Incorporating PSMA-Targeting Theranostics Into Personalized Prostate Cancer Treatment: a Multidisciplinary Perspective

Recent developments in prostate-specific membrane antigen (PSMA) targeted diagnostic imaging and therapeutics (theranostics) promise to advance the management of primary, biochemically recurrent, and metastatic prostate cancer. In order to maximize the clinical impact of PSMA-targeted theranostics, a coordinated approach between the clinical stakeholders involved in prostate cancer management is required. Here, we present a vision for multidisciplinary use of PSMA theranostics from the viewpoints of nuclear radiology, medical oncology, urology, and radiation oncology. We review the currently available and forthcoming PSMA-based imaging and therapeutics and examine current and potential impacts on prostate cancer management from early localized disease to advanced treatment-refractory disease. Finally, we highlight the clinical and research opportunities related to PSMA-targeted theranostics and describe the importance of multidisciplinary collaboration in this space.


INTRODUCTION
Prostate cancer is the second most common malignancy in men and the fifth leading cause of cancer-related death worldwide (1). Localized indolent disease has a good prognosis; however, advanced localized, recurrent and metastatic disease often portend poor outcomes (1,2). Prostatespecific membrane antigen (PSMA) is increasingly appreciated as a promising imaging and therapeutic target for prostate cancer (3). As these agents become FDA-approved and clinically available, opportunities and challenges will arise to incorporate them appropriately into the management armamentarium for prostate cancer. Success in this endeavor will require coordination and collaboration among the clinical stakeholders in prostate cancer management, including imaging physicians, medical oncologists, urologists and radiation oncologists. In this review, we provide a multidisciplinary viewpoint of how PSMA-targeting agents will advance clinical management of prostate cancer. We outline the PSMA-targeted agents for imaging and therapy and their roles in the management of both localized and metastatic disease. Finally, we identify opportunities for crossspecialty collaboration to advance the utility of PSMA-targeted agents for prostate cancer management.

PSMA: A PROMISING IMAGING/ THERAPEUTIC TARGET
PSMA is expressed at 100-1000-fold higher levels in prostate cancer compared to healthy prostate tissue, and importantly, shows highest expression in high-grade and castration-resistant prostate cancer (3,4). Multiple studies have demonstrated correlation between PSMA expression and prostate cancer aggressiveness (5), Gleason score (6), metastatic potential (7) and castration resistance (8,9), suggesting that PSMA is a promising imaging/therapeutic target.

PSMA-TARGETED IMAGING AGENTS
The first FDA-approved molecular imaging agent developed to target PSMA was the radiolabeled monoclonal antibody indium-111 ( 111 In)-capromab pendetide (ProstaScint) for single-photon emission computed tomography (SPECT) imaging detection of sites of biochemical recurrence (10). Clinical adoption of ProstaScint has remained low due to the relatively poor resolution of SPECT imaging as well as limited sensitivity due to an unfavorable biodistribution and the antibody targeting an intracellular epitope of PSMA (11)(12)(13).
Several SPECT-imaging agents targeting PSMA were developed after ProstaScint, including agents labeled with 99m Tc (14-16) and 123 I (17). However, more recent attention has been focused on positron emission tomography (PET) agents, which offer higher sensitivity and spatial resolution compared to SPECT (4,18).
The pharmacokinetics of small molecules with their fast clearance and good tumor penetration results in a high tumor to background ratio (19). These properties make them ideal as imaging agents. Table 1 lists the most common PSMAtargeting small molecule agents that are actively used in trials and clinically worldwide. At the time of writing, two of these agents, 68 Ga-PSMA-11 and 18 F-DCFPyL, have been FDA-approved (but awaiting CMS approval). Beyond favorable imaging profiles (20), these agents have been demonstrated in multiple retrospective and prospective studies to be superior compared to standard cross-sectional imaging, (CT/MRI) (21,22) nuclear medicine assays (bone scintigraphy) (23,24), 18 F-fluciclovine (25-29), 11 C-choline PET/CT (30,31), and other modalities (32,33) for characterizing disease burden across the spectrum of the disease (Figure 1). Applications include the localized disease setting for both intraprostatic localization and staging (34)(35)(36), detection of lesions during biochemical recurrence (22,37), and for stratification and treatment monitoring in metastatic disease (38). Furthermore, PSMA-targeted imaging has shown synergy with other modalities such as multiparametric prostate MRI (39,40) and FDG-PET for improved characterization of disease burden (41) and image guidance for bone biopsies (42).

ROLE OF PSMA IMAGING IN LOCALIZED DISEASE
Accurate staging is critical for risk stratification and treatment decisions. Surgery and radiation therapy are curative treatments for localized disease, offer potential cure for biochemically recurrent disease (i.e., salvage radiotherapy or salvage prostatectomy), and can offer durable control in the oligometastatic disease setting. To the extent PSMA imaging can identify micrometastatic disease and reclassify clinical stage, patient selection for local therapies can be expected to improve. Further, the success of radiation largely centers on accurate identification and encompassing of disease within a radiation field in the setting of localized or salvage radiation, or to precisely target disease with stereotactic ablative radiation therapy (SABR) for patients with oligometastatic prostate cancer. Conventional imaging has low sensitivity and low specificity for detection of prostate cancer spread. Thus, PSMA imaging is being explored to determine its role in early stage disease, including for accurate assessment of intraprostatic tumor burden, with higher PSMA uptake previously shown to be associated with histological identification of focal lesions (39,43,44). This can guide focal SABR escalation at these sites (45,46).

High-Risk Disease
Early data exploring the role of PSMA PET/CT in high-risk disease suggest that it can lead to changes in treatment decisions. The proPSMA trial recruited men with high-risk localized prostate cancer randomized to either conventional imaging or PSMA PET/CT as first-line imaging, followed by second-line cross-over imaging for patients with fewer than three distant metastases (21). PSMA PET/CT as first-line imaging led to change in management in 28% of patients (compared to 15% following conventional imaging), half of which comprised a change in surgical or radiotherapy technique. In patients who underwent second-line imaging, PSMA PET/CT similarly led to a change in management in 25% of patients, compared to only 5% following conventional imaging. A separate retrospective study of 138 prostate cancer patients who underwent 68 Ga-PSMA-PET/CT imaging at initial diagnosis evaluated the number and anatomical location of PSMA-positive lymph nodes (47). Overall, 441 PSMA-positive lymph node metastases were identified (most frequently of which were internal iliac lymph nodes [25%]). The PSMA-positive lymph nodes were mapped onto a CT planning scan and the standard pelvic radiotherapy fields were overlaid on top for comparison. Extending the cranial border of the pelvic field from L5/S1 to L4/L5 increased accuracy of covering potentially involved nodes. Another recent study used data from two prospective trials with PSMA PET/CT imaging in high-risk individuals with cN0M0 disease per conventional imaging to develop a nomogram to help identify high-risk patients who might benefit from the addition of a PSMA PET/ CT (48).

Localized Salvage Therapy
Biochemical recurrence after radical prostatectomy or primary radiation can potentially be cured with localized salvage therapy such as pelvic-targeted radiation or salvage prostatectomy (49). Biochemical recurrence can now be detected at earlier PSA  values, with the definition of failure at 0.2 ng/mL (50). At these low PSA levels, conventional imaging has poor sensitivity for detecting sites of recurrence. PSMA imaging has been shown to be more sensitive in this setting in multiple prospective studies (27,37,(51)(52)(53). The enhanced detection of local and distant lesions with PSMA-targeted imaging has ramifications for treatment planning, including choice of localized vs. systemic therapy. For example, a study in 79 radio-recurrent patients using 18 F-DCFPyL PET/CT not only showed superior disease detection compared to conventional imaging (87% vs. 67% overall, 30% vs. 15% for identifying distant metastases), but changed the proposed management in 43% of patients (54). However, it currently remains unknown whether these changes in management are appropriate or will improve overall disease outcomes.

Oligometastatic Disease
The role of surgery and radiation therapy is evolving in the management of low-burden metastatic disease, also known as oligometastatic disease. Early data suggest that aggressive radiation targeted at metastatic lesions may improve outcomes (55)(56)(57) (59). Taken together, these data support that aggressive metastasis-directed treatment to all PSMA PET-avid lesions may be curative in a subset of patients with low-burden metastatic disease.

Surgical Guidance With PSMA-Imaging
Molecular imaging approaches are increasingly being adopted for surgical guidance (60). Pelvic lymph node dissection (PLND) is the standard approach for nodal staging or management of local lymphatic metastases (61). PSMA-targeted radiolabeled and fluorescent probes are being tested for identifying lymph node metastases intraoperatively during PLND, for confirming appropriate surgical margins, and for correlation with pathological assessment (62)(63)(64)(65). These approaches may improve surgical outcomes by increasing the likelihood that all clinically significant disease is resected at the time of surgery.

PSMA-Targeted Radioligand Therapy
Systemically delivered radiotherapies already play a key role in metastatic prostate cancer management, especially with the use of 223 Radium for management of osseous lesions (66). PSMAtargeted radiotherapies are poised to offer an even more impactful alternative, being effective for both PSMA-expressing bone and soft tissue metastases (67). To date, the most tested PSMA-targeted agent is 177 Lu-PSMA-617, among other agents outlined in Table 1 (71,72). Based on the promising results of this trial, regulatory approval for this agent is expected to be imminent. Another randomized phase II trial (TheraP) demonstrated that 177 Lu PSMA-617 compared with cabazitaxel in men with mCRPC led to a higher PSA response and fewer grade 3 or 4 adverse effects (73). Several studies have also extended the use of these agents for management of micrometastases in the setting of localized disease (74) and oligometastases (75). Correlation with PSMA imaging is key for patient stratification since patients with high PSMA expression level and low tumor heterogeneity show better outcomes (76,77). PSMA radioligand therapy is an area of active investigation, with most notable areas focused on testing various choices of radionuclides and ligands to improve outcomes and reduce toxicity (78). For instance, several radiopharmaceuticals have been engineered to enable radiolabeling of the same ligand using both imaging and therapeutic radionuclides, allowing an accurate pharmacokinetic readout using imaging prior to radioligand therapy (75) (4). Other areas of investigation focus on the development of therapeutic agents with more favorable pharmacokinetics for therapeutic payload delivery such as antibody constructs with longer biological half-lives and different organ toxicity profiles (79,80). Additionally, the optimal choice of radionuclides is also being assessed. Commonly used radionuclides including 177 Lu and 90 Y for PSMA-therapy predominantly exert their cytotoxic actions via beta particle emission, with spatial range of action on the order of mm. Alpha particles, such a 225 Ac or 209 Pb, can confer higher linear energy transfer (up to 20x) compared to beta particles, but act on a shorter spatial range (81). 225 Ac-PSMA-617 alone or in tandem with 177 Lu-PSMA-617 have been studied clinically, with promising results (82). Auger emitters, which impart high energy at a shorter range than alpha particles, may also be useful in the setting of micro-metastases (83). Further preclinical and clinical studies are needed to understand and optimize the interplay between these design parameters, and their effects on efficacy.

PSMA-Targeted Bispecific Agents
Multiple PSMA-targeted bispecific molecules have advanced to early phase clinical evaluation in patients with mCRPC. These antibody-derived bispecific molecules bind to PSMA and a Tcell-specific antigen such as CD3 or CD28, resulting in activation of T-cell response to PSMA-expressing prostate cancer cells. PSMA-targeted bispecific agents are being developed as monotherapies a nd in combination with immune checkpoint inhibitors.
Pasotuxizumab (AMG 212) is a bispecific T-cell engager (BiTE) engineered to engage PSMA and CD3 and demonstrated reasonable tolerability, immunogenicity, and clinical activity in a phase 1 dose-escalation study in mCRPC patients (84). PSA declines ≥50% (PSA 50 ) occurred in 29% and 19% of patients treated with subcutaneous and intravenous dosing, respectively, including 2 long-term responders (11-17 months to tumor progression). Pasotuxizumab was limited by a short half-life, and a half-life extended anti-PSMA x CD3 BiTE acapatamab (AMG 160) was developed for further clinical evaluation. Preliminary results from the phase 1 study of acapatamab in heavily pretreated mCRPC patients showed promising activity and manageable toxicity (85). PSA 50 responses were seen in 34% of evaluable patients, including a patient who previously progressed on lutetium-PSMA therapy. Cytokine release syndrome (CRS) was observed in 91% of patients, but most cases were grade 1-2 and decreased in severity after cycle 1. Combination therapy with anti-PD-1 immune checkpoint inhibitors, abiraterone, or enzalutamide is planned (85,86).
HPN424 is a PSMA-targeting T-cell engager with three binding domains: anti-PSMA, anti-CD3, and anti-albumin for half-life extension (87). Preliminary results from the phase 1/2 study of HPN424 in mCRPC patients demonstrated PSA 50 responses in 3 (5%) patients. In the highest fixed dose cohort evaluated to date, 3 of 7 patients had PSA declines and 1 patient had a confirmed partial response by RECIST. CRS events occurred in 63% of patients, with 4% of patients experiencing grade 3 CRS. The study continues in dose escalation.
Additional PSMA-targeted bispecific agents are entering the clinical setting. REGN5678 is a first-in-class human IgG4-based bispecific engineered to target PSMA and the T-cell costimulatory receptor CD28, and will be evaluated in a phase 1/2 first-in-human study as monotherapy and in combination with the anti-PD-1 antibody cemiplimab (88). TNB-585 and CCW702 are anti-PSMA x CD3 bispecific agents entering phase 1 evaluation (89,90).

PSMA-Targeted CAR-T
Chimeric antigen receptor (CAR) T cell therapies are a powerful class of genetically-engineered T cells with synthetic receptors that redirect their specificity, function, and metabolism, and represent a major advancement in the treatment of certain refractory hematologic malignancies (91). Prostate cancer serves as an attractive target for evaluation of CAR-T therapy in solid tumors due to the relative specificity of PSMA as target antigen. An early generation PSMA-targeted CAR-T was evaluated in a small phase 1 study that reported clinical partial responses in 2 of 5 mCRPC patients, with PSA declines of 50% and 70% (92). A second generation PSMA-targeted CAR-T demonstrated evidence of cytokine activation and prolonged stable disease for >6 months in 2 of 7 patients dosed (93).
More modern CAR-T therapies are now entering clinical evaluation for mCRPC patients, with some reporting very preliminary results to date. CART-PSMA-TGFbRDN cells involving autologous T cells engineered to express a dominant negative form of TGFbRII and a CAR with specificity to PSMA reported PSA 50 decreases in 2 of 3 patients with one-month follow-up, including a patient with >95% PSA decline (94). However, one patient developed grade 2 CRS that progressed to fatal encephalopathy and multi-organ failure despite aggressive immunosuppressive therapy. A second CART-PSMA-TGFbRdn study has reported early results with PSA 50 decline in 1 of 10 patients (98% decline) and PSA 30 decline in 3 additional patients (95). Grade 2+ CRS was seen in 5 of 7 patients treated at higher dose. However, the therapy was associated with lethal neurotoxicity and sepsis. P-PSMA-101 is an autologous CAR-T product being evaluated in the U.S. (NCT04249947), while several PSMA-targeted CAR-T products are in clinical trials in China (NCT04053062, NCT04768608, NCT04429451). PSMA-imaging has also been harnessed as a means to track CAR-T trafficking (96).

PSMA-Targeted Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) comprise a monoclonal antibody binding to a target antigen that is highly specific to tumor cells, a synthetic linker domain, and a potent cytotoxic c h e m o t h e r a p y p a y l o a d ( 9 7 ) . A D C s c a n d e l i v e r chemotherapeutics in a more targeted manner to tumor cells, while sparing normal cells. PSMA represents a rationale target for the development of ADCs.
MLN2704, PSMA ADC, and MEDI3726 are three PSMAtargeted ADCs that have undergone clinical investigation to date. MLN2704 is comprised of a de-immunized anti-PSMA monoclonal antibody (J591) with high affinity to the external domain of PSMA complexed via a thiopentanoate linker to maytansinoid-1, a potent anti-microtubule chemotherapeutic (98). PSMA ADC is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody complexed to the anti-mitotic agent monomethyl auristatin E via a valine-citrulline linker, which is more stable than thiol linkers in plasma (99). MEDI3726 is comprised of J591 conjugated to the DNA cross-linking agent pyrrolobenzodiazepine (100). These PSMA-targeted ADCs have been evaluated in separate early phase clinical trials in mCRPC patients, with MLN2704 and PSMA ADC treatments associated with PSA 50 response in 8% and 14% of patients, respectively, while MEDI3726 reported a modest 12% composite response rate involving radiographic, PSA 50 , and circulating tumor cell (CTC) responses. However, these PSMA-targeted ADCs have been limited by neuropathy, skin toxicities, and cytopenias. Nonetheless, the clinical studies further validate PSMA as a therapeutic target in mCRPC, and future development of ADCs may focus on improving synthetic linkers that limit deconjugation of the chemotherapeutic payload outside of the tumor microenvironment.

MULTIDISCIPLINARY OPPORTUNITIES AND CHALLENGES IN THE ERA OF PSMA-TARGETED PROSTATE CANCER MANAGEMENT
PSMA-targeted imaging and therapy are poised to play key roles in the management of prostate cancer. Evaluation of their clinical utility will require high-level evidence from prospective clinical studies (101). Precision medicine principles guided by theranostics should be incorporated in the design of these trials, and will require collaboration across radiology/nuclear medicine, urology, medical and radiation oncology. Standardized acquisition methods, and interpretation criteria of PSMA-based imaging exams, such as with recently proposed criteria like the PROMISE staging system (102) or PSMA-RADS (103) will be paramount in this regard. In addition, collaborative efforts at both pre-clinical and clinical levels to examine combination treatments involving the different PSMA-targeting modalities are vital to understanding their optimal role in the treatment armamentarium for prostate cancer.
In summary, exciting opportunities abound with the multiple PSMA-targeted imaging and therapy agents in the clinical pipeline. Collaboration across the different clinical disciplines in the prostate cancer management team will be crucial to maximize the potential of these agents.

AUTHOR CONTRIBUTIONS
All authors contributed to the article and approved the submitted version.

FUNDING
This work is supported in part by a Thrall Innovation Grant from the Department of Radiology, Massachusetts General Hospital (TN) and 1K08CA249047-01(PH).