Gallium-68 PSMA-617

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with ⁶⁸Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and ⁶⁸Ga-RM2 (⁶⁸Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm³), ⁶⁸Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and ⁶⁸Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered ⁶⁸Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of ⁶⁸Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 (P < 0.0001) or 2 (P = 0.0002). There were no significant differences in uptake between ISUP scores for ⁶⁸Ga-RM2. Median ⁶⁸Ga-RM2 SUV_max was significantly higher than median ⁶⁸Ga-PSMA-617 SUV_max in the ISUP-2 subgroup (P = 0.01). Conclusion: ⁶⁸Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and ⁶⁸Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions.

To determine the prevalence of intra‐patient inter‐metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic castration‐resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs).

This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra‐patient inter‐metastatic heterogeneity will be determined with triple‐tracer imaging using fluorine‐18 fluorodeoxyglucose (18F‐FDG), gallium‐68‐(68Ga)‐prostate‐specific membrane antigen (PSMA)‐617 and 68Ga‐DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The 68Ga‐PSMA‐617 and 18F‐FDG PET/CT scans will be performed first. If at least one PSMA‐negative/FDG‐positive lesion is observed, an additional PET/CT scan with 68Ga‐DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter‐metastatic heterogeneous disease and may be offered a biopsy.

The proposed triple‐tracer approach will allow whole‐body mCRPC characterisation, investigating the inter‐metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on 68Ga‐PSMA‐617 or 68Ga‐DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE‐based RLT will be assessed. Non‐invasive whole‐body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features.

This study will add novel, biologically relevant dimensions to molecular imaging: the non‐invasive detection of inter‐metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi‐tracer PET/CT strategy to further personalise the care of patients with mCRPC.