The prostate-specific membrane antigen is a transmembranous glycoprotein with enzymatic value (synonym: glutamatcarboxypeptidase II) that is over-expressed in prostate cancer but not, as the name suggests, entirely specific for the prostate. It can also be found in healthy human tissue, for example, in salivary and lacrimal glands, the small intestine and the kidneys, which is of importance when using PSMA as a target for diagnostic and especially radioligand therapy [2
]. PSMA-targeting radioligands, i.e., Glu-ureido based PSMA inhibitors bind to the zinc active site of PSMA. The inhibitor/PSMA complex becomes subsequently internalized into PSMA-positive tumor cells by clathrin-mediated endocytosis. This results in deposition of the PSMA-tracer both on the cell surface and in the cytosol where the tracer remains. At the same time, unbound tracer clears from the body. This leads to a high tumor-to-background ratio, making this class of theranostic radioligands feasible for sensitive imaging and efficient endoradiotherapy of PSMA-positive prostate cancer. As several retrospective studies show, the over-expression of PSMA in prostate cancer correlates directly and conveniently with the tumor grade, progression state and presence of metastases, and is a significant indicator for disease outcome (please see in all detail corresponding reviews on PSMA-tracers in [1
This descriptive study gives an overview of the recent developments and the status quo of prospective clinical trials in the field of PSMA-radioligands for the diagnosis and therapy in prostate cancer patients. The strong increase of prospective clinical PSMA-trials registered on ClinicalTrials.gov
shows how promising the use of PSMA radioligands has become in recent years for radiopharmaceutical and nuclear medical research and development. Our results can serve as a basis for radiopharmacists and nuclear medicine physicians as well as regulators and policy makers.
In order to give a detailed and informed description of the current status of PSMA-tracers, we carefully processed the original data set to glean and then to evaluate information concerning radiopharmaceutical and clinical parameters. Moreover, we point out specific characteristics and outline (regulatory) features which are special for prospective trials with innovative radiotracers for theranostics. In the subsequent sections, we will discuss the results of our registry data analysis in the context of the current literature from a radiopharmaceutical and organizational perspective. We will then delineate potential future fields of research and point out limitations of our analysis.
4.1. Development and Current Status of the Clinical Translation of PSMA-Radioligands
The clinical impact of PSMA-tracers for the diagnosis and therapy of prostate cancer in nuclear medicine can only further develop by initiation of (inter-)national prospective clinical trials. Only with these corresponding clinical trials can the safety and tolerability be confirmed, which is needed even when applying the microdosing concept. Moreover, of utmost interest is the determination of key variables such as sensitivity and specificity, and of the primary endpoints such as overall survival (OS) and progression free survival (PFS). With the establishment of these facts, the benefit for the patients can be proven unequivocally which, subsequently, will lead to newly implemented applications in nuclear medicine under marketing authorization.
We detected a fairly sudden and fast increase of prospective trials in the field of PSMA-tracers for prostate cancer, especially over the last years. Even though the concept of PSMA-targeting agents has been around for a long time [2
], it was not till the development of small molecule PSMA-radiotracers and with it the new concept of theranostics, that PSMA-radioligands gained clinical relevance on a large scale. As our data illustrates, there is nowadays a vast number of different PSMA-radiotracers. Our study results show though, that, to date, in two-thirds (66%) of the investigated registered prospective trials, three PSMA-radioligands were by far the most frequently validated. As may be deduced from Table 1
, these are tracers with different radionuclides (68
Ga vs. 18
F for diagnostic purposes and 177
Lu for radioligand-therapy). It will be very interesting to see which tracers will prevail in the long run. It is to be presumed that only a very small number of PSMA-tracers with unique characteristics, and/or application fields that show favorable radiopharmaceutical and clinical properties, will prevail in the clinical setting. In this context, it has to be noted that the tracers that we found to be the most frequently applied in prospective clinical trials as of now, will not necessarily be the ones to prevail in the future, especially since our analysis did not include any kind of evaluation or assessment of the radiopharmaceutical and clinical abilities and performance of the different tracers.
Beyond that, our study results show that there is a high number of PSMA-tracers coupled with 68
Ga and 18
F respectively. Taking into consideration the different radiopharmaceutical and clinical properties as well as assets and draw-backs concerning production, transport and handling of the radioligands, this seems very sensitive. For the production of 68
Ga-PSMA-radioligands for example, a 68
Ga-generator is primarily used whereas you need a highly regulated cyclotron infrastructure for the production of 18
F-tracers. Advantages of the latter include a higher production yield and a longer half-life compared to 68
Ga-ligands (110 vs. 68 min). It is, therefore, possible to transport 18
F-tracers over a certain distance, for instance, to external hospitals or application sites for the (Hybrid-) PET scan [34
]. Taking into account these specific differences in the manufacturing and transportation process, there is also an economic incentive for the use of one or the other radionuclide. Hospitals with a rather small number of prostate cancer patients and/or without a cyclotron on-site could opt for 68
Ga-PSMA-radioligands produced with a 68
Ga-generator, because the acquisition of a cyclotron comes with a great financial and organizational investment. Clinics, with a high number of patients needed to treat, and a cyclotron on-site, on the other hand, will generally pick the 18
F-radioligands as their PSMA-tracer of choice amongst others because of the decreasing marginal costs. As an alternative, they could also opt for the production of 68
Ga-tracers via the cyclotron if there is only a need for a small amount for in-house use.
Tracers for radioligand-therapy enable the personalized treatment of prostate cancer patients applying the theranostic principle and, therefore, cover a different application spectrum. There is a total of n = 18 trials in our data set that we identified by means of the reported applied tracer as well as the study description as therapeutic. With n = 15 177Lu was, by far, the most frequently used radionuclide for radioligand therapy. With n = 2 for 131I and n = 1 225Ac, the alternatives were scarce. 177Lu is currently one of the favorable beta particle emitting radionuclides for endoradiotherapy. Its production is possible with research reactors which are also used for the production of 131I and 99Mo. Its nuclear decay properties make 177Lu feasible and optimal for interval short-term applications. Due to the small amount of gamma emission, the radioligand distribution can be monitored by scintigraphy and/or SPECT. Additionally, with 177Lu there are less side effects because beta irradiation on salivary and lacrimal glands results mainly in reversible xerostomia.
4.2. Study Organization and Patient Recruitment
Taking a closer look at the organizational structures of the included clinical trials, it has to be noted that the vast majority were single-center studies who recruited their patients at one trial site only. The main reason for this could be the considerably smaller organizational and financial effort of monocentric trials in comparison to decentralized recruitment at different trial sites. In order to conduct prospective multicenter trials with PSMA-radioligands, there are a huge number of requirements to meet or to agree upon, i.e., approvals like positive ethics votum and a production license for each trial site, highly regulated guidelines to follow including laws from different federal and local authorities (including radiation protection), the harmonized production and application of the IMP, calibrated PET-cameras for the scans at the different sites and, last but not least, the documentation and storage of left-over trial tracers. Especially in the case of prospective multicenter trials for PSMA-radioligands with a short half-life like 68
Ga-tracers, there is the difficulty of producing the PSMA-tracers harmonized and in accordance with the legal and regulatory guidelines, as well as being GMP-compliant at all the different trial sites. Zippel, Neels et al. are discussing the most relevant aspects of initiating a prospective multicenter trial with short-lived PSMA-radioligands by means of one of the trials included in our data set ([68
Ga]Ga-PSMA-11 in high-risk Prostate Cancer, NCT03362359) for the D-A-CH region [35
The data analysis further shows that with 95% of all trials, the vast majority were national studies. Only 5% of all trials recruited patients internationally. One reason could be a strategic edge in the approval process. Probably equally important are the difficulties obtained by differing regulatory requirements for the production of the IMP and trial admission in different countries [36
]. The VISION-Trial, a study about radioligand-therapy with [177
Lu]Lu-PSMA-617, was the only multicenter trial in the data set that is recruiting patients in different countries and across continents (NCT03511664) [37
The authors strongly believe that the initiation of (inter-/national) multicenter trials will gain importance in the very near future, in order to achieve the needed number of patients to be enrolled for prospective clinical trials for radiotracers in a foreseeable time frame and within the limits of narrow inclusion criteria in a more and more individualized treatment regimen in precision oncology. Keeping in mind the aforementioned regulatory and organizational challenges, especially where short-lived tracers like 68Ga are concerned, it seems sensible to further strengthen already existing regulatory set-ups for the decentralized manufacturing and application of PSMA-radiotracers with sufficient recruitment numbers to facilitate a quick and therewith comparatively cheap translation of promising new radioligands into the clinic. This applies specifically for investigator-initiated trials, which make up the vast majority in our data set, with usually limited financial resources and/or a tight budget.
4.3. Research Perspectives
The rapid increase in registered prospective PSMA-trials on ClinicalTrials.gov
over the last couple of years (see Figure 1
) is a clear indicator for the increasing importance of the collection of patient-based endpoints and proof of patient benefit derived from prospective trials in nuclear medicine. This applies to diagnostic as well as therapeutic PSMA-tracers. This descriptive study may only give a first indication and point out a trend regarding the recent developments of prospective PSMA-trials for prostate cancer. The authors state that further research in the field is needed, especially in the areas of but not necessarily limited to:
Multivariate analyses, for example of comparable study designs;
Study (design) specific subanalyses of the different PSMA-radiotracers and their application fields (primary/secondary staging, BCR, radioligand-therapy, patient management);
Compare and combine the prostate cancer-related trial registry entries on ClinicalTrials.gov
with the data from other registries such as from Europe (e.g., DRKS), Asia (JPRN, ChiCTR) or Oceania (ANZCTR);
Longitudinal studies to identify future developments in the field of novel PSMA-radiotracers, be they diagnostic or therapeutic;
Additional detailed analyses of the free-text sections of the evaluated registry data concerning, for example, primary/secondary end points, inclusion/exclusion criteria and outcome measures.
Furthermore, there was a number of trials concerning PSMA-radiotracer-use for non-prostate cancer in the original, not processed data set; for example, in thyroid cancer, different kinds of gynaecological cancers, renal cancer, transitional cell carcinoma, glioblastoma and other solid tumors. We excluded these trials because they did not fit our study’s aim. The assessment of potential benefits and perspectives in this field are, therefore, beyond the scope of our analysis. Further research in this direction could be of great value.
The registry data from ClinicalTrials.gov
enables analyses of a multitude of systematically collected, study-specific detailed information of high quality over a period of time. A method-inherent error of our investigative approach is, that our data set only represents a subset of all initiated PSMA-trials around the globe, since the PI or sponsor of the respective clinical trial may as well choose a different registry to list their study accordingly. Examples, as listed above, are the Deutsches Register für Klinische Studien (DRKS) in Germany or the Australian New Zealand Clinical Trials Registry (ANZCTR). The latter includes, for instance, the so called “LuPSMA trial” a phase-II trial for radioligand-therapy with [177Lu]Lu-PSMA-617 (Identifier: 12615000912583) [20
], that is listed exclusively at ANZCTR. It is possible and, as our data confirms, quite common to register a trial in more than one registry, which again makes a comparison of data between different registries quite difficult due to potential duplications. In addition, different (usually national) study registries collect trial data with differing reporting options and obligations, and have different study search functions and data export functions resulting in a very heterogeneous information set when compared to other registries. This illustrates the importance of harmonizing the fairly large number of registries to prospectively create (also linguistically) more uniform data sets. This, in turn, would facilitate and improve the knowledge transfer from a methodological point of view.
Furthermore, common limitations of clinical registry (meta-) data analyses apply, which may impair the data quality [23
]. This includes, in particular, incorrect or not at all answered sections of the registry form. While processing our data set, we detected, for example, that multiple studies stated “treatment” as a primary study purpose even though the PSMA-tracers applied were clearly for diagnostic purposes. Sometimes this was the case, when the trial used PSMA-tracers to decide on how to proceed with patient treatment or how the imaging affects the treatment or radiation plan.
Last but not least, it has to be assumed that since ClinicalTrials.gov
is an U.S. American registry, there is a disproportionately high number of registered clinical trials conducted in North America. Our study results strongly support this hypothesis (see Table 2
), seeing that the vast majority of trials recruited in the USA and Canada. This may possibly lead to distortions in comparison to the status of PSMA-tracer-trials in, for example, Europe or Asia. Our study’s aim was, therefore, solely to illustrate a trend in this recently evolving field of nuclear medicine. Additionally, since ClinicalTrials.gov
is by far the biggest and most renowned registry for clinical trials with currently more than 320,000 listed clinical trials from all over the world [40
], the authors conclude that this is a very suitable data set for an overview on the current status of PSMA-radioligands.