An Examination of PSMA Variants for PET/CT

Hildegard Kaulen, PhD
Photography by Carsten Büll

Prostate-specific membrane antigen (PSMA) is of benefit to medicine as it is a highly specific protein found on prostate cancer cells that can bind to small-molecule ligands. Coupled with a low- or high-dose radionuclide, a PSMA ligand is a tracer used in diagnostic PET/CT and endoradiotherapy. Its potential, originally identified in the USA many years ago, was recognized by professors Michael Eisenhut, PhD; Matthias Eder, PhD; and Klaus Kopka, PhD, of the German Cancer Research Center (DKFZ), as well as professors Uwe Haberkorn, MD; and Frederik Giesel, MD, of Heidelberg University Hospital in Germany. Giesel, a vice chair of the nuclear medicine department at Heidelberg, and Kopka, current director of the Institute of Radiopharmaceutical Cancer Research at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR)—and previous head of radiopharmaceutical chemistry at the DFKZ (2013-2019)—have advocated the use of PSMA-based diagnostics and endoradiotherapy for some years: and their efforts have paid off.

“PSMA-based tracers are now being used all over the world,” says Giesel, with a hint of pride. “The utilization of PSMA PET/CT in staging and restaging prostate cancer is increasingly recognized,” he elaborates. “Our retrospective data show that PSMA PET/CT leads to a change in therapeutic management in about half of all patients with a biochemical recurrence of prostate cancer. Patients who have a PSMA PET/CT are less likely to receive systemic treatment, and radiotherapy can be more personalized,” states Giesel. “We published these results in 2018 in the Journal of Nuclear Medicine”.1

Frederik Giesel and Klaus Kopka sit at DKFZ to discuss the imaging possibilities presented by various PSMA variants.
Frederik Giesel and Klaus Kopka sit at DKFZ to discuss the imaging possibilities presented by various PSMA variants.

Under the umbrella of the German Consortium for Translational Cancer Research (DKTK), Giesel and Kopka also lead an academically funded phase-I/-II study to determine the safety and efficacy of the gallium-labeled tracer known as 68Ga-PSMA-11.[a] “The aim of this study is to show that distribution of the tracer in PET/CT imaging is largely consistent with the extent of the tumor at the time of surgery,” says Giesel. “At the end of the day, our colleagues need a high degree of certainty that what they see in the imaging are in fact tumor lesions.”

Eleven centers in Germany, Austria, and Switzerland are taking part in the DKTK study. Similar studies are also ongoing in other regions of the world: in Japan and South Korea the research is part of a German Federal Ministry of Education and Research project, also led by Kopka and Giesel. “The DKTK study will involve 173 patients with prostate cancer, 170 of whom have already enrolled,” explains Kopka. “The data are expected to be analyzed and published next year,” adds Kopka. “It’s too early to talk about the results, but we can say it appears that the tracer is well tolerated and does not cause any side effects.”

How does the added value of PSMA PET/CT affect the clinical management of prostate cancer at Heidelberg? “In patients with biochemical recurrence, PSMA PET/CT allows us to detect and localize the recurrent tumor at PSA values as low as 0.2-0.5 ng/ml,” explains Giesel, referring to another Heidelberg study published in the Journal of Nuclear Medicine.2 “If we only detect a local recurrence, radiotherapy or surgery is a possibility. Solitary lymph node metastases are also treated surgically, while a few metastases may be treated with radiotherapy. Thanks to this differentiated approach, we can offer much more specific treatment and frequently delay hormone therapy. The patients are very grateful for that.”

Frederik Giesel, MD, Heidelberg University Hospital

Two PSMA tracers of similar structure, biodistribution, and tumoral uptake were developed in Heidelberg:
68Ga-PSMA-11 and 18F-PSMA-1007.[a]

Which one might be more successful?

“It’s not possible to say,” answers Kopka, “both have advantages and disadvantages.” A plus point for fluorine-18 is that the radionuclide can be used worldwide. Furthermore, fluorine-18 has a longer half-life at 110 minutes as opposed to gallium-68 at 68 minutes. This makes it possible to produce the fluorine variant centrally and deliver it to satellite centers. Additionally, fluorine-18 has a lower positron energy, which enables better image quality. Yet a key argument in favor of the gallium variant is its production method: gallium-68 generators allow convenient batch production for two to four patients, whereas the production of a fluorine variant requires a cyclotron.

“The benefit of the fluorine variant is that it has limited excretion through the kidneys and bladder but is excreted mainly through the liver and intestine,” explains Kopka.3 “With low clearance via the urinary tract, local relapses are not concealed. But in the end, availability will also be decisive. Some companies have already begun approval trials.” According to Giesel, a “cold kit” is a possibility for the gallium variant—in which substances need only be mixed and shaken—which would aide in the ease of handling in combination with a gallium-68 generator.

Klaus Kopka, PhD, Institute of Radiopharmaceutical Cancer Research (HZDR); German Cancer Research Center (DKFZ)

Will health insurers cover the cost of PSMA PET/CT? Giesel and Kopka can only comment on the situation in Germany and Switzerland, not in other countries. In Germany, PSMA PET/CT was included as an optional recommendation in last year’s updated version of the S3 guideline on prostate cancer.4 “This optional recommendation shows experts recognize value in the study,” says Giesel. “However, there is no billing code yet. In Germany, it is currently at the discretion of health insurance companies whether they reimburse PSMA-PET/CT imaging. In some regions of Germany, such as Berlin and North Rhine-Westphalia, there is already an agreement in place with health insurance companies,” he states, adding that 68Ga-PSMA-11 has been approved in Switzerland pending the outcome of ongoing trials.

There is also progress in the development of the therapeutic variant 177Lu-PSMA-617.[a] The radionuclide is being tested on advanced prostate cancer that no longer responds to hormone therapy. “The phase-II study, led by Michael Hofman and his colleagues at the Peter MacCallum Cancer Centre in Australia, was published in The Lancet Oncology and backed up our experience with the therapeutic variant,” says Giesel. “Hofman’s data shows for many patients, the PSA level declines following endoradiotherapy with 177Lu-PSMA and the tumor shrinks, but we can’t yet say anything about progression-free survival and overall survival,” he adds.5

Hildegard Kaulen, PhD, is a molecular biologist. After stints at the Rockefeller University in New York and the Harvard Medical School in Boston, she moved to the field of freelance science journalism in the mid-1990s and contributes to numerous reputable daily newspapers and scientific journals.