Danielle P. Meyrick, PhD, Chief Scientific Officer, GenesisCare
Nat P. Lenzo, MD, Medical Director, GenesisCare; Clinical Associate Professor in Medicine, University of Western Australia
Prostate cancer is the second most common cancer in men globally, making up about 15% of male cancer diagnoses (1). Initial treatment decisions at diagnosis are normally reasonably clear-cut, with active surveillance for low-grade tumors. For higher grade tumors, brachytherapy, surgical removal of the prostate, and/or external radiotherapy are effective treatments for cancer that has not spread (2). Following this initial treatment, unfortunately, a percentage of patients will eventually experience a cancer recurrence signaled by a rise in prostate specific antigen (PSA). Current management options range from active surveillance, hormone therapy, chemotherapy, and additional radiotherapy through to newer treatments, such as immunotherapy.
A less well-known option at this stage is targeted radioligand or radiopeptide therapy (also known as Peptide Receptor Radionuclide Therapy - PRRT), which falls under the growing area of medicine known as theranostics. This type of treatment leverages the molecular properties of prostate cancer to both image the tumor as well as to guide targeted treatment. The word, “theranostic” combines two words, therapeutic and diagnostic.
In prostate cancer, a unique protein is found on the surface of prostate cancer cells called prostate-specific membrane antigen (PSMA). In about 95% of prostate cancers, the amount of PSMA protein present on the prostate surface is 100- to 1000-fold higher than other cells in the body (3). Metastatic prostate cancer manifests the PSMA protein in the areas of metastases. Theranostic approaches targeting PSMA are being used increasingly worldwide for patients with recurrent prostate cancer.
The mainstays of diagnostic investigations for prostate cancer for many decades have been physical examination, blood tests for PSA levels, and biopsy. Imaging investigations, mainly CT, bone scan, specialized MRI techniques, and the recently developed PSMA theranostic imaging, give additional information. CT and MRI mainly highlight changes in internal anatomy, while theranostic imaging gives a location of prostate cancer tissue by highlighting PSMA, providing useful information about the extent and location of the disease to patients and clinicians. Used together, all these diagnostic techniques can give complementary information on the status of the prostate cancer.
The history of theranostic imaging in prostate cancer goes back more than twenty years with an imaging injection known as Prostascint®, developed at Johns Hopkins University (4). The field has grown rapidly since then, with many advancements in the last five years. Special molecules that attach to the PSMA on prostate cancer cells, called ‘PSMA ligands,’ are used. These molecules are connected to a radioactive atom (gallium-68, 68Ga or more recently fluorine-18, 18F). When injected into a patient, these radiolabeled molecules circulate through the blood and attach to PSMA on the surface of the cancer cells. 68Ga-PSMA ligands for PET imaging is now becoming an almost routine part of the diagnosis and management of prostate cancer in some countries, like Australia and Germany.
68Ga-PSMA imaging has been used most extensively in patients with rising PSA levels after surgery or radiation. A recent study of 1,007 patients found that recurrent cancer was detected by this method in 79.5% of patients whose PSA began to rise after their initial treatment (5). This technique works particularly well at low PSA levels when conventional techniques, such as CT alone, often don’t show the cancer. A recent analysis found detection rates of returned prostate cancer with 68Ga-PSMA ligand of 58% in patients with PSA between 0.2 to 1.0 ng/mL, 76% for PSA between 1.0 and 2.0 ng/mL, and 95% for PSA > 2.0 ng/mL (6). At our centers in Australia, we have found improved rates of cancer detection with 68Ga-PSMA PET imaging relative to CT alone, especially at low levels of blood PSA (7). This means decisions about treatment can be made earlier, and therapy can be started sooner.
The presence of PSMA on the surface of cancer cells can be used to target cancer cells directly for therapy. This is utilized almost exclusively for metastatic cancer. For therapy, the gallium-68 tagged to the PSMA ligand for the PET imaging is replaced by lutetium-177 (177Lu). This radioactive atom emits radiation that is able to damage cancer cells. The PSMA ligand molecule transports the radiation to the tumor site so that the remainder of the patient’s body is not exposed to high levels of radiation. Up till now, 177Lu-PSMA therapy has been used when the disease has metastasized and other treatments have failed, or when other standard therapies are not well tolerated. In certain patients, it appears to produce long-term remission (8). Prospective trials are currently underway in Europe, the USA, and Australia to confirm and quantify the benefit of this new treatment method.
177Lu-PSMA therapy is generally administered over several cycles (often 2 to 4), with about 6 to 8 weeks between each cycle. Response to therapy is assessed by a decrease in blood PSA, and a decrease in size of tumor/s on imaging by 68Ga-PSMA PET/CT scanning. In a recent report (9), a PSA decrease was found in just over 80% of 56 patients with metastatic prostate cancer resistant to hormone therapy. In about 60% of these men, the PSA declined by more than half, while on imaging, the prostate cancer had completely or partially remitted or stabilized in 68% of patients.
Another report (10) of 145 patients found an overall response to 177Lu-PSMA based on a 50% or greater blood PSA decline in 45% of patients after all cycles of therapy, with 40% of patients responding in this way after only one therapy cycle. Patients received one to four cycles of therapy, 8 to 12 weeks apart. Complete response based on conventional imaging was reported in 2% of cases, with partial response in 45%, stable disease in 28%, and progressive disease in 25% reported.
Reports of response to 177Lu-PSMA therapy continue to become available as centers around the world treat an increasing number of patients. Stabilization of disease and symptom relief seems to be the predominant outcome.
Treatment Side Effects
Once the radioactive solution is injected and circulates to the prostate cancer cells, it may also damage some healthy cells. Since the PSMA protein is also found in the salivary and lacrimal glands, kidneys, and small intestine, the PSMA ligand may also transport some radiation to these healthy tissues. Any damage to these areas, however, has been shown to be minimal (9). Main side effects of this type of therapy include dry mouth, fatigue, and a brief decline in the production of blood cells (11). Some patients with extensive bone disease may develop a bone pain ‘flare’ for up to 14-days post-therapy, which is usually managed with painkillers and steroids. A small group of patients experience nausea and, very occasionally, vomiting or abdominal pain. Most patients can continue with their normal activities throughout their treatment regimen.
The Future of PSMA Treatment
Currently, PSMA targeting therapy is used in patients with advanced cancer who are not able to tolerate, or no longer respond to, other therapies. There is interest to evaluate its use in combination with other therapies and to assess its use earlier in the treatment course, and there are clinical trials in the pipeline to address these questions. There are also possibilities to use different radioactive atoms besides 177Lu that may more effectively deliver a therapeutic dose of radioactivity to the tumor. It is important to note that, although not a cure for metastatic prostate cancer, these new targeted therapies can extend life in some patients and improve symptoms and quality of life in a significant group of patients.
Ervik, M, Lam, F, Ferlay, J, Mery, L, Soerjomataram, I, Bray, F, et al. Cancer Today, Lyon, France: International Agency for Research on Cancer. 2016. Available at http://gco.iarc.fr/today/home [Accessed 16 February 2018]
Paller, CJ, Antonarakis, ES, Management of Biochemically Recurrent Prostate Cancer After Local Therapy: Evolving Standards of Care and New Directions, Clin Adv Hematol Oncol. 2013; 11(1): 14-23
Silver, DA, Pellicer, I., Fair, WR, Heston, WD, Cordon-Cardo, C, Prostate-specific membrane antigen expression in normal and malignant human tissues, Clin Cancer Res, 1997; 3: 81-85
Bander, NH, Trabulsi, EJ, Kostakoglu, I, Yao, D, Vallabhajosula, S, Smith-Jones, P, et al., Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate-specific membrane antigen, J Urol. 2003; 170:1717-21
Afshar-Oromieh, A, Holland-Letz, T, Giesel, FL, Kratchowil, C, Mier, W, Haufe, S, et al. Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017; 44: 1258-68
Perera, M, Papa, N, Christidis, D, Wetherell, D, Hofman, MS, Murphy, DG, et al., Sensitivity, specificity, and predictors of positive 68Ga-PSMA-PET in advanced PC: a systematic review and meta-analysis. Eur Urol. 2016; 70: 926-37
Asokendaran, M., Meyrick, DP, Skelly, LA, Lenzo, NP, Henderson, A, Gallium-68 PSMA PET/CT compared with diagnostic CT in relapsed prostate cancer, under review
Kulkarni, HR, Singh, A, Schuchardt, C, Niepsch, K, Sayeg, M, Leshch, Y, et al. PSMA-based radioligand therapy for mCRPC: the Bad Berka experience since 2013. J Nucl Med. 2016; 57:97S-104S
Baum, RP, Kulkarni, HR, Schuchardt, C, Singh, A, Wirtz, M, Wiessalla, S, et al, Lutetium-177 PSMA radioligand therapy of mCRPC: safety and efficacy. J Nucl Med. 2016; 57: 1006-13
Rahbar, K, Ahmadzadehfar, H, Kratochwil, C, Haberkorn, U, Schäfers, M, Essler, M, et al, German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced PC-patients. J Nucl Med. 2017: 58: 85-90
Virgolini, I, Decristofor, C, Haug, A, Fanti, S, Uprimny, C, Current Status of Theranostics in Prostate Cancer. Eur J Nucl Med Mol Imaging 2018; 45:471-495