PSMA: A Windfall for PET/CT Imaging

Hildegard Kaulen, PhD |  2017-08-23

Retrospective clinical data suggest PET/CT imaging using 68Ga-labelled PSMA-11 will radically transform diagnostics, staging and operation planning of prostate cancer. A prospective multicenter trial is currently under way, offering a compelling example of translational medicine.

Affecting almost 420,000 people in Europe alone, prostate cancer is one of the most common carcinomas among men. Currently, diagnosis requires a biopsy, which also provides the data used for staging. With only one in seven prostate carcinomas requiring aggressive treatment, it would be very helpful to have a non-invasive diagnostic method that provides information on the status and the spread of the lesions. Many prostate carcinomas remain symptom-free and therefore do not have to be addressed at all. A target that helps to tell the difference and combines diagnosis and therapy on a theranostic basis is urgently needed.

The prostate-specific membrane antigen (PSMA) is a protein that ticks a number of boxes, thus making it an excellent target candidate. It is very specific, occurring from a hundred up to a thousand times more frequently on prostate cancer cells than on the cells of normal organs. Its presence correlates with an unfavorable prognosis. It can bind small-molecule ligands that are quickly cleared from the blood with low background activity. Not only that, but PSMA is internalized by the prostate cancer cell after binding of the ligand resulting in an effective trapping. Coupled either with a diagnostic or a therapeutic radionuclide, a PSMA ligand is an ideal tracer for diagnostic PET/CT imaging, and treatments such as endoradiotherapy. 68Ga-labelled PSMA-111 and 177Lu-labelled PSMA-617 are a perfect theranostic duo.

68Ga-labelled PSMA-11 was developed by Professor Michael Eisenhut and Matthias Eder, MD at the German Cancer Research Center (DKFZ) in Heidelberg, Germany. Professor Uwe Haberkorn, who directs the nuclear medicine clinic in Heidelberg, first deployed the novel tracer in compassionate use four years ago. In the meantime, several hundred such instances worldwide have shown that 68Ga-labelled PSMA-11 detects recurrent prostate cancer at a high level of sensitivity in PET/CT scans.2, 3, 4 Detection of lymph node metastases is below the threshold of other usual imaging methods. However, there is still a lack of prospective clinical data on 68Ga PSMA-11 imaging.

These data are now to be captured in an exclusively academically funded multicenter clinical trial under the umbrella of the German Consortium for Translational Cancer Research (DKTK), or in short, the German Cancer Consortium. This makes the clinical trial a great milestone in translational medicine. Responsible for planning and organization are Professor Frederik Giesel at Heidelberg University Hospital and Professor Klaus Kopka at the DKFZ. Giesel is vice chair of the Nuclear Medicine department and the clinical trial director. Kopka is a chemist who heads the Division of Radiopharmaceutical Chemistry at the DKFZ. He is responsible radiopharmaceutical coordinator of the prospective study. The two are an excellent tandem crew for this unique bridging of basic research and clinical practice.

On the way to being included in clinical guidelines

Why is this prospective phase I and II clinical trial so important? “The PET/CT imaging data gathered for prostate carcinoma with 68Ga-labelled PSMA-11 so far are retrospective data, where the PSMA-PET/CT imaging was compared with the choline-PET/CT imaging that is usually used for the diagnosis of prostate carcinoma,” explains Giesel. “While these results are groundbreaking to the extent they have shown that 68Ga-labelled PSMA-11 is more sensitive than the choline tracer for diagnosing recurrent prostate cancer,2, 3, 4 only prospective trials count when it comes to inclusion in clinical guidelines and having the costs covered. So retrospective studies aren’t really much use,” continues Giesel.

They are not accepted as a basis for guidelines because they are not homogenized (harmonized) and are only based on individual cases of compassionate use. But the potential of the new diagnostic tracer is already underscored by the fact that due to the extraordinarily good results for PSMAPET/ CT imaging in retrospective studies, the method has already been included, even without prospective data, in the proposed amendments for the next revision of the German clinical guidelines. Which centers are behind the prospective clinical trial? “Seven of the eight DKTK centers will be involved, along with four other sites,” says Kopka, “including one in Austria, and one in Switzerland.” He explains the trial will be funded primarily by the German Cancer Consortium, and that it is already seen as a type of role model for translational clinical studies in nuclear medicine. “Our trial is a flagship project. In Germany, we’re right at the forefront in terms of translation in cancer research.”

Trial will be launched in 2017

What precisely are they planning? “The clinical trial will include 150 high-risk patients with prostate cancer before radical prostatectomy,” says Giesel. “It will begin in quarter 2 of 2017. Patients with a high PSA value and a positive biopsy, and have not yet received therapy, are included. 68Ga-labelled PSMA-11 PET/CT imaging will then be done prior to prostatectomy to check the extent to which the tracer correctly reflects the staging and the spread of the lesions determined in surgery,” Giesel continues. To assure the comparability of data, the biopsy and the pathological examination of the tissue samples will be standardized. “The 68Ga-labelled PSMA-11 PET/CT scan will be quantified by cross-calibrating with a phantom,” explains Kopka.

But PSMA is not just an excellent candidate for imaging; together with a therapeutic radionuclide it can also be used for therapy. Did they consider the possibility of combining diagnosis and therapy from the outset? “It developed as things progressed,” says Kopka. “Imaging allows you to get to the tumor and decide whether endoradiotherapy makes sense. Given the biodistribution of 68Ga-labelled PSMA-11, it was immediately clear that we should develop a therapeutic option. We then did precisely that with 177Lu-labelled PSMA-617.” This therapeutic variant has already been licensed out to ABX advanced biochemical compounds.

“With this academically funded study we also want to give something back to the healthcare system and society. We have high expectations. Then we’ll see what happens.” Professor Klaus Kopka, MD, Head of Radiopharmaceutical Chemistry, DKFZ Heidelberg, Germany

18F instead of 68Ga

Kopka and his team are also pursuing a diagnostic option with fluorine-18, 18F-labelled PSMA-1007. “There are various reasons for this,” explains the chemist. “Like gallium-68, the cyclotron-produced positron-emitter fluorine-18 can be also used all over the world. However, in some countries, such as in Japan, they don’t use gallium-68 at all. Fluorine-18 also has a longer half-life than gallium-68: around 110 minutes versus only 68 minutes. Despite this, there will still be a place for gallium-68, because not every center has a cyclotron, and centers without a cyclotron will continue to work with generator-produced 68Ga-labelled PSMA-11,” says Kopka. Initial results show that 18F-labelled PSMA-1007 and 68Ga-labelled PSMA-11 are similar in terms of structure, biodistribution and uptake by prostate cancer cells. Just last year we introduced PSMA-1007 also successfully into the clinic also with very impressive tracer-characteristics (see Giesel et al., EJNMMI 2016).

What role will these therapies play in the future? Kopka believes it is time for nuclear medicine to leave behind the reputation of being only responsible for niche treatments. Therefore, the concept of theranostics should be developed further in oncology. This would also justify the personnel-intensive collaboration with radiochemistry and radiopharmacy. Giesel shares this view. While he concedes that nuclear medicine is a small discipline, he believes this will change once it gets involved in diagnosing and treating common cancers. “With almost 80,000 new cases a year in Germany, prostate carcinoma are highly relevant,” says Giesel. “The retrospective data have shown that after a 68Ga-labelled PSMA-11 PET/CT imaging
fifty percent of patients receive a different therapy in radio-oncology. That’s a very important finding.” The radiologist and nuclear medicine specialist participated in a meeting in Seoul, under the umbrella of the IAEA, which included discussion on how nuclear medicine could best develop in emerging countries. Giesel says the consensus was that this would only be possible by way of theranostics and prospective clinical trials. This is why 68Ga-labelled PSMA-11 is so important, because it could potentially help give PET/CT imaging high status in terms of diagnosing and therapeutic management.

Kopka also points to the other common cancers, for example melanoma, mammary, colon, pancreas, or bronchial carcinoma, that can be addressed with theranostics. He explains there is plenty of work in progress, also in his division. But first the prospective clinical trial on prostate carcinoma has to be driven forward. “With this academically funded study we also want to give something back to the healthcare system and society,” he says. “We have high expectations. Then we’ll see what happens.”

About the Author

Hildegard Kaulen, PhD, is a molecular biologist. After sojourns at Rockefeller University in New York and Harvard Medical School in Boston, she has worked as a freelance science journalist since the mid-1990s, writing for prestigious daily newspapers and science magazines.

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168Ga-labelled PSMA-11 referenced herein is not currently recognized by the US FDA as being safe and effective, and Siemens does not make any claims regarding its use.

2Afshar-Oromieh, A. et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol I 41, 11–20 (2014).

3Schwenck, J. et al. Comparison of 68Galabelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol I 44, 92–101 (2016).

4Perera, M. et al. Sensitivity, Specificity, and Predictors of Positive 68Ga–Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta.

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