Prostate cancer is the second most commonly diagnosed malignant disease and the fifth leading cause of death among men in the world [1]. Localized prostate cancer has a good prognosis with treatment such as surgery and radiation, but recurrent or metastatic cancer leads to a lethal disease called castration-resistant prostate cancer (CRPC). Drugs, such as second-generation antiandrogens (enzalutamide [2], abiraterone [3], apalutamide [4], darolutamide [5]), taxanes (docetaxel [6], cabazitaxel [7]), PARP inhibitors (olaparib [8]), and radium-223 [9], have prolonged prognosis in CRPC patients, but CRPC remains difficult to cure. However, the situation is changing with the recent discovery of a cancer-specific protein called prostate-specific membrane antigen (PSMA). There has been remarkable development in “theranostics”, in which antibodies or small molecular compounds that bind to PSMA are coupled with the diagnostic emitter or therapeutic alpha- or beta-emitters to diagnose or treat prostate cancer, respectively. Then, in March 2022, the US Food and Drug Administration (FDA) approved ¹⁷⁷Lu-PSMA-617, a radioligand therapy for PSMA (PSMA-RLT), based on the results of the VISION trial [10]. In the VISION trial, ¹⁷⁷Lu-PSMA-617 extended prognosis in heavily pretreated CRPC patients. However, although ¹⁷⁷Lu-PSMA-617 offers a longer-term prognosis for some patients, the overall survival difference was only 4 months compared to the control group, and hence CRPC remains a fatal disease. In addition, despite the inclusion of only PSMA-positron emission tomography (PET) positive patients in this study, some patients do not show an adequate treatment response. Therefore, ¹⁷⁷Lu-PSMA-617 does not always benefit all CRPC patients, and it is unclear which patients would benefit from this therapy.

2. PSMA-PET Imaging in Prostate Cancer

Several tracers are used in PSMA-PET. The most commonly reported PSMA-PET diagnostic agent is ⁶⁸Ga-PSMA-11. Other ligands and 18F-labeled tracers are also outlined here. The current status of PSMA-PET images in radiological reading is also discussed.

2.1. PSMA-Targeted Monoclonal Antibody

Horoszewicz et al. developed 7E11, a mouse-derived monoclonal antibody (mAb) that specifically binds to PSMA-positive cells, as the first PSMA-binding antibody for nuclear medicine [11]. However, PET drugs with 7E11 antibodies were not suitable for RLT due to their long persistence in the body and poor migration to bone and microtissues [12]. To improve these problems, the J591 antibody was developed, which showed faster clearance than 7E11 and was considered to be useful because of its high specificity for the target [11]. However, Phase I/II imaging studies using 89Zr-labeled J591 concluded that the mAb has practical limitations in terms of clearance [13]. Drug development for short-lived antibodies derived from single-chain fragments is still underway.

2.2. Low Molecular Weight (LMW) PSMA Agents

Low molecular weight (LMW) PSMA ligands are typically based on a skeleton containing a specific PSMA-binding entity (urea-based), a linker, and a chelator for labeling with a radionuclide. This LMW compound is combined with a radionuclide for PET and used as a PSMA-PET agent. The European Association of Urology (EAU) ^[14][15][14,15] and National Comprehensive Cancer Network (NCCN) [16] guidelines recommend the use of PSMA-PET for lesion evaluation in biochemical recurrence patients, staging of high-risk localized prostate cancer, and expression evaluation in metastatic prostate cancer before PSMA-RLT. Herein, three widely used PSMA-PET agents are described.

2.2.1. ⁶⁸Ga-PSMA-11

⁶⁸Ga-PSMA-11 is a drug approved by the FDA on 1 December 2020. The most widely used PSMA-PET agent is created by synthesizing PSMA-11 with [68]-gallium extracted from a germanium/gallium (Ge/Ga) generator. It was approved by the European Medicines Agency (EMA) on 2 February 2023 as gozetotide (Locametz^TM). It is approved for diagnosis of recurrence after radical treatment, staging of localized prostate cancer, and metastatic prostate cancer. ⁶⁸Ga-PSMA-11 shows high accumulation in prostate cancer, but it should be discontinued in the diagnosis of perineural recurrence due to urinary excretion [17]. This point is reported to be reduced by the administration of furosemide, hydration, and urination ^[18][19][20][18,19,20]. If a Ge/Ga generator is available, it is relatively easy to create, but the short half-life of ⁶⁸Ga [21] makes it unsuitable for delivery.

2.2.2. ¹⁸F-PSMA-1007

In general, agents using 18F have a longer half-life than ⁶⁸Ga agents, making them suitable for image evaluation at later time points and mass production. ¹⁸F is generally synthesized in cyclotrons and has a longer half-life than ⁶⁸Ga [21], which may be superior in production and supply, but production facilities are limited due to the need for huge cyclotrons. ¹⁸F-PSMA-1007 is characterized by biliary excretion and low urinary excretion, which is considered an advantage in the evaluation of local lesions [22]. However, it is highly concentrated in the liver, which may mask liver metastatic lesions, and may not be suitable for patients with severe hepatic dysfunction [23]. Some reports suggest that it is advantageous in the diagnosis of recurrence after total prostatectomy because of its lower urinary excretion compared to other agents, but others report that there was no difference in diagnostic performance [22]. Although this drug has not been approved by the FDA and EMA, it is currently being compared to Ga-PSMA-11 [24] and is a promising agent for future approval.

2.2.3. ¹⁸F-DCFPyL

¹⁸F-DCFPyL is an agent approved by the FDA in 1/DEC/2020 as piflufolastat^TM; it is not yet approved by the EMA. The indications are the same as for ⁶⁸Ga-PSMA-11, which is approved for the diagnosis of recurrence after radical therapy, staging of localized prostate cancer, and metastatic prostate cancer. It is excreted from the urine and liver, but its accumulation in the liver is reported to be milder than that of ¹⁸F-PSMA-1007, and it may be safer than ¹⁸F-PSMA-1007 in patients with hepatic dysfunction [23].

2.3. Reading and Diagnosis of PSMA-PET

2.3.1. Diagnostic Ability of PSMA-PET

Most of the current reports of PSMA-PET were performed using PSMA-PET/CT. PSMA-PET has a lot of evidence for primary staging evaluation in localized intermediate- and high-risk prostate cancer and diagnosis of biochemical recurrence (BCR) after radical prostatectomy (RP) or radiotherapy, but there are many challenges for diagnosis in metastatic prostate cancer and CRPC. In a prospective phase III trial of 764 intermediate- and high-risk prostate cancer patients with RP, the diagnostic sensitivity and specificity of ⁶⁸Ga-PSMA-11 PET/CT for lymph node metastatic stage were 0.40 (95% CI: 0.34–0.46) and 0.95 (95% CI: 0.92–0.97), respectively [25]. In another meta-analysis of 37 studies on the primary staging by ⁶⁸Ga-PSMA-11 PET/CT, the sensitivity and specificity for the diagnosis of lymph node metastases were 77% and 97%, respectively, in a patient-based analysis [26]. PSMA-PET for local staging in the primary staging of prostate cancer is not approved and is still experimental. PSMA-PET/MRI has been reported to be more effective than PET/CT for primary staging [27] and has been noted to have better diagnostic ability for T3a and T3b [28]. If PSMA-PET/MRI enables TNM classification staging in a single scan, it should be potentially beneficial to patients, and future studies are warranted.  An attempt to fusion-biopsy using PSMA-PET/MRI for men with elevated PSA (NCT03187990) is ongoing, and future results are expected. With regard to the primary staging of bone metastases, 12 studies, including a systematic review, reported that the sensitivity and specificity of PSMA-PET/CT for the primary staging of high-risk localized prostate cancer were better than CT/bone scintigraphy on both sensitivity (median sensitivity per lesion 33–92% and per patient 66–91%) and specificity (median specificity per lesion 82–100% and per patient 67–99%) [29]. In a prospective comparative trial (ProPSMA) of 302 patients with high-risk localized prostate cancer prior to RP or radiation therapy, the diagnostic accuracy for lymph node or distant metastasis of ⁶⁸Ga-PSMA-11 PET/CT was 27% (95% CI: 23–31) higher than CT and bone scan (92% (95% CI: 88–95) vs. 65% (95% CI: 88–95)) [30]. Thus, in localized prostate cancer, Ga-PSMA-PET has a high metastasis detection rate, but it remains unclear whether reclassification of the clinical stage based on these imaging results alters the patient’s post-treatment prognosis. In persistently elevated PSA after RP patients, the detection rate of metastasis of PSMA PET/CT was 42, 58, 76, and 95% in patients with PSA levels of 0–0.2, 0.2–1, 1–2, and >2 ng/mL, respectively [26]. In a prospective multicenter study of 323 patients with BCR, PSMA PET/CT significantly reduced the number of patients with unknown recurrence sites (77 vs. 19%, p < 0.001) and significantly increased the number of patients with metastatic disease (11 vs. 57%) compared to conventional imaging (CT and bone scan), and as a result, the treatment plan was changed in 62% of patients [31]. PSMA-PET was indicated to have a potentially important role in treatment planning for salvage radiation therapy after curative treatment [32], but further reports are needed. The optimal use of PSMA-PET as a pre-treatment patient selection tool for metastatic prostate cancer prior to PSMA-RLT remains unclear. In the TheraP phase II trial [33] of ¹⁷⁷Lu-PSMA-617 treatment for CRPC patients, 29 of 291 patients (10%) were excluded from the trial due to low ⁶⁸Ga-PSMA-11 accumulation. Due to tumor heterogeneity in metastatic prostate cancer, PSMA-PET accumulation is expected to differ between patients and tumors. There are no established criteria for deciding which metastatic lesions are eligible for PSMA-RLT, and therefore, it is necessary to explore the optimal selection criteria based on actual clinical studies in the future.

2.3.2. Development of Standardized Image Interpretation

As PSMA-PET has become more widely used, discrepancies in findings between radiologists have increased due to uptake in benign lesions and non-prostatic malignancies ^{[34][35][36][37][38][39]}[34,35,36,37,38,39]. Three guidelines (criteria) are currently reported to resolve this problem: PROMISE criteria [40], PSMA-RADS [41], and EANM criteria [17]. The external validity of these criteria has recently been evaluated, and although they have good reproducibility in the assessment of ⁶⁸Ga-PSMA-11, there are factors that cause disagreement among readers, and further research is needed to standardize the reading of PSMA-PET imaging [42]. Based on these studies, the EANM standardized reporting guidelines v1.0 for PSMA-PET (E-PSMA guideline) were suggested [23]. The guideline recommends that PSMA accumulation be described on a four-point scale (Table 1) and that TNM stages be described by molecular imaging TNM (miTNM) classification according to the PROMISE criteria (Table 1). The guidelines also indicate that PSMA-PET can be positive in other malignancies such as renal, lung, breast, and liver cancers, as well as in ganglia, benign bone lesions, benign neurogenic tumors, and sarcoidosis. Despite these efforts to standardize reading, it is important to understand that these guidelines are primarily intended for biochemical recurrence and not for metastatic prostate cancer.

2.3.3. PSMA-PET Imaging in Metastatic Prostate Cancer

The role of PSMA-PET imaging in the treatment of progressive prostate cancer is under development. In non-metastatic CRPC (nmCRPC) with conventional imaging modalities, PSMA-PET has been proven to detect metastatic sites [43], but it is unclear whether this subgroup can help identify who would benefit from the stratification of patients with this imaging PSMA-PET is also currently being investigated for use in the evaluation of treatment of metastatic prostate cancer, and the PSMA PET progression (PPP) criteria have been suggested [44]. This set of criteria defines treatment responses in three distinct phases: (1) the appearance of two or more new PSMA-positive distant lesions; (2) the appearance of one new PSMA-positive lesion plus consistent clinical or laboratory data and recommended confirmation by biopsy or correlative imaging within 3 months of PSMA PET; and (3) an increase of ≥30% in size or uptake plus consistent clinical or laboratory data and confirmation by biopsy or correlative imaging within 3 months of PSMA PET. This criteria set should be considered when reporting PSMA-PET in patients receiving systemic therapy, but its efficacy needs to be validated in the future. PSMA-PET is also used for pre-treatment evaluation of RLT for advanced prostate cancer, but there are no clear criteria at present. Two prospective comparative studies on PSMA-RLT have been completed at this time: the VISION trial [10] and the TheraP trial [33]. Both trials used PSMA-PET/CT to identify patients with high PSMA expression, but the thresholds used to define indications differed among the trials, and no fixed criteria have been established; thus, future studies are needed.