Diagnostic Accuracy of Fully Hybrid PET/MRI with [ 68 Ga]Ga-PSMA-11 and [ 68 Ga]Ga-RM2 in Detecting Primary Prostate Cancer: A Phase 2 Trial with Histology as Gold Standard

The primary aim of this study was to compare the diagnostic accuracy of [⁶⁸Ga]Ga-PSMA-11 PET, [⁶⁸Ga]Ga-RM2 PET, and multiparametric MRI (mpMRI) for the detection of primary prostate cancer (PCa) using histopathology as the reference. The secondary aims of the study were to assess the agreement among imaging modalities and identify noninvasive biomarkers for the diagnosis and risk stratification of patients. Methods: Forty-two patients with biopsy-confirmed, high-risk PCa were enrolled in this single-center, prospective, phase 2 clinical trial between September 2020 and May 2023 at San Raffaele hospital. All patients underwent [⁶⁸Ga]Ga-PSMA-11 PET/MRI with mpMRI, and 36 had additional imaging with [⁶⁸Ga]Ga-RM2 PET/MRI. All patients were included in the patient-level T staging analysis. Twenty-five patients were treated with radical prostatectomy with extended lymphadenectomy and considered for N staging analysis. Sixteen patients underwent all imaging and surgical procedures needed for coregistration between imaging and histology and were included in the lesion-based analysis for T staging. Two expert nuclear medicine physicians reviewed [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-RM2 PET images with knowledge of the patients' available clinical and imaging information. mpMRI was interpreted as the standard of care by 2 expert radiologists using Prostate Imaging Reporting and Data System, version 2, criteria. Peripheral whole-blood samples were collected at the time of patient's enrollment to assess their association with lymph node involvement on histology. Results: In the patient-based analysis, [⁶⁸Ga]Ga-PSMA-11 PET and mpMRI identified at least 1 intraprostatic lesion in all patients, whereas [⁶⁸Ga]Ga-RM2 PET results were negative in 3 of 36 patients. The lesion-level analysis performed in 16 patients showed that, in this cohort, the dominant intraprostatic lesion was always detected by [⁶⁸Ga]Ga-RM2 PET, whereas both [⁶⁸Ga]Ga-PSMA-11 PET and mpMRI missed it, reporting a false-positive finding elsewhere. For N staging analysis, [⁶⁸Ga]Ga-PSMA-11 PET had the highest sensitivity among the investigated imaging modalities (sensitivity, 0.375). Blood analysis showed that a higher fraction of polymorphonuclear-myeloid-derived suppressor cells (MDSCs) over monocytic MDSCs was significantly associated patients with lymph node involvement on histology (P = 0.0285). Conclusion: All imaging modalities showed high sensitivity for the preoperative detection of primary PCa, but only [⁶⁸Ga]Ga-RM2 PET correctly identified the dominant lesion in all patients who underwent lesion-based subanalysis. The identification of lymph node involvement remains challenging, with [⁶⁸Ga]Ga-PSMA-11 PET reaching a sensitivity of only 0.375. In this regard, the polymorphonuclear MDSC-to-monocytic MDSC ratio may represent a valuable biologic marker of lymph node involvement in patients with high-risk PCa and warrants further investigation.