The era of prostate-specific membrane antigen for the diagnosis and treatment of prostate cancer: A novel horizon

BRIEF HISTORY OF PROSTATE-SPECIFIC MEMBRANE ANTIGEN

Prostate cancer is the most common malignancy in men and is associated with high morbidity and mortality [1]. Therefore, initial accurate evaluation of the extent of the disease is important for determining further treatment. However, conventional imaging modalities such as computed tomography (CT) and bone scintigraphy have limitations for detecting lesions in patients who experience recurrence of prostate cancer with low levels of prostate-specific antigen (PSA), i.e., less 5 ng/mL (<5 µg/L) [2]. Considering that the limited diagnostic utility of conventional imaging is not optimal for patients with high-risk prostate cancer or biochemical recurrence after primary treatment, there is a possibility of inappropriate overtreatment or insufficient treatment if accurate clinical staging is not established. Therefore, the demand for novel imaging techniques to improve the accuracy of conventional imaging has risen.

In 1987, Murphy and Horoszewicz’s team first developed the 7E11-C5 monoclonal antibody. 7E11-C5 is specific to an antigen present on normal and malignant prostate epithelium and in the serum of some prostate cancer patients. Using 7E11-C5 monoclonal antibody, Heston and colleagues succeeded in cloning the PSMA gene (encoding prostate-specific membrane antigen [PSMA]) in 1993 [3]. Although expression of PSMA is observed in normal prostate and non-prostate organs including the kidneys, salivary glands, lacrimal glands, small bowel, liver, spleen, and parasympathetic ganglia at various intensities, PSMA is overexpressed at obviously high levels in prostate cancer (up to 100–1,000 times the normal level).

Therefore, PSMA has been recognized as an ideal target for diagnosis or treatment of prostate cancer. In 2020, the U.S. Food and Drug Administration approved ⁶⁸Ga-PSMA-11 as a diagnostic radionuclide material for positron emission tomography (PET). Since the approval of ⁶⁸Ga-PSMA-11, another PSMA-based imaging agent, ¹⁸F-DCFPyL, was approved in 2021. Unlike ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL has the benefit of mass production based on a cyclotron.

USEFULNESS OF PSMA AS A PRIMARY DIAGNOSTIC MODALITY FOR PROSTATE CANCER

In a recent meta-analysis, PSMA PET-CT showed sensitivity and specificity in a pooled analysis of 0.97 and 0.66, respectively, with a negative likelihood ratio of 0.05 for the primary diagnosis of prostate cancer in patients with clinical suspicion, with use of the pathologic report as the reference. Furthermore, a retrospective analysis reported that PSMA PET-CT showed higher sensitivity for clinically significant prostate cancer compared with multiparametric magnetic resonance imaging (mpMRI) (94.85% vs. 86.03%; p=0.022) [4,5].

After prostate cancer is identified, it is still important to precisely locate the intraprostatic tumor foci for targeted biopsy or focal therapy. mpMRI has been widely used for this purpose, although concerns remain that mpMRI might underestimate the real extent of intraprostatic tumor foci. PSMA PET could improve the accuracy of mpMRI. For estimation of intraprostatic tumor volume, sensitivity and specificity were reported to be 86% and 87%, respectively, for PSMA PET; 58% and 94%, respectively, for mpMRI; and 91% and 84%, respectively, for the combination of PSMA PET and mpMRI [6].

In terms of primary staging, PSMA PET has been reported to present high specificity and positive predictive values for lymph node or bone metastatic lesions but suboptimal sensitivity (even if it is still higher than that of other traditional imaging). There is a restriction for PSMA PET to detect lymph node lesions smaller than 5 mm in diameter. In contrast, PSMA showed substantially higher accuracy for staging high-risk prostate cancer. The proPSMA study, which was the first multicenter, two-arm, randomized study to compare PSMA PET and traditional imaging, demonstrated that PSMA PET showed higher accuracy (92% vs. 65%), better sensitivity (85% vs. 38%), higher impact on further treatment plans (28% vs. 15%), and lower prevalence of indeterminate findings (7% vs. 23%) than other conventional imaging. The authors concluded that PSMA PET might replace traditional imaging for staging high-risk prostate cancer. The Appropriate Use Criteria for PSMA PET also commented that PSMA PET could be indicated for primary staging of unfavorable intermediate- and high/very high-risk prostate cancer, especially if CT and bone scintigraphy show distant metastasis of five or fewer lesions [4,5,6]. Despite these previous studies suggesting substantially improved diagnostic values of PSMA PET for primary prostate cancer, PSMA PET has not yet achieved the level needed for a strong recommendation in the current guidelines.

USEFULNESS OF PSMA PET AS DIAGNOSTIC MODALITY FOR PROSTATE CANCER RECURRENCE AND METASTASIS

Besides its substantial performance for primary diagnosis or staging of prostate cancer, PSMA PET has remarkable diagnostic value for recurrence of prostate cancer after initial definitive treatment. In this regard, PSMA PET was reported to be superior to existing PET modalities including ¹¹C-choline or ¹⁸F-fluciclovine PET, with improved scan positivity as the PSA level increased. However, there is not yet an officially standardized definition of positive PSMA PET findings. For the reasons above, the PSMA-Reporting and Data System, E-PSMA, and Prostate Cancer Molecular Imaging Standardized Evaluation staging system have been introduced to build consensus for defining a positive PSMA PET finding. However, reliable studies on the association of positive PSMA PET findings with long-term survival outcome are lacking. Most previous studies were retrospective or had short-term follow-up periods. Currently, the Randomized Phase 3 Trial of ⁶⁸Ga-PSMA-11 PET/CT Molecular Imaging for Prostate Cancer Salvage Radiotherapy Planning study (NCT03582774), a 5-year follow-up, phase 3 randomized study, is in progress and aims to evaluate the success rate of salvage radiotherapy based on conventional imaging or ⁶⁸Ga-PSMA-11 PET findings after radical prostatectomy [4,5,6].

USEFULNESS OF PSMA AS A THERAPEUTIC FOR PROSTATE CANCER

The first PSMA-targeted radionuclide developed as a therapeutic material for prostate cancer was 7E11-C5.3 (⁹⁰Y-caoromab pendetide), which failed to pass phase 1/2 clinical trials. Since then, there have been several trials to develop new PSMA-targeted radionuclides for therapeutic purpose, such as humanized J591, but the radionuclides had multiple adverse effects.

Currently, there are two types of PSMA ligand for ¹⁷⁷Lulabeled radioligand therapy: PSMA-617 and PSMA I&T. After PSMA-671 was reported to be developed and clinically utilized by Eder’s team and Kretochwil et al. (University Hospital Heidelberg), ⁶⁸Ga-PSMA-617 was introduced as a promising PET tracer. In 2015, ¹⁷⁷Lu-PSMA-617 was first used to treat patients with metastatic castration-resistant prostate cancer and succeeded in achieving radiologic and PSA-based responses. PSMA I&T, which was developed as an improved derivative of PSMA-DOTAGA-FFK (Sub-KuE), was first reported by Weineisen and colleagues (Technische Universität Munchen) in 2015. Among these two PSMA ligands, PSMA-617 has been more frequently utilized in clinical practice because of it low rate of renal absorption [3,7].

LIMITATIONS OF PSMA PET

Despite the substantially enhanced sensitivity of PSMA PET, there is a risk for false-negative findings ranging from 5% to 10%. These false-negative results stem from absent or insufficient expression levels of PSMA, heterogeneous expression of PSMA within a tumor, or the presence of small tumors (less than 4 mm) that are under the level of resolution of PET. In addition, PSMA-negative findings are present in very advanced, dedifferentiated types of prostate cancer, such as small cell neuroendocrine prostate cancer.

There is also the possibility of false-positive findings on PSMA PET in patients with granulomatous diseases such as sarcoidosis, fibrous dysplasia, bone fractures, Paget disease, and tumors of neurogenic origin, including schwannomas. In addition to its expression in these benign diseases, PSMA can be expressed in neovascular solid cancers such as hepatocellular cancer, glioblastoma, kidney cancer, thyroid cancer, and colon cancer. Furthermore, even normal organs can express PSMA, such as the kidneys, lacrimal/salivary glands, duodenum, liver, spleen, and parasympathetic ganglia. The concerns about how to minimize adverse effects on these normal tissues during PSMA-targeted radioligand therapy while maintaining therapeutic efficiency should be considered. Moreover, when a small suspicious lesion is identified only in PSMA PET images, it is still unclear whether treatment of these lesions will lead to survival gain in the patients.

CURRENT STATUS AND FUTURE OF NOVEL PSMA LIGANDS

Several domestic studies are in progress. As diagnostic PSMA ligands, ¹⁸F-FC-303 (FutureChem Co. Ltd.) and ⁶⁸Ga-PSMA-NOTA-GUL (or ⁶⁸Ga-PSMA-NGUL) (CellBion Co. Ltd.) have been developed and are undergoing clinical testing; in addition, ¹⁷⁷Lu-FC705 (FutureChem Co. Ltd.) and ¹⁷⁷Lu-PSMA-DOTA-GUL (or ¹⁷⁷Lu-PSMA-DGUL) (CellBion Co. Ltd.) are under clinical testing for PSMA-targeted radioligand therapy [7].

As mentioned above, PSMA PET could improve the limited accuracy of conventional imaging, especially in patients with high-risk prostate cancer or with biochemical recurrence after initial definitive therapy. For these patients, PSMA PET could help clinicians to modulate further treatment strategies by revealing potential tumor lesions that conventional imaging could not detect. Moreover, the expression level of PSMA in prostate cancer cells is reported to be affected by the androgen level, increasing by 5 to 10 times under androgen deprivation therapy. This suggests that PSMA-based diagnostic or therapeutic modalities could show their values in patients undergoing androgen deprivation therapy.