PSMA Emerges as Versatile Target in Prostate Cancer and Beyond

Named the medical invention of the Year by TIME magazine at the turn of the millennium,¹ positron emission tomography/ computed tomography (PET/CT) has changed the landscape of cancer diagnosis, facilitating earlier detection and more accurate staging of a range of tumor types.²

Along with magnetic resonance imaging (MRI) and bone scans, PET/CT has become a pillar of prostate cancer management, which is often challenging because of the disease’s highly varied clinical course. These imaging technologies, however, have limitations, particularly regarding the detection of disease recurrence after primary treatment.³

Investigators are looking at prostate-specific membrane antigen (PSMA), a highly prostate-restricted membrane protein, to fill the need for more sensitive imaging technologies. The possible applications of PSMA-targeted PET/CT run the gamut from initial staging to better identification of biochemical recurrence.

Accumulating evidence also suggests that it could serve as a tool to guide treatment and improve patient outcomes.

Besides its role in cancer imaging, multiple ways of therapeutically targeting PSMA for prostate cancer, and potentially even other types of cancer, are under active study. These strategies include radiolabeled small molecule inhibitors and antibodies (Figure).⁴ Although the therapeutic potential of targeting PSMA is less well developed, emerging clinical trial data suggest value with this approach.

Although most of the ongoing clinical trials are focused on prostate cancer settings, early-phase trials are ongoing in renal cell carcinoma, gynecologic malignancies, and ovarian, thyroid and urothelial cancers (Table). The future of PSMA in prostate cancer and beyond looks extremely bright.

Managing Risk With Imaging

Figure. Mechanism of PSMA-Based Therapy Using a Radiopharmaceutical⁴

In prostate cancer, the clinical course of disease is extremely varied, and to avoid overdiagnosis or unnecessarily aggressive treatment, investigators have developeed riskadapted management strategies, resulting in 5-year survival rates of 100% for patients with localized and regional disease.⁵ Unfortunately, a significant proportion of patients see their tumors return within a decade of primary treatment; the risk of recurrence after radical prostatectomy ranges from 20% to 80%, depending on a variety of risk factors. If detected early, recurrent disease can be managed highly effectively by salvage treatment, which offers long-term control in about half of patients. Once tumors metastasize, survival rates plummet.^6,7 Molecular imaging technologies have revolutionized the management of advanced and recurrent prostate cancer. PET/CT scans in particular have enabled noninvasive monitoring of changes in disease burden at the whole-body level over time. Along with MRI and bone scintigraphy, these scans assist in primary staging of advanced prostate cancer and in the detection biochemical recurrence in patients.^8,9

Prior to PET/CT scanning, patients are given an injection of a radioactive tracer that travels through the bloodstream and is taken up by cancer cells, such that the scanner can subsequently detect the radiation they emit, helping to localize the tumor cells. Three PET tracers are currently approved by the FDA for prostate cancer imaging: 11C-choline, 18F-fluciclovine, and 18F-sodium fluoride.^3,8,9

Rising levels of prostate-specific antigen (PSA), an enzyme secreted by the epithelial cells of the prostate, signal returning disease but are not a completely reliable biomarker because distant metastases can develop even with stable PSA levels. Thus, performing scans could help to confirm the presence of recurrent disease when it is at the localized stage and more readily treatable with salvage therapy.^7,10

Current guidelines recommend that patients undergo salvage radiation therapy when PSA levels are <0.5 ng/mL.¹¹ The approved PET tracers are limited in their ability to detect recurrent disease and assessment of the metastatic burden, particularly in patients with low PSA levels.^12,13 This presents a challenge because treatment is most effective if it is initiated early and if the irradiated areas encompass all areas of recurrent disease.⁶

A Promising Prostate Target

Table. Select Ongoing Clinical Trials of PSMA-Targeting Theranostics

Like PSA, PSMA is a highly prostate-specific protein, except that it is found on the surface of cells rather than in the bloodstream. PSMA, first discovered in the late 1980s,¹⁴ is a glycoprotein that spans the cell membrane and has enzymatic activity. It typically acts as a glutamate carboxypeptidase that catalyzes the release of glutamate residues from the C-terminal end of certain proteins.⁷ Its function depends on the tissue in which it is expressed; it is found at low levels in several different tissue types. The precise function of PSMA in the prostate is not yet clear. PSMA has been a focus in prostate cancer research circles for decades. What makes it such an exciting target are its substantial overexpression on prostate cancer cells and low expression on normal tissues.^15,16 In addition, PSMA has been shown to be taken up into cells upon binding of its ligand, which offers the potential for enhanced uptake and retention in tumors.¹⁷ What’s more, PSMA expression may have prognostic value; several studies have demonstrated that it correlates with disease state.^18,19

Investigators recently uncovered a potential role for PSMA in the transition to castrationresistant disease. One of the mechanisms thought to underlie the development of castration-resistant prostate cancer (CRPC) involves the PI3K pathway, which is activated in most patients with CRPC.²⁰ In releasing glutamate, PSMA was shown to indirectly activate PI3K, with glutamate acting as a second messenger and switching on signaling pathways upstream of PI3K.²¹

PSMA expression is not specific to prostate cancer. Although there is limited overexpression on the tumor cells themselves in other types of cancer, PSMA is frequently substantially overexpressed on the endothelial cells of the abnormal vasculature surrounding a variety of nonprostate cancers, most commonly breast, lung, colorectal, and renal cancers. Results from some studies have also shown an association with more aggressive features in these tumors.^22,23 Numerous ongoing clinical trials are evaluating the potential role of PSMA targeting in nonprostate cancers

PSMA-Targeting PET Tracers

Table. Select Ongoing Clinical Trials of PSMA-Targeting Theranostics (Con't)

Two leading strategies have emerged for targeting PSMA: monoclonal antibodies and small molecule inhibitors. For the purposes of imaging, these agents are conjugated to a radioactive atom that a PET scan detects. The first PSMA-targeted antibody to be developed was capromab pendetide (7E11-C5.3), which was conjugated to indium 111 to produce the PET imaging agent ProstaScint.²⁴ In 1996, the FDA approved its use for the detection and staging of newly diagnosed disease in patients facing an elevated risk of pelvic lymph node disease and for those at risk of recurrence after prostatectomy.^25,26 However, widespread adoption was limited by a poor tumor-tobackground signal ratio and ultimately, the manufacturer discontinued development in April 2018.^25,27 Investigators are currently evaluating an antibody-based prostate cancer imaging agent, ⁸⁹Zr-DFO-huJ591, in clinical trials (NCT01543659).

Small molecule inhibitors of PSMA are predominantly either urea- or phosphorusbased molecules and, to date, have proved to be the most effective in the clinic for prostate cancer imaging.¹³

⁶⁸Ga-PSMA-11

Presently, the most widely studied PSMA-based PET tracer is ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA- 11). It is being evaluated in 6 phase III clinical trials in the prostate cancer setting. A growing body of evidence suggests that ⁶⁸Ga-PSMA-11 outperforms traditional imaging technologies in the primary staging of prostate cancer and in detecting biochemical recurrence.^28,29

Large, prospective clinical trials are still lacking, but investigators are starting to address this need. Recently, the results of a multicenter, single-arm, prospective trial in 635 patients with biochemically recurrent prostate cancer (262 post prostatectomy, 169 post radiation therapy, and 204 who had undergone both treatment modalities) reinforced the high accuracy, reproducibility, and safety of ⁶⁸Ga-PSMA-11 in this patient population.

Overall, this type of PSMA-PET imaging was able to localize recurrent prostate cancer in 75% of patients, and the likelihood of a positive hit increased with rising PSA levels, reaching 97% when PSA was >5 ng/mL. Importantly, the rate of detection was 38% for PSA levels <0.5 ng/mL, demonstrating the superiority of PSMA-PET to detect recurrent prostate cancer at the recommended PSA levels for initiating salvage therapy.³⁰

¹⁸F-DCFPyL

Fluorine 18 (¹⁸F) is one of the most widely used imaging radioactive isotopes because it can be easily produced in large quantities and that it has a short half-life and a high positron emission yield.^{13 18}F-PSMA-11 is being investigated as an alternative to ⁶⁸Ga-PSMA-11; a phase III trial is comparing the 2 agents (NCT03911310).

The first ¹⁸F-labeled PSMA-targeted agent to be developed was ¹⁸F-DCFBC, which showed PSMA-specific uptake into tumors. A next-generation tracer, ¹⁸F-DCFPyL, has a significantly higher binding affinity for PSMA and has been examined in a range of clinical trials.¹³

In an initial evaluation in patients with prostate cancer, ¹⁸F-DCFPyL was found to be safe and to accumulate in presumed primary and metastatic tumors.³¹ Other studies have demonstrated its superiority to conventional imaging in patients with metastatic prostate cancer and its comparable efficacy with ⁶⁸Ga-PSMA-11.^32,33

⁶⁸Ga-THP-PSMA

The potential for widespread adoption of PSMA-PET imaging may be limited by the complex, time-consuming, and expensive production requirements. The need for simplified production methods has led to the development of newer radiopharmaceuticals, such as ⁶⁸Ga-tris(hydroxypyridinone) (THP)—PSMA. It features a modified ligand (THP) that allows greatly simplified 1-step, kit-based radiolabeling.

A phase I study of this agent was recently published. There were 2 patient cohorts: Cohort A included 8 patients with proven prostate cancer scheduled to undergo prostatectomy, and cohort B comprised 6 patients with positive ⁶⁸Ga-PSMA-11 PET/CT results. Both cohorts underwent ⁶⁸Ga-THP-PSMA PET/CT imaging.

There were no adverse events, and 6 of the patients in cohort A demonstrated PSMA-PET uptake that correlated with PSMA immunohistochemistry on prostatectomy specimens. In cohort B, there was lower background uptake compared with ⁶⁸Ga-PSMA-11, and 5 of the 6 patients demonstrated concordance in the number of metastases detected by the 2 tracers.³⁴ A sterile cold kit formulation of ⁶⁸Ga-PSMA-11 is also in clinical development (NCT03183544).

Potential for Guiding Therapy

PSMA-PET imaging has clearly and consistently demonstrated sensitivity, specificity, positive and negative predictive value, and accuracy in prostate cancer diagnostics. Accumulating evidence also suggests that PSMA-PET could be used to guide treatment.

Lymph nodes are the second-most-common site of metastases in men with prostate cancer, and PSMA-PET has been shown to be highly sensitive and to outperform morphologic imaging in the assessment of lymph node metastases in patients undergoing lymphadenectomy.¹²

In a recent post hoc analysis of the impact of PSMA-PET on the planning of salvage radiation therapy in patients with PSMA-positive primary prostate cancer, the use of ⁶⁸Ga-PSMA-11—PET imaging had a major impact on radiation therapy planning in 16.5% of patients when radiation fields included the prostate, seminal vesicles, and pelvic lymph nodes and in 37% of patients when just the prostate and seminal vesicles were covered. Further clinical trials are needed to delineate the role of PSMA-PET imaging in treatment planning, and a phase III trial is among those ongoing (NCT03582774).³⁵

Despite the paradigm-altering success of PSMA-PET in prostate cancer, potential interpretative pitfalls exist. These include PSMA expression on benign tumors and nonprostate cancers, which could lead to false-positive and false-negative scans. Additionally, androgen deprivation therapy (ADT) can drive higher expression of PSMA.³⁶ An ongoing clinical trial is exploring the impact of ADT on PSMA-PET imaging (NCT03876912).

PSMA-Based Therapeutics on the Horizon

In the age of molecularly targeted cancer therapies, the specificity of PSMA for prostate cancer cells lends itself to the development of novel therapeutics. Radiolabeled anti-PSMA antibodies and small molecule inhibitors can also be employed in a therapeutic fashion, guiding the delivery of therapeutic radioisotopes that emit a type of radiation different from that used for PET imaging.

J591 is a second-generation PSMA-targeted monoclonal antibody.⁷ In addition to the unconjugated antibody, which clinical trials are evaluating in the treatment of prostate cancer, several radiolabeled versions are in development. Lutetium 177 (¹⁷⁷Lu) is the most widely used radioisotope in this setting.

In a phase II trial of ¹⁷⁷Lu-J591, 47 patients with metastatic CRPC received either a 65- or 70-mCi/m² dose of the study drug. Overall, 59.6% of patients experienced a decline in PSA following a single treatment, and 36.2% had a 30% or greater reduction. The higher dose resulted in more substantial declines and longer survival than did the lower dose but at the expense of increased toxicity.³⁷

The most clinically successful PSMA-targeted therapeutic, however, is the ¹⁷⁷Lu-labeled small molecule inhibitor PSMA-617. A recently reported phase II trial demonstrated favorable activity and low toxicity in men with PSMA-positive metastatic CRPC.³⁸ Updated results, including those of a 20-patient extension cohort, were presented at the Genitourinary Cancers Symposium this year.³⁹

A total of 50 patients who had progressed after standard therapies received up to 4 cycles of ¹⁷⁷Lu-PSMA-617 every 6 weeks. A PSA decline of ≥50% was achieved in 64% of patients, and 44% had a PSA decline of ≥80%. The overall response rate according to RECIST 1.1 was 56% in patients with measurable soft tissue at baseline.

The most common toxicities were grade 1 or 2 and were dry mouth, nausea, and fatigue. Grade 3/4 toxicities were thrombocytopenia and anemia. Some patients who progressed were administered further rounds of ¹⁷⁷Lu-PSMA-617 treatment, and 64% of those patients experienced a decline in PSA of 50% or more.^38,39 Several phase III trials evaluating this agent are ongoing, including the VISION trial (NCT03511664), in which it is being compared with standard therapy.

In addition to the diagnostic and therapeutic potential of ¹⁷⁷Lu-PSMA-617, the idea that the 2 roles might be combined in a so-called theranostic approach is being actively explored. In a recently reported phase II trial, ⁶⁸Ga-PSMA-11 imaging was performed in 14 patients treated with ¹⁷⁷Lu-PSMA-617. Investigators observed a PSA response in 71% of patients, with a mean reduction of 59% in PSA levels.

A patient’s PSMA-PET standardized uptake value at screening was predictive of a ≥30% PSA reduction. In patients for whom PSMA-PET imaging was performed again after completion of treatment, investigators observed 3 distinct patterns of disease progression. In this way, the authors suggested, PSMA-PET could ultimately help to provide guidance on the best subsequent treatment options.⁴⁰

Finally, another intriguing application of PSMA-targeted therapy could help to advance immunotherapy applications in metastatic CRPC, which thus far have suffered from limited efficacy. Investigators have developed a PSMA-targeted chimeric antigen receptor (CAR) construct using a single-chain variable fragment from the J591 antibody. In a preclinical study, T cells transfected with the CAR construct were able to selectively kill PSMA-positive prostate cancer cells.⁴¹ A phase I trial is enrolling patients with metastatic CRPC (NCT03089203).

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