–0.85) for PSA 0.5 to <1.0 ng/mL, and varied between 0.61 (95% CI: 0.43–0.79) and 0.75 (95% CI: 0.58–0.91) for PSA ≥0.5 ng/mL, indicating GRPR-targeted PET probably has better diagnostic performance in patients with higher serum PSA levels and a plateau may be evident when PSA exceeds a certain value. Given that low PSA concentration often correlate with small tumor burden (46), GRPR expression may be too minimal for reliable detection in patients PSA <0.5 ng/mL. The DRs plateaued when PSA ≥0.5 ng/mL in this meta-analysis. However, Fendler et al. (47) reported a single-arm clinical trial that DRs of [68Ga]Ga-PSMA-11-targeted PET in prostate cancer with BCR increased from 0.57 for PSA 0.5 to <1.0 ng/mL to 0.97 for PSA ≥5.0 ng/mL. Similarly, Chandekar et al. (48) conducted a meta-analysis of rhPSMA-targeted PET in BCR of prostate cancer showing the DRs rose from 0.80 for PSA 0.5 to <1.0 ng/mL to 0.95 for PSA ≥2.0 ng/mL. The cause of this discrepancy probably stems from the fact that GRPR expression in prostate tumor cells appears to be independent of PSMA expression (49), indicating that GRPR-targeted PET imaging may provide complementary value to PSMA. However, more future clinical trials are warranted to confirm this relationship and explore its underlying mechanisms.

In two of the included studies (35,37), an “unclear concern” regarding the reference standard was identified due to insufficient reporting of its application. This lack of clarity prevents definitive exclusion of potential bias, which may consequently weaken the overall strength of the evidence. Moreover, the inclusion of heterogeneous radiotracers across studies may further compromise the reliability of the findings. To assess the robustness of our meta-analysis findings against this potential bias, a sensitivity analysis was performed using the leave-one-out method. Recalculation of the pooled DRs demonstrated that the results were minimally influenced by studies with potential bias risks and remained statistically significant (P<0.01) (Figure S4). In the setting of biochemically recurrent prostate cancer, the absence of a globally accepted composite reference standard for diagnosis may lead to divergent interpretations Future studies should adhere more rigorously to established reporting guidelines to improve the transparency and completeness of research documentation.

There are several limitations of this study. Firstly, the number of studies on GRPR-targeted PET in BCR of prostate cancer is limited for inclusion. Secondly, although the pooled analysis did not demonstrate any significant heterogeneity, the differences in the study design, radiotracers, and reference standards might be the potential sources of heterogeneity. Notably, among most included studies, composite reference standard was used to validate the PET imaging findings, including histopathology, follow-up imaging findings, or post-treatment serum PSA response. Finally, although all the radiopharmaceuticals included in our meta-analysis are all from GRPR family, the clinical performance differences still exist. More future comparative studies are required to systematically elucidate the radiopharmaceutical variations in pharmacokinetics, targeting specificity, and radiation dosimetry.

Conclusions

In the present meta-analysis, GRPR-targeted PET showed comparable diagnostic performance to PSMA and better than conventional imaging in patients with BCR of prostate cancer. Further large-sample prospective trials comparing GRPR-targeted PET against first-line methods are required to define its clinical value in diagnostic accuracy and clarify its role in the current diagnostic or therapeutic algorithm in BCR.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-DTA reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1809/rc

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1809/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Huang H, Huang Y, Xie Z, Tian R, Shen G. Diagnostic performance of gastrin-releasing peptide receptor-targeted positron-emission tomography in biochemically recurrent prostate cancer—a systematic review and meta-analysis. Quant Imaging Med Surg 2026;16(1):11. doi: 10.21037/qims-2025-1809

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