Current status of theranostics in prostate cancer

Recognized imaging agents for prostate cancer (PC) include ¹⁸F- / ¹¹C–choline, ¹¹C–acetate, ¹⁸F–fluciclovine (FACBC), ¹⁸F-16β-fluoro-5α-dihydrotestosterone (FDHT), ¹⁸F–NaF and conventional ^99mTc-labeled phosphonates. The theranostic history of PSMA ligands started with radiolabeled anti-PSMA antibodies (e.g., Prostascint®) [1] first introduced more than 20 years ago at the John Hopkins’ University [2]. These compounds did not gain wide-spread clinical acceptance until 2012 when the first human studies with the ⁶⁸Ga- PSMA-11-ligand [3] were performed at Heidelberg [4]. Within the last 5 years, the rapid development of different PSMA ligands and their clinical use has resulted in numerous publications, which established a new and comprehensive area of nuclear medicine from imaging to personalized peptide radionuclide ligand therapy (PRLT) of PC patients.

PSMA is a cell-surface enzyme that is continually internalized (synonym: glutamate carboxypeptidase II; folate hydrolase I; [5, 6]. This cell-surface protein (750 amino acids, 84 kDa) is overexpressed in PC [7] and its expression increases progressively in higher-grade tumors, metastatic or hormone-refractory disease, and under androgen deprivation therapy [ADT]. The level of PSMA expression is a significant indicator for disease outcome [8]. PSMA is not entirely prostate-specific, and it is expressed physiologically in normal cells including the small intestine, proximal renal tubulus, thyroid neoplasms, salivary and lacrimal glands (with potential impact on the side effect profile when used as targeting molecule) but also in other cancers such as renal cell cancer [9] due to an overexpression of PSMA on cancer-related neovascular structures.

A variety of PSMA ligands for PET as well as SPECT imaging have been introduced into the clinic over the recent years. Most literature exist for ⁶⁸Ga-PSMA-11, but there are also some publications for ⁶⁸Ga-PSMA-I&T and ⁶⁸Ga-PSMA-617. The EANM and SNM guidelines [10] assume that the differences in the diagnostic capacity of these new radioligands are marginal, although no direct comparative studies are available.

In general, data from prospective multicenter trials are not yet available for ⁶⁸Ga-PSMA ligands. None of these tracers has been approved, neither by the European Medicines Agency (EMA) nor the United States Food and Drug Administration (FDA). This is also a limitation within the most recent registration of the first ⁶⁸Ge/⁶⁸Ga generator describing “a medicinal product which allows direct, simplified preparation of ⁶⁸ Ga-radiopharmaceuticals in combination with licensed kits” [11].

Since the life expectancy of patients with localized PC is more than 10 years [12], a careful choice of therapy approach is warranted. The National Comprehensive Cancer Network (NCCN) guidelines for PC [13] provide multidisciplinary recommendations on the clinical management of patients with PC based on clinical evidence and expert consensus. In newly diagnosed local PC, “active surveillance” and “watchful waiting” for low-risk patients is appropriate. Intermediate-risk patients have a risk of 3.7 to 20.1% for lymph node (LN) involvement and dissection should be performed if the risk exceeds 5% [14]. High-risk patients should undergo radical prostatectomy (RP) combined with extended LN dissection and locoregional radiation therapy (RT) [15]. Multimodality treatment is appropriate for high-risk disease including imaging procedures and long-term ADT. PC patients are generally treated by salvage RT to the prostate bed when local relapse is suspected and by ADT when systemic relapse is suspected. During follow-up, about 50% of patients treated initially by RP or RT experience biochemical recurrence (BR) [16]. Metastases-directed therapies could play a significant role in PC patients with CR if the imaging tool could accurately locate the lesions. ¹¹C–Choline PET/CT has been proven to be a superior imaging tool compared to conventional imaging with significant impact on patient management despite of relatively low sensitivity in patients with low PSA levels [17].

Given that bone is the major site of distant metastases formation bone-targeted imaging and radionuclide therapy for bone pain palliation (¹⁵³Sm- ethylendiamine-tetramethylen-phosphonate(EDTMP), ²²³Ra (Xofigo® [18]), ¹⁷⁷Lu-labeled bisphosphonates [19], and direct bone marrow tumor cell killing [20]) have been implemented.

“Theranostic imaging” (therapy: Greek therapeia: to treat medically; knowledge: Greek: gnosis) refers to the combination of a predictive biomarker with a therapeutic agent [21]. The theranostic concept based on PSMA overexpression led to the use of PSMA ligands for systemic therapy in patients with castration-resistant (CR) PC. The aim of this review is to report on the current status of PSMA-directed theranostics in PC patients. The value of ⁶⁸Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving peptide radioligand therapy (PRLT) in CRPC is assessed. The current available literature envisions that the theranostics of PC will be commonplace in the personalized care of men.

Table 1 gives an overview of PSMA ligands that have been studied in PC patients both for diagnosis and therapy. A variety of other PSMA-targeting radiopharmaceuticals have been reported, but so far not been evaluated in patients.

The current clinical success of radiolabeled PSMA ligands is based on a small motif binding to the catalytic N-acetyl-l-aspartyl-l-glutamate hydrolyzing site in the PSMA molecule. This 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) motif was first described by Kozikowski et al. [34]. Eder et al. [3] introduced a specific chelator for gallium, N,N′-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N′-diacetic acid(HBED-CC) via a Lys-Ahx linker resulting in the compound PSMA-11, and showed that the lipophilicity of the HBED-CC-chelator revealed superiority over well-established 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), at the same time maintaining high-affinity to PSMA [22]. As HBED-CC only binds ⁶⁸Ga and not other trivalent radiometals such as ¹⁷⁷Lu or ¹¹¹In, the same authors developed a specific DOTA-based compound, PSMA-617 [23] by introducing a p-iodo phenyl substitution in the linker between the DUPA motif and DOTA ensuring the required lipophilicity in the side chain. Early patient studies with ¹⁷⁷Lu-PSMA-617 [35] confirmed the high uptake by PSMA-expressing tumors and at the same time showing reduced kidney retention as compared to PSMA-11, which makes this ligand suitable for radionuclide therapy applications. However, as the reduced kidney retention is based on slower pharmacokinetics, the imaging properties seem to be inferior compared to ⁶⁸Ga-PSMA-11. PSMA-617 was also applied in patients labeled with ²²⁵Ac for therapy [36] and ⁶⁴Cu for diagnosis [37]. In parallel, Weineisen et al. [24] reported on another DOTA-PSMA ligand, “PSMA-I&T”, with two phenyl substitutions in the side chain, but also based on the DUPA motif. This compound was labeled both with ⁶⁸Ga and ¹⁷⁷Lu for theranostic applications and was shown to efficiently target PSMA-expressing tumors in PC patients. Recently, the same group has reported PSMA-I&S to be labeled with ^99mTc [25]. It is based on the DUPA motif with a mercaptoacetyltriserine (MAS3) as chelating moiety for ^99mTc involving a linker with a lipophilic naphthyl and Tyr residue. Already Molecular Insight Pharmaceuticals developed a series of ^99mTc-PSMA ligands based on the DUPA motif and introduced it into prospective clinical trials [26], two compounds, MIP-1404 and MIP-1405, both based on an imidazole modification for binding the Tc-tricarbonyl-core. The same company also developed radioiodinated compounds using a p-iodo phenyl substitution. One of them, MIP-1095, showed excellent targeting properties when labeled with ¹²³I [27] and was used subsequently labeled with ¹³¹I for therapy studies.

Furthermore, ¹⁸F–labeled compounds have been developed and used for PSMA imaging. The first were developed by the group of Pomper et al. [28] at the John Hopkins University, using a F-fluorobenzyl-l-cysteine attachment to the DUPA motif, called ¹⁸F–DCFBC. A further development, ¹⁸F–DCFpyl with a fluoro-nicotinic acid substitution [29], was introduced to clinical trial by Progenics Pharmaceuticals. Most recently, the group in Heidelberg presented an ¹⁸F–labeled version, PSMA-1007, introducing a lipophilic spacer with naphthyl substitution [30] and showing comparable imaging performance in patients to ⁶⁸Ga-PSMA-11 [31].

Before the DUPA motif was described to target PSMA in a highly specific way, already other strategies have been pursued in the attempt to develop PSMA-targeting radiopharmaceuticals. In particular, antibody-based constructs were developed for radiolabeling directed against the PSMA-protein. ¹¹¹In-capromab pendetide (ProstaScint®), based on the murine monoclonal antibody 7E11-C5.3, was widely used, particularly in the US for SPECT imaging of PC [32]. It is directed against an intracellular domain of PSMA, therefore not reaching high sensitivity in imaging. This concept was further developed towards the humanized antibody J591, directed against the extracellular domain of PSMA and was labeled with ¹¹¹In for dosimetry and ⁹⁰Y as well as ¹⁷⁷Lu for therapeutic applications [2]. It showed promising results in a number of clinical trials. As intact antibodies exhibit well-known limitations regarding slow tumor targeting and delayed clearance from non-target tissue, recently Pandit-Tasker et al. [33] reported on the application of the minibody IAB2M derivatized with desferrioxamine for ⁸⁹Zr labeling. This 80-kDa molecule, genetically engineered from the intact antibody J591 (150 kDa), lacking the Fc-receptor interaction domains and making it pharmacologically inert, showed favorable biodistribution and kinetics for targeting metastatic PC in this phase I trial [32]. Imaging at 48 h p.i. provided good lesion visualization when labeled with ⁸⁹Zr for PET.

According to the European Association of Urology (EAU)-European Society for Radiotherapy & Oncology (ESTRO)-International Society of Geriatric Oncology (SIOG) guidelines [15], in high-risk localized PC or high-risk locally advanced PC, staging should be performed with pelvic mpMRI and cross-sectional abdominal pelvic imaging and bone scanning for metastatic screening. These imaging procedures may eventually also be useful in patients with intermediate-risk PC, whereas the guidelines do not recommend additional imaging for staging purpose in low-risk PC patients as the accuracy of conventional imaging procedures is limited especially regarding the detection of small LN.

In primary PC, the diagnostic accuracy of ⁶⁸Ga-PSMA-ligand PET/CT is not yet proven and only a few studies have been published so far. Along with the first registered ⁶⁸Ge/⁶⁸Ga generator [11] by Galliapharm, a prospective European multicenter trial is finally under way in high-risk PC patients with a Gleason Score (GS) > 7 [38].

Sachpekidis et al. [39] aimed to retrospectively assess the pharmacokinetics and biodistribution of Ga-PSMA-11 in 24 patients suffering from primary PC by means of dynamic (pelvic) and whole-body PET/CT. Overall, 23/24 patients (95.8%) were ⁶⁸Ga-PSMA-11 PET positive and in 9/24 patients (37.5%) metastatic lesions were detected. Time–activity curves derived from PC-associated lesions revealed an increasing Ga-PSMA-11 accumulation during the dynamic PET acquisition procedure.

In line with these observations, we retrospectively investigated the value of ⁶⁸Ga-PSMA-11 PET/CT in primary staging of PC [40] in 90 patients (GS 6–10; median prostate-specific antigen (PSA): 9.7 ng/ml) with transrectal ultrasound (TRUS)-guided biopsy-proven PC. The SUV_max of the primary tumor was assessed in relation to both PSA level and GS. Eighty-two patients (91.1%) demonstrated pathologic tracer accumulation in the primary tumor that exceeded the physiologic tracer uptake in normal prostate tissue (median SUV_max: 12.5 vs. 3.9). Tumors with GS of 6, 7a (3 + 4) and 7b (4 + 3) showed significantly lower ⁶⁸Ga-PSMA-11 uptake, with median SUV_max of 5.9, 8.3, and 8.2, respectively, compared to patients with GS > 7 (median SUV_max: 21.2; p < 0.001). PC patients with PSA ≥10.0 ng/ml exhibited significantly higher uptake than those with PSA-levels < 10.0 ng/ml (median SUV_max: 17.6 vs. 7.7; p < 0.001). In 24/90 patients (26.7%), 82 LN with pathologic tracer accumulation consistent with metastases were detected (median SUV_max: 10.6). Eleven patients (12.2%) revealed 55 pathologic bone lesions suspicious for bone metastases (median SUV_max: 11.6). The results allow the conclusion that ⁶⁸Ga-PSMA-11 PET/CT should be preferentially applied for primary staging in patients with GS > 7 or PSA-levels ≥10 ng/ml.

Maurer et al. [41] retrospectively evaluated the diagnostic efficacy of ⁶⁸Ga-PSMA-11 PET compared to conventional imaging (CT/mpMRI) for LN-staging in 130 consecutive patients with intermediate- to high-risk PC prior to RP. LN metastases were found in 41/130 patients (31.5%). On patient-based analysis the sensitivity, specificity, and accuracy of ⁶⁸Ga-PSMA-11 PET were 65.9, 98.9, and 88.5%, and those of morphological imaging were 43.9, 85.4, and 72.3%, respectively. Of 734 dissected LN templates, 117 (15.9%) showed metastases. On template-based analysis, the sensitivity, specificity, and accuracy of ⁶⁸Ga-PSMA-11-PET were 68.3, 99.1, and 95.2%, and those of morphological imaging were 27.3, 97.1, and 87.6%, respectively. The results demonstrate that in patients with intermediate- to high-risk PC, preoperative LN staging with ⁶⁸Ga-PSMA-11-PET is superior to standard routine imaging and thus has the potential to replace current standard imaging for this indication.

Budäus et al. [42] retrospectively compared preoperative ⁶⁸Ga-PSMA PET/CT LN findings with histologic work-up after RP in 30 patients and found that LN metastasis detection rates were substantially influenced by LN metastases size. In 92.9% of patients, the intraprostatic tumor foci were correctly predicted. Overall, 608 LNs containing 53 LN metastases were detected. LN metastases were present in 12/30 patients (40%), which were found by ⁶⁸Ga-PSMA PET/CT in four patients (33.3%). Median size of ⁶⁸Ga-PSMA-PET/CT-detected vs. undetected LN metastases was 1.36 vs. 0.43 cm (p < 0.05). Overall sensitivity, specificity, positive predictive value, and negative predictive value of ⁶⁸Ga-PSMA PET/CT for LN metastases detection were 33.3, 100, 100, and 69.2%, respectively. Per-side analyses revealed corresponding values of 27.3, 100, 100, and 52.9%. Compared to Maurer et al. [41], who reported a higher sensitivity, the limitations of this retrospective assessment are not only the smaller number of pooled patients from five different institutions but also differences in the report protocols, which may lead to variations in the assessment and thus lower sensitivity [43]. On the other hand, also van Leeuwen et al. [44], who performed a prospective study in 30 intermediate- to high-risk patients, reported size-dependence of positively imaged LN.

In a cohort of 34 PC patients, Herlemann et al. [45] reported a sensitivity of 84%, specificity of 82%, PPV of 84%, and NPV of 82% for detection of LN in patients with intermediate- to high-risk PC. Postoperative histopathology was taken as a reference standard after primary (n = 20) or secondary LN dissection (n = 14). ⁶⁸Ga-PSMA-11 PET/CT detection rates were superior to CT alone before primary (sensitivity 88 vs. 75%) as well as secondary (sensitivity 77 vs. 65%) LN dissection in 14 patients.

Upon initial staging, Demirkol et al. [46] in eight patients, Sterzing et al. [47] in 15 patients, and Sahlmann et al. [48] in 12 patients confirmed the potential value of ⁶⁸Ga-PSMA-11 PET.

In PC with BR after primary therapy, conventional imaging techniques have a low detection rate at the PSA levels at which targeted therapy with curative intent, such as salvage radiotherapy is effective. A magnitude of data indicate that ⁶⁸Ga-PSMA-PET can detect recurrent PC or small LN metastases that are ¹⁸F–choline PET-negative.

Recently, Perera et al. [49] overviewed mostly retrospective data from 16 studies on ⁶⁸Ga-PSMA PET efficiency in PC patients with rising PSA values. At BR, a pooled PET-detection rate of 76% was reported for PSA ranges of 1–2 ng/ml and of 58% for PSA ranges of 0.2–1.2 ng/ml, which demonstrates the improved diagnostic performance for PC patients. Most literature exists for ⁶⁸Ga-PSMA-11 compared with ⁶⁸Ga-PSMA-I&T and ⁶⁸Ga-PSMA-617. These data are somewhat critical, as the authors summarize results collected from studies using different peptides, i.e., PSMA-11, PSMA-I&T, and PSMA-617, and furthermore from mixed patient populations as well. The authors also did not take into account important features of imaging protocols such as imaging time or medication (i.e., ADT).

The first data by Ceci et al. [50] in 70 consecutive PC patients identified an association of PSA level and PSA kinetics in terms of PSA_{doubling time (dt)} with a pathological ⁶⁸Ga-PSMA-11 PET/CT in PC patients with BR after RP. A positive PET scan was observed in the PSA range 0.14 to 35.07 ng/ml (median, 2.39) and a negative PET scan in the range 0.21 to 5.00 ng/ml (median, 0.81 ng/ml). ROC analysis showed that a PSA_dt of 6.5 months and a PSA of 0.83 ng/ml were optimal cut-off values for ⁶⁸Ga-PSA PET-positivity, which was observed in 17 of 20 patients (85%) with PSA < 2 ng/ml and PSA_dt > 6.5 months.

Verburg et al. [51] retrospectively investigated 155 patients. PET/CT was positive in 44, 79, and 89% of patients with PSA levels of ≤1, 1–2, and ≥2 ng/ml, respectively. Patients with high PSA levels showed higher rates of local PC tumors (p < 0.001), extrapelvic LN (p = 0.037), and bone metastases (p = 0.013). A shorter PSA_dt was significantly associated with pelvic LN (p = 0.026), extrapelvic LN (p = 0.001), bone (p < 0.001), and visceral (p = 0.041) metastases. A high GS was associated with more frequent pelvic LN metastases (p = 0.039). In multivariate analysis, both PSA and PSA_dt were independent determinants of scan positivity and of extrapelvic LN metastases. These data show that higher PSA levels and shorter PSA_dt are independently associated with scan positivity and extrapelvic metastases, and can be used for patient selection for ⁶⁸Ga-PSMA-11 PET.

⁶⁸Ga-PSMA-11 PET/CT-guided salvage retroperitoneal LN dissection for disease relapse after RP was first reported in 2015 [52]. ⁶⁸Ga-PSMA has a high detection rate of PC recurrence outside the prostatic fossa in patients being considered for salvage RT. In fact, ⁶⁸Ga-PSMA-11 PET/CT appears to be useful for re-staging of PC in patients with rising PSA who are being considered for RT even at PSA levels < 0.5 ng/ml. The only available prospective study by van Leeuwen et al. [53] in a total of 300 consecutive patients considered for salvage RT identified 70 patients with a BR of PSA ≥0.05 and < 1.0 ng/ml after RP. Among patients with PSA levels of 0.05 to 0.09 ng/ml, 8% were definitely positive; the corresponding percentages for the other PSA ranges were as follows: PSA 0.1 to 0.19 ng/ml, 23%; PSA 0.2 to 0.29 ng/ml, 58%; PSA 0.3 to 0.49 ng/ml, 36% and PSA 0.5 to 0.99 ng/ml, 57%. Noteworthy, as a result of the ⁶⁸Ga-PSMA PET-findings, the authors report a major management change in 20 (28.6%) patients, which will have future importance of changes in the RT volume to be applied.

Afshar-Oromieh et al. retrospectively [54] investigated 319 patients of whom 82.8% had at least one ⁶⁸Ga-PSMA-11 PET-positive lesion. Tumor detection was positively associated with PSA level and ADT, whereas GS and PSA_dt were not associated with tumor detection. Among lesions investigated by histology, 30 were false-negative in four different patients, and all other lesions (n = 416) were true-positive or true-negative. A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) revealed values of 76.6, 100, 91.4, and 100%. A patient-based analysis revealed a sensitivity of 88.1%. Of 116 patients available for follow-up, 50 received local therapy after ⁶⁸Ga-PSMA PET/CT. In the range of PSA < 0.2 ng/ml, the scan was positive in 8/17 patients (47.1%). The authors concluded that PET/CT can help to delay systemic therapy of PC. In their recent report, Afshar-Oromieh et al. [55] retrospectively analyzed 1007 patients with BR. In 801/1007 (79.5%) of patients, at least one lesion was detected on ⁶⁸Ga-PSMA-11 PET/CT and scan sensitivity was significantly associated with PSA level and ADT. Multivariate analysis found, however, no relevant correlation with PSA_dt or PSA velocity as well as GS and PET positivity. GS and amount of injected activity were not associated with PET positivity. Noteworthy, in patients with PSA < 0.2 ng/ml 32/69 (46%), PET-scans were positive and 15 patients had PSA levels < 0.1 ng/ml.

Eiber et al. [56] investigated 248 patients with PC after RP and found pathological findings in 202/248 (89.5%) by ⁶⁸Ga-PSMA-11 PET/CT. The detection rates were 96.8, 93.0, 72.7, and 57.9% for PSA levels of ≥2, 1 to < 2, 0.5 to < 1, and 0.2 to < 0.5 ng/ml, respectively. Whereas detection rates increased with a higher PSA velocity, no significant association could be found for PSA_dt. ⁶⁸Ga-PSMA-ligand PET (as compared with CT) exclusively provided pathologic findings in 81 (32.7%) patients. In 61 (24.6%) patients, it exclusively identified additional involved regions. In patients with higher GS (≤7 vs. ≥8), detection efficacy was significantly increased (p = 0.0190), however, not with ADT. In a recent report [57], the same group, however, reported in a more homogeneous cohort of patients after RT a significant higher detection rate for patients under ADT (p = 0.0381; 44/45 [97.7%] vs. 63/73 [86.3%]) and positive association with increasing PSA levels. The detection rates were 81.8 (36/44), 95.3 (41/43), and 96.8% (30/31) for PSA of 2 to < 5, 5 to < 10, and ≥10 ng/ml, respectively (p = 0.0377). ⁶⁸Ga-PSMA ligand PET/CT indicated local recurrence in 68 of 107 patients (63.5%), distant lesions in 64 of 107 patients (59.8%), and local recurrence as well as distant lesions in 25 of 107 patients (23.4%).

Kabasakal et al. [58] reported a PET positivity of 31% (n = 4), 54% (n = 13), and 88% (n = 14) in patients with a PSA level of less than 0.2, 0.2–2, and 2–5 ng/ml, respectively. A positive correlation was also observed between positivity and GS. According to patient-based analysis, a sensitivity of 76.5% and a specificity of 91.7% were found.

Sachpekidis et al. [59] found in 22/31 (71.0%) patients with BR after RP a ⁶⁸Ga-PSMA-11-positive scan. The median PSA value in the ⁶⁸Ga-PSMA-11-positive group was significantly higher (median = 2.35 ng/ml; range = 0.19–130.0 ng/ml) than in the ⁶⁸Ga-PSMA-11-negative group (median value: 0.34 ng/ml; range, = 0.10–4.20 ng/ml). Time–activity curves derived from PC recurrence-indicative lesions revealed an increasing ⁶⁸Ga-PSMA-11 accumulation during dynamic PET acquisition over 60 min.

The limited value of conventional CT and MR in the detection of local recurrence and LN metastases is well known [60]. In 48 patients with BR and a median PSA of 1.31 ng/ml, Rauscher et al. [61] compared ⁶⁸Ga-PSMA PET to CT or MRI and histopathology following salvage lymphadenectomy. PET detected 53/68 histologically proven LN fields (78%), whereas morphological imaging was positive in only 18/67 (27%) resulting in a p < 0.001. PET-positive LN had a mean size of 8.3 ± 4.3 mm (range, 4–25 mm).

Albisinni et al. [62] recently reported subsequent change in management in 99/131 (76%) of patients imaged after RP, RT, or both, for BR. The authors found a positive scan in 45% of patients with a PSA level of ≤0.5 ng/ml and in 75% with PSA level of 0.5 to 1.0 ng/ml.

Lesion detectability increases with acquisition time, reaching its maximum at PET acquisition time of 4 min per PET position [63]. Furthermore, PET-acquisition duration has a significant impact on the incidence of the halo artifact around kidneys and bladder, decreased lesion detectability and lower SUV, as well as lower arm attenuation values [64]. Positioning the arms down was shown to be significantly associated with the appearance of the halo artifact [65].

Despite the fact that the guidelines of the EAU [15] as well as the National Comprehensive Cancer Network (NCCN) [13] suggest the use of ¹⁸F- or ¹¹C–choline PET in PC patients with recurrent disease, the accuracy of choline PET is not well assessed, as most published studies are retrospective. The detection rate for ¹¹C–choline-PET/CT in patients with PSA < 1.0 ng/ml was 19% in 51 patients [76]. In the largest study published so far [77], reporting more than 4000 ¹¹C–choline PET/CT scans, the detection rate was 27% in patients with PSA < 1.16 ng/ml.

Fanti et al. [78] found in a comprehensive literature search 425 studies and finally analyzed 18 articles critically, which evaluated the role of ¹¹C–choline PET/CT at initial staging of PC in a total of 2126 patients providing a pooled detection rate of 62%. In 12 articles with 1270 participants, the pooled sensitivity was 89% and the pooled specificity was 89%. For LN disease in seven studies with 752 participants, the pooled detection rate was 36%.

A similar meta-analysis was published by Evangelista et al. [79] for intermediate- to high-risk PC patients using either ¹⁸F- or ¹¹C–choline PET/CT. The meta-analysis included ten selected studies with a total of 441 patients and showed a pooled sensitivity of 49% and a pooled specificity of 95%.

⁶⁸Ga-PSMA PET/CT was superior to ¹⁸F–choline in patients with BR and identified in 43.8% of patients recurrent disease, which was ¹⁸F–choline -negative [80]. Similar data stating a better detection rate of ⁶⁸Ga-PSMA PET/CT as compared to choline PET/CT have been reported by other authors [81, 82]. To indirectly compare PSMA and choline as PET/CT tracers to identify lesions in patients with early BR, we reviewed the published data stratified by PSA values (Fig. 2). As demonstrated, the performance of PSMA PET/CT is superior to choline PET/CT, with an estimated detection rate of 40–60% at early BR (PSA < 1.0 ng/ml), and this assumption is also confirmed in a recent meta-analysis [83].

A recent reappraisal of 20 years of clinical PET/CT studies with choline presented by Giovacchini et al. [84] summarizes that choline-PET/CT should be used in BR patients with PSA > 1 ng/ml, pointing to the “undoubted” fact that ⁶⁸Ga-PSMA PET/CT may be more promising for centers with the required technical equipment. The only available prospective study that compared ⁶⁸Ga-PSMA-11 with ¹⁸F–choline PET/CT in PC patients with rising PSA after curative treatment was reported by Morigi et al. [85]. They imaged 38 patients, 34 (89%) had undergone RP and four (11%) had undergone RT. The scan results were positive in 26 patients (68%) and negative with both tracers in 12 patients (32%). Of the 26 positive scans, 14 (54%) were positive with ⁶⁸Ga-PSMA alone, 11 (42%) with both ¹⁸F–choline and ⁶⁸Ga-PSMA, and only one (4%) with ¹⁸F–choline alone. When PSA was below 0.5 ng/ml, the detection rate was 50% for ⁶⁸Ga-PSMA versus 12.5% for ¹⁸F–choline. When PSA was 0.5–2.0 ng/ml, the detection rate was 69% for ⁶⁸Ga-PSMA versus 31% for ¹⁸F–choline, and when PSA was above 2.0, the detection rate was 86% for ⁶⁸Ga-PSMA versus 57% for ¹⁸F–choline. On lesion-based analysis, ⁶⁸Ga-PSMA detected more lesions than ¹⁸F–choline (59 vs. 29, P < 0.001). There was a 63% (24/38 patients) management impact, with 54% (13/24 patients) being due to ⁶⁸Ga-PSMA imaging alone.

Pfister et al. [80] compared ⁶⁸Ga-PSMA-11 PET results in 38 patients with ¹⁸F–choline PET results in 28 patients before salvage lymphadenectomy using histology as the standard. For ¹⁸F–choline and ⁶⁸Ga-PSMA-11, the respective sensitivity was 71.2 and 86.9%, specificity was 86.9 and 93.1%, PPV was 67.3 and 75.7%, NPV was 88.8 and 96.6%, and accuracy was 82.5 and 91.9% identifying a better performance of ⁶⁸Ga-PSMA-11 PET/CT for the detection of locoregional recurrent and/or metastatic lesions prior to salvage lymphadenectomy.

Licensed ⁶⁸Ge/⁶⁸Ga generators are available in Europe and GMP-produced, with FDA-accepted quality, in the US. Dependent on demand, 1–2 generators will typically be required annually for local production. ⁶⁸Ga has a half-life of 68 min and thus can only be shipped to close satellite centers. Recently, cyclotron-produced ⁶⁸Ga has been introduced to potentially allow the production of larger quantities for centralized use [97]. In contrast, ¹⁸F has a half-life of 110 min and offers the possibility for using established satellite shipping infrastructure. The production demand for ¹⁸F is well scalable to adapt for the requested number of examinations. If necessary, also delayed imaging can be performed over a longer time. The positron energy of ⁶⁸Ga is 1.90 MeV and its penetration depth is theoretically higher (lungs) but widely negligible in solid tissues using standard reconstruction algorithms and adjusted filtering. ¹⁸F has a positron energy of 0.65 MeV with theoretically higher resolution and also lower radiation burden. The labeling of ⁶⁸Ga is done with chelator molecules, offering the possibility of kit-based formulations, whereas for ¹⁸F, prosthetic group molecules are necessary, which means hot cells, remotely controlled radiosynthesizers are due. ⁶⁸Ga potentially offers an one-molecule theranostic approach, whereas ¹⁸F needs a tandem approach with a different chemical structure of diagnostic and a structurally related therapeutic tracer (e.g., PSMA-1007 / PSMA-617, DCFPyl / MIP-1095).

To date, the published experience with ¹⁸F–labeled PSMA-ligands is limited to about 100 patients. There are two potential radiolabeled ligands, ¹⁸F–DCFPyL [98‐100] and ¹⁸F–PSMA-1007 [101, 102].

In a direct comparative study ¹⁸F–DCFPyL was compared to ⁶⁸Ga-PSMA-11 in 25 patients with BR; another 62 patients underwent ¹⁸F–DCFPyL and 129 patients ⁶⁸Ga-PSMA-11 PET [100]. The distribution pattern of both tracers was strongly comparable. However, in 36% of PSMA-positive patients, additional lesions on ¹⁸F–DCFPyL scan were observed. The authors suggested similar performance of ¹⁸F–DCFPyL and that the ¹⁸F–labeled ligand may even exhibit improved sensitivity in localizing relapse after RP for moderately increased PSA levels. Sensitivity increased abruptly when PSA values exceeded 0.5 μg/l. For PSA 0.5–3.5 μg/l, the sensitivity was 15/17 (88%) for ¹⁸F–DCFPyL and 23/35 (66%) for ⁶⁸Ga-PSMA-11. Although the standard acquisition protocols, used for ¹⁸F–DCFPyL and ⁶⁸Ga-PSMA-HBED-CC in this study, stipulate different activity and tracer uptake times after injection, the findings provide a promising rationale for validation of ¹⁸F–DCFPyL in future prospective trials. Furthermore, initial observation also indicates that ¹⁸F–DCFPyL is superior to conventional imaging modalities [103].

¹⁸F–PSMA-1007 is a promising alternative to ⁶⁸Ga-PSMA-11 for diagnostic purposes as ¹⁸F–PSMA-1007 and ¹⁷⁷Lu-PSMA-617 seem to be a perfect theranostic tandem [101]. In ten patients with biopsy-confirmed high-risk PC ¹⁸F–PSMA-1007 PET/CT had a NPV of 68% and an accuracy of 75%, while additional mpMRI in nine patients resulted in a NPV of 88% and an accuracy of 73% for total agreement. Near total agreement analysis resulted in a NPV of 91% and an accuracy of 93% for PET/CT and of 90 and 87% for mpMRI, retrospectively.

Recent studies have demonstrated the potential of ⁶⁴Cu-labeled PSMA-617 ligand in patients with recurrent disease and in selected patients for primary staging with progressive local disease. Grubmüller et al. [37] detected a positive PC tumor binding in 23/29 patients, with the salivary glands, kidneys, and liver showing the highest tracer uptake. Moreover, Cantiello et al. [104] showed for 23 patients with intermediate to high-risk PC a sensitivity of 87.5% and a specificity of 100% for primary LN staging at 4-h postinjection before RP. ⁶⁴Cu allows the concept for satellite distribution to clinical PET centers that lack radiochemistry facilities for the preparation of ⁶⁸Ga-PSMA ligand due to longer-lived positron emitter with good image quality. ⁶⁴Cu-PSMA-617 may also offer the possibility of pre-therapeutic dosimetry in the theranostic approach. Tables 2, 3 and 4 and Fig. 2 list the current available data on ⁶⁸Ga-PSMA PET/CT results.

Initially, almost all patients with hormone-naive PC have a good response to the well-established anti-androgen treatments. Over the last several years, even for patients with CRPC, significant improvements were observed following treatment with the androgen-receptor antagonist enzalutamide or the CYP17A1-inhibitor abiraterone [110]. However, resistance to these treatments occurs frequently within 1 to 2 years. For this reason, a targeted radionuclide approach could be an attractive therapy option. The PSMA-targeting theranostic concept potentially offers advantages not only in regard to diagnosis but also the therapy of CRPC patients, if labeled with ¹⁷⁷Lu [111‐124], ¹³¹I [125, 126], Auger [127], or an alpha-emitting isotope [128‐130].

So far, most patients received theranostics for PC under compassionate use conditions according to the Declaration of Helsinki [131] after treatment failure following chemotherapy, monoclonal antibody therapy, hormonal therapy, or ²²³Ra-chloride therapy receiving PRLT as an ultimate treatment option. As a matter of fact, so far, centers reporting data on PRLT have been well established with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors in the past. Usually, the precursors are commercially obtained, labeled with the radionuclide in specified radiochemical laboratories, and applied to patients using similar conditions as with radiolabeled somatostatin analogues. Hereto, fractionation of the dose applied to the patient was a prerequisite of the treatment scheme and dosimetry mandatory as well as follow-up of the patient by ⁶⁸Ga-PSMA-directed PET/CT or PET/mpMRI using the PERCIST criteria.

The current status of theranostics in prostate cancer (“Prostanostics”) is summarized in Fig. 6.