Why Targeting of PSMA Is a Valuable Addition to the Management of Castration-Resistant Prostate Cancer: The Urologist’s Point of View

Prostate cancer (PC) is the most common cancer and the third most common cause of cancer-related deaths in men in developed countries (1). In general, PC starts out as an androgen-dependent tumor. Thus, androgen-deprivation therapy represents the backbone of treatment for metastatic PC (2). However, disease progression usually occurs within a few years despite castrate levels of serum testosterone, defining a state called castration-resistant PC (CRPC). Most of these patients develop resistance to castration due to a reactivation of the androgen receptor signaling axis. In the last decade, several drugs have been shown to provide a survival benefit for men with metastatic CRPC. However, prediction of response is challenging and the optimal choice of several treatment options has to be made on an individual basis. Currently, the most frequently used first-line treatments for asymptomatic or minimally symptomatic metastatic CRPC are abiraterone acetate (AA) plus prednisone, enzalutamide, or sipuleucel-T (in North America). AA is an inhibitor of CYP17, which is a key enzyme required in testosterone synthesis. Enzalutamide is a second-generation antiandrogen that inhibits androgen binding to androgen receptors, inhibits androgen receptors from entering the cell nucleus, and inhibits androgen receptors from binding to DNA and from serving as a transcription factor. Sipuleucel-T is a personalized, autologous, cellular vaccine against prostatic acid phosphatase combined with granulocyte–macrophage colony-stimulating factor. Secondline therapy and therapy for symptomatic CRPC consist of taxane chemotherapy (docetaxel or cabazitaxel), 223Ra, or AA/enzalutamide (whichever has not been used as the firstline therapy). Taxanes disrupt the orderly microtubule function, whereas 223Ra is a calcimimetic that decays while emitting a-radiation and internally irradiates bone metastases. In contrast to androgen receptor–targeting strategies, “unspecific” cytostatic chemotherapies can be effective in metastatic CRPC, even when firstand second-line hormonal therapies fail. However, these are associated with considerably more side effects. In patients not willing to be treated with chemotherapy or not eligible for chemotherapy because of the respective toxicity profile, AA or enzalutamide is often used as the second-line therapy of choice. However, the second-line treatment success of AA or enzalutamide is often limited and short-lived because of cross resistance caused by, for example, alternative splicing of the androgen receptor (3,4). Novel targeted therapies with favorable toxicity profiles are therefore needed to broaden the therapeutic armamentarium. Among others, the prostate-specific membrane antigen (PSMA), a transmembrane protein that is physiologically expressed in prostate cell membranes but highly overexpressed in primary PC and increasingly more in CRPC metastases, seems to be a promising molecular target both for imaging of tumor spread and for radioligand therapy (5,6). Over the past few years, PSMA-targeting PET tracers such as 68Ga-PSMA-11 have significantly improved diagnostic pathways in PC (7). PSMA PET/CT or PET/MRI should be considered the new gold standard for imaging of men with biochemical recurrence. A general challenge for PSMA imaging is the presence of few tumors without PSMA expression. Ligandspecific challenges for 68Ga-PSMA-11 PET/CT are evaluation of bladder infiltration (because of the excretion of PSMA-11 via the urinary tract), the limited availability of the radionuclide (because of generator capacity), and the short half-life of 68Ga (68 min), which prohibits delivery to distant PET centers. Therefore, investigations are under way of 18F-labeled PSMA tracers that can be produced in large amounts in a cyclotron and whose longer half-life (110 min) would enable transfer to satellite institutions (8,9). Besides imaging, PSMA-targeted endoradiotherapy of metastatic CRPC is emerging. Several recent retrospective studies have shown a high potential for the PSMA-targeted radioligand 177Lu-PSMA-617 applied under a compassionate-use provision in end-stage metastatic CRPC patients (10–16). On ligand binding, PSMA and its bound molecule are internalized via clathrincoated pits and subsequent endocytosis. Because internalization enhances uptake of activity and retention, targeting of PSMA results in a high local intracellular deposit for therapeutic applications. While the b-ray–emitting component of 177Lu-PSMA-617 efficiently irradiates these cells, the g-component can be used for imaging. As demonstrated by promising PSA declines, this innovative therapy is effective and exhibits a favorable toxicity profile in patients with end-stage metastasized PC (10–16). A recent study on 177Lu-PSMA-617 radioligand therapy in the largest cohort of patients so far (248 therapy cycles in 145 men) has shown a considerable response rate, with a PSA decline of 50% or more in 45% of patients (12). An alkaline phosphatase level of less than Received May 10, 2017; revision accepted May 11, 2017. For correspondence or reprints contact: Boris A. Hadaschik, Department of Urology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. E-mail: boris.hadaschik@uk-essen.de Published online May 18, 2017. COPYRIGHT© 2017 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.117. 194753