J Urol Oncol > Volume 22(1); 2024 > Article
Suh and Cheon: Multidisciplinary Team Approach in Prostate-Specific Membrane Antigen Theranostics for Prostate Cancer: A Narrative Review

Abstract

In managing prostate cancer, the integration of multidisciplinary team (MDT) with prostate-specific membrane antigen (PSMA) theranostics marks a significant advancement, addressing the disease's spectrum from indolent forms to aggressive metastatic stages. MDTs, comprising urology, oncology, radiation oncology, pathology, radiology, and nuclear medicine experts, are pivotal in delivering tailored, evidence-based care, essential for the varied clinical presentations of prostate cancer. The introduction of PSMA-targeted theranostics and PSMA positron emission tomography imaging has impacted the approach to diagnosis and treatment, offering enhanced precision in disease localization and enabling more nuanced management strategies for conditions such as oligometastatic prostate cancer, metastatic hormone-sensitive prostate cancer, and metastatic castration-resistant prostate cancer. The collaborative approach of MDTs in utilizing PSMA-targeted radioligand therapy emphasizes meticulous patient selection, predictive assessment of therapy response, and careful management of therapy-related toxicities. Additionally, recent strategies, including combination therapies from ENZA-P and Lu-PARP trials, show potential for improving treatment efficacy. This unified approach showcases the critical role of MDTs in optimizing treatment outcomes, underscoring the importance of collaboration in advancing the treatment of prostate cancer with PSMAtargeted therapies, thereby setting a new paradigm in personalized prostate cancer management.

MULTIDISCIPLINARY TEAM APPROACH IN PROSTATE CANCER

The management of prostate cancer, characterized by its biological heterogeneity and complex clinical presentations, demands a multifaceted and nuanced approach [1,2]. This variability, ranging from indolent to aggressive metastatic disease, underscores the necessity for personalized treatment strategies that are sensitive to the risks of both undertreatment and overtreatment. It is within this context that multidisciplinary team (MDT) becomes indispensable, combining expertise from urology, medical oncology, radiation oncology, pathology, radiology, and nuclear medicine to ensure a coordinated and evidence-based approach to patient care [3]. The emerging concept of prostate-specific membrane antigen (PSMA) targeted theranostics further exemplifies the need for such a collaborative approach, as it introduces novel diagnostic and therapeutic options that require integrated expertise for optimal application in clinical practice [4].
MDTs significantly enhance prostate cancer management by facilitating a comprehensive evaluation of each patient’s case, thus ensuring that all treatment options are considered and that management strategies are tailored to individual patient preferences and clinical profiles. Studies have shown that MDTs can lead to changes in treatment plans, reduce biases, and increase adherence to evidence-based guidelines, potentially improving clinical outcomes [3,5-11]. Gomella et al. [7] conducted a retrospective analysis comparing outcomes for newly diagnosed localized prostate cancer patients managed by a single-center MDT with those from the SEER (Surveillance, Epidemiology, and End Results) database. The findings revealed significantly longer overall survival (OS) for MDT-managed patients with stage III disease (p=0.0007) and a trend towards longer OS for Stage IV disease (p=0.0847), with over 90% of patients reporting the MDT clinic experience as good or very good. Similarly, Knipper et al. [9] examined the impact of adherence to MDT recommendations for adjuvant radiotherapy on clinical outcomes in patients at high risk of recurrence postradical prostatectomy. Their analysis showed that adherence to MDT recommendations led to significant improvements in outcomes, including biochemical recurrence-free survival (57.7% vs. 20.1%), metastasis-free survival (76.5% vs. 75.4%), cancer-specific survival (91.7% vs. 87.4%), and OS (80.4% vs. 75.8%) at 8 years. By leveraging the collective expertise of MDTs, patients are afforded access to the most advanced care options, including PSMA-targeted treatments, which have been shown to significantly impact disease progression and patient quality of life. This collaborative model not only optimizes the utilization of emerging therapies but also fosters a patient-centered approach to care, ensuring that decisions are made with a comprehensive understanding of the potential benefits and risks of each treatment option.

CONCEPT OF PSMA THERANOSTICS

Theranostics, a pivotal advancement in personalized medicine, integrates diagnostic and therapeutic functionalities into a singular platform, enabling clinicians to precisely visualize and target diseases [12,13]. Central to this approach is the concept of using ligands attached to radioisotopes, which can switch between diagnostic and therapeutic functions. This innovative principle, "We see what we treat, and we treat what we see," is materialized by administering a diagnostic radioisotope to accurately image and locate disease sites, followed by a therapeutic radioisotope to deliver targeted treatment to the same sites [14]. This seamless transition from diagnosis to therapy not only ensures that treatment is directly aimed at the disease but also significantly enhances the specificity and effectiveness of treatment, minimizing damage to surrounding healthy tissues.
PSMA has emerged as a particularly promising target for theranostic applications in prostate cancer due to its significant overexpression in prostate cancer cells—up to 1,000 times higher than in normal tissues [15,16]. This differential expression provides a unique advantage for the selective targeting and treatment of prostate cancer cells. Furthermore, PSMA-targeted ligands are designed with a cell internalization moiety, which, upon binding to PSMA, facilitates the internalization of the ligand-radioisotope complex into cancer cells [17]. This process enhances the retention of therapeutic radioisotopes within the cells, increasing the efficacy of the treatment.
The chemistry of PSMA ligands has evolved from earlier methods using monoclonal antibodies to the current use of urea-based small-molecule PSMA inhibitors, characterized by structures such as glutamate-urea-glutamate or glutamateurea-lysine dimers [18]. These molecular designs are essential for attaching to PSMA’s catalytic domain, marking a significant shift towards treatments with improved specificity and quicker clearance from the body. The combination of targeted ligand design and refined chemistry has propelled PSMA to the forefront of theranostic targets, offering a promising pathway for the development of more effective prostate cancer treatments.

APPLICATION OF PSMA IMAGING IN PROSTATE CANCER MDT

The clinical breakthrough of 68Ga-based PSMA radioligands, particularly 68Ga-PSMA-11, since its introduction in 2011 and U.S. Food and Drug Administration approval in 2020, has set a precedent for PSMA-targeted imaging [19]. The radiopharmaceutical agents 68Ga-PSMA-11, 68Ga-PSMA-I&T, 18F-DCFPyL, 18F-PSMA-1007, and 18F-rhPSMA-7 are at the forefront of clinical adoption and/or receiving regulatory clearance [20-23]. These radioligands exhibit variations in radionuclide labeling, radiochemical foundations, and patterns of distribution in organs. Distinct differences in physiological distribution and challenges in interpreting imaging have been identified. Yet, up to this point, no conclusive evidence suggests that any specific PSMA radioligand outperforms others in terms of diagnostic accuracy or clinical outcomes [22].
Currently, in Korea, 68Ga-PSMA-11 and 18F-PSMA-1007 are clinically available. Reimbursement policies in Korea cover the deployment of PSMA-ligand imaging under particular clinical circumstances. Initially, this includes the staging process where prostate cancer diagnosis is confirmed via histological analysis or when the probability of cancer is high based on alternative imaging modalities. In instances of potential biochemical recurrence, which is indicated by a postsurgical serum prostate-specific antigen (PSA) level increase to more than 0.2 ng/mL, or a rise of more than 2.0 ng/mL above the lowest level after radiotherapy. Reimbursement is also provided for evaluating the effectiveness of ongoing treatment and guiding potential adjustments to the treatment plan through PSMA-ligand positron emission tomography (PET) scans.

1. PSMA Imaging for Oligometastatic Prostate Cancer

The condition known as oligometastatic prostate cancer represents a state of cancer characterized by a limited but potentially curable number of metastases [24]. This stage calls for a coordinated effort from a team that includes urologists, medical and radiation oncologists, radiologists, and nuclear medicine experts. The advent of PSMA PET imaging has brought significant advancements in this area, enabling the detection of metastatic lesions at lower PSA levels and driving a reevaluation of disease classifications and treatment methodologies [25].
The influence of PSMA PET imaging on the management of oligometastatic prostate cancer is particularly evident in the realm of metastasis-directed therapy (Fig. 1). Highlighted by the ORIOLE trial, the use of stereotactic body radiation therapy (SBRT) has been shown to delay the need for androgen deprivation therapy (ADT), with patients undergoing SBRT experiencing a median ADT-free survival of 21 months, a notable increase from the 13 months observed in patients under surveillance [26]. A noteworthy aspect of the ORIOLE trial was the utilization of PSMA PET scans in the SBRT arm to track disease progression. The findings revealed that only 5% of patients without any untreated PSMA-avid lesions showed disease progression at 6 months, as opposed to 38% of those who had untreated lesions (p=0.03). This underscores the precision of PSMA PET in identifying metastatic sites and its potential to guide targeted therapy. Long-term outcomes of metastatic-directed SBRT were highlighted in a retrospective study, covering a cohort of 103 patients with a median follow-up period of 5 years [27]. The study discloses that 15% of participants remained free from any biochemical failure at 5 years, with a median time to biochemical failure of 1.1 years. Notably, at 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years, endorsing the potential of metastasisdirected therapy to delay disease progression and the need for ADT.
Recent clinical trials increasingly incorporate PSMA PET imaging to define oligometastasis and to further delineate the role of PSMA PET in the treatment of oligometastatic prostate cancer [28-31]. The SPARKLE trial, a multicentre randomized phase III trial, focuses on whether the addition of short-term ADT during 1 month or short-term ADT during 6 months together with an androgen receptor pathway inhibitor (ARPI) to metastasis-directed therapy significantly prolongs polymetastasis free survival [30]. Oligometastatic prostate cancer in the study is defined by a maximum of 5 extracranial metastases identified using PSMA PET scans. Findings from the trials are awaited to provide evidence of the benefits of treatment strategies informed by PSMA PET (Table 1). These developments emphasize the importance of an MDT approach in leveraging the collective expertise of specialists to advance patient outcomes in the treatment of prostate cancer with oligometastatic spread.

2. Redefining Prostate Cancer Tumor Burden With PSMA PET

The advent of PSMA PET imaging has introduced a paradigm shift in the stratification of metastatic hormone-sensitive prostate cancer (mHSPC), presenting a nuanced challenge to traditional disease burden assessment methodologies. Historically, pivotal trials like CHAARTED and STAMPEDE have delineated treatment protocols based on tumor burden assessed through conventional imaging modalities, such as computed tomography, magnetic resonance imaging, and bone scans. These trials underscored the significance of accurately gauging tumor volume to predict treatment response, with CHAARTED demonstrating the benefits of chemohormonal therapy in high-volume disease patients, and STAMPEDE showing improved failure-free survival with radiotherapy in lowvolume disease patients [32,33]. However, the high sensitivity of PSMA PET in detecting prostate cancer lesions necessitates a reevaluation of these volume-based classifications, as it identifies a greater number of lesions than traditional imaging, potentially altering disease categorization and subsequent treatment pathways.
A retrospective study aimed to align PSMA PET findings with the CHAARTED/STAMPEDE criteria, highlighting the impact of enhanced detection capabilities [34]. In this study, PSMA PET identified additional lesions in 62% of mHSPC patients, resulting in a hypothetical migration from CHAARTED-defined low-volume disease to highvolume disease in approximately 19% of cases. Similarly, a preliminary study, incorporating data from 4 international centers, demonstrates a notable stage migration in patients when assessed by PSMA PET, with 38.6% experiencing a shift in disease volume classification [35]. Particularly, 22% were upstaged to high-volume disease, while 22.8% were downstaged, indicating a considerable discrepancy between conventional imaging and PSMA PET evaluations. This nuanced understanding emphasizes the need for cautious interpretation of existing trial data and the integration of PSMA PET imaging in future research to refine treatment selection.
The introduction of PSMA PET-based criteria into clinical practice highlights an urgent need for their validation by linking them with actual clinical outcomes, beyond their capability for enhanced detection. Such validation is crucial to confirm that the increased sensitivity of PSMA PET translates into tangible benefits for patient care and treatment outcomes. Furthermore, the complex data provided by PSMA PET necessitate a multidisciplinary approach to treatment, underlining the importance of collaborative decision-making in interpreting the implications for disease classification and therapy planning. It is imperative to integrate a thorough understanding of how PSMA PET’s comprehensive disease mapping affects the choice and effectiveness of both systemic and localized treatments. Current research lacks in providing a clear association between tumor burden as defined by PSMA PET and clinical outcomes, indicating a gap in the evidence-based application of these new criteria. Therefore, there is a significant need for further studies to establish and validate new definitions of tumor burden based on PSMA PET findings, ensuring they are effectively correlated with patient outcomes before they are adopted into routine practice.

MDT APPROACH FOR PSMA RADIOLIGAND THERAPY

Radioligand therapy consists of 2 components: a ligand that seeks out and binds to specific surface molecules on cancer cells, and a radioactive isotope that delivers radiation causing lethal DNA damage to the targeted cells and nearby microenvironment, leading to cell death and tumor regression [36] (Fig. 2). The only regulatory-approved PSMA-targeted radioligand therapy to date is 177Lu-PSMA-617 in the setting of metastatic castration-resistant prostate cancer (mCRPC) [37]. The efficacy of 177Lu-PSMA-617 in treating mCRPC was highlighted by the VISION study, a phase III trial that showed improved radiographic progression-free survival (rPFS; median, 8.7 vs. 3.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.29-0.57) and OS (median, 15.3 vs. 11.3 months; HR, 0.62; 95% CI, 0.52-0.74; p<0.001) in patients treated with 177Lu-PSMA-617 compared to standard care alone [38]. This led to FDA approval in 2022 for PSMA-positive mCRPC patients. The TheraP phase II study, comparing 177Lu-PSMA-617 to cabazitaxel, revealed a higher PSA response rate (66% vs. 37%, p<0.000) and fewer grade 3 or higher adverse effects (33% vs. 53%) in the 177Lu-PSMA-617 group, indicating not just an efficacy advantage but also a potentially more favorable tolerability profile [39]. These studies collectively underpin the specified indication for PSMA radioligand therapy with 177Lu-PSMA-617, in patients with PSMApositive mCRPC, who progressed under at least one ARPI (e.g., enzalutamide or abiraterone) and at least one taxane regimen [40,41].

1. Patient Selection for PSMA Radioligand Therapy

The effectiveness of PSMA-targeted therapy hinges on the presence of sufficient PSMA expression on tumor lesions [42]. In the VISION study, PSMA-positive mCRPC was defined as having at least one tumor lesion with 68Ga-PSMA-11 uptake greater than the normal liver [38]. Patients were excluded from enrollment if any lesions, defined by the conventional imaging, exceeding certain size criteria in the short axis had uptake less than or equal to uptake in normal liver. Under these criteria, 13% of patients were excluded from the enrollment. The definition of “PSMA-positive” for the trial was carefully crafted to ensure tumors with sufficient target expression were identified for likely response to therapy, avoiding reliance on standardized uptake value (SUV) cutoffs due to variability across sites [43]. The criteria developed were based on visual assessment against the liver as an internal reference, deemed more consistent than the spleen and avoiding the need for measuring SUVs, with a binary assessment chosen for clarity. This methodology underlines the intricate balance between ensuring a robust and feasible selection process that aligns with existing criteria and the practical execution of global clinical trials. However, there are several considerations when deciding whether to treat an individual patient.
Firstly, patient outcomes may differ according to the PSMA uptake. Post hoc analysis of the VISION trial, revealed a significant correlation between higher PSMA expression, as quantified by SUVs (mean SUV [SUVmean] and maximum SUV [SUVmax]), and improved clinical outcomes such as rPFS and OS [44]. Notably, patients with higher wholebody SUVmean, particularly those in the highest quartile (SUVmean ≥10.2 for rPFS; ≥9.9 for OS), exhibited a median rPFS and OS of 14.1 and 21.4 months, respectively, compared to significantly lower survival rates in the lowest quartile. Furthermore, a preliminary study suggests that clinically meaningful anti-tumor activity predominantly occurs in patients exhibiting more than one-fold parotid uptake across the majority of lesions (approximately SUV>10), emphasizing the necessity for consideration of treatment sequencing in patients with suboptimal PSMA uptake [45]. Secondly, different PSMA ligands may show variable tumor and normal organ uptake [22,23]. 18F-PSMA-1007 shows higher liver and gall bladder accumulation than 68Ga-PSMA-11 due to hepatobiliary excretion and no or only minimal excretion via the urinary system [46,47]. Furthermore, organ uptake may show variability due to scanner calibration parameters, which further complicates the patient selection process.
The decision to proceed with 177Lu-PSMA radioligand therapy involves a thorough evaluation by an MDT, considering not only the PSMA PET imaging results but also the patient’s overall health, prior treatments, and the potential for response based on PSMA expression levels [5]. This MDT approach ensures that all aspects of the patient’s condition are considered, allowing for personalized treatment planning. As research continues to refine the criteria for PSMA radioligand therapy eligibility, the goal remains to optimize outcomes for mCRPC patients through targeted, effective therapy that minimizes exposure to non-responsive individuals.

2. Treatment-related Toxicity of PSMA Radioligand Therapy

The ability to visualize the distribution of radiopharmaceuticals before treatment provides predictive insight into potential radiation effects on normal organs, allowing for a more individualized assessment of risk and benefit [36]. Expected short-term toxicities associated with PSMA radioligand therapy include dose-dependent myelosuppression and xerostomia [40]. In the VISION trial, the most common adverse events (AEs) reported were fatigue, dry mouth, and nausea, predominantly of grade 1 or 2 severity [38]. A preliminary study provides insight into the longterm (at least 6 months of follow-up) toxicity profile of various PSMA-targeted radioligand therapies, indicating that most AEs could be attributed to alternate etiologies [47]. In particular, only 2 grade ≥3 AEs were attributed to possibly being related to PSMA radioligand therapy: 1 case of grade 4 renal dysfunction (creatinine elevation) and 1 case of grade 3 ALT elevation. Studies collectively affirm the safety and efficacy of PSMA-targeted radioligand therapy in treating mCRPC, with manageable toxicity profiles [48,49].
However, it’s important to acknowledge the limitations in predicting specific adverse effects that may manifest in individual patients. Patients exhibiting impaired renal function, extensive prior chemotherapy, or prolonged hematological toxicity may have a higher susceptibility to experiencing more severe myelotoxicity [50]. There is limited clinical data on patients with moderately impaired renal function (GFR 30-50 mL/min), suggesting a gap in understanding the full impact of 177Lu-PSMA radioligand therapy in this subgroup [51,52]. In cases where patients began 177Lu-PSMA radioligand therapy with already diminished kidney function, worsening renal conditions were observed, though these could also be attributed to the typical risk factors associated with chronic kidney disease [52,53]. These observations indicate a crucial need for careful patient selection and monitoring within MDT, particularly for those with pre-existing conditions that might elevate the risk of adverse outcomes from radioligand therapy.
The management of AEs in radioligand therapy, including marrow toxicity and dry mouth, generally follows symptombased approaches similar to those used for conventional chemotherapy side effects. For marrow toxicity, strategies include delaying subsequent treatments to allow for marrow recovery, especially in patients responding well to treatment; administering supportive care such as platelet or red blood cell transfusions; and considering the use of marrowstimulating agents, albeit with caution due to the risk of exacerbating toxicity in future cycles [40,41,50]. For dry mouth, a common toxicity in PSMA radioligand therapy, assessing severity through careful history-taking at baseline and follow-ups is crucial. Although no consensus exists on reducing salivary gland toxicity, symptomatic relief can be sought through lubricating rinses, and treatment delays may help in salivary gland function recovery [54]. Decisions regarding treatment delays or symptom management should be made comprehensively, taking into account the overall benefit-risk balance for the patient.

3. Enhancing PSMA Radioligand Therapy Through Strategic Combinations

In the evolving landscape of mCRPC treatment, studies like the ENZA-P (NCT04419402) and Lu-PARP (NCT03874884) trials offer promising insights into enhancing treatment responses through innovative combination therapies. The ENZA-P trial underscores the potential of combining enzalutamide, an ARPI, with PSMA-targeted radioligand therapy, predicated on the premise that ARPI upregulates PSMA expression, thereby potentially enhancing the efficacy of PSMA-targeted therapies [55]. This synergy was hinted at in preclinical studies and observed through PSMA PET in men commencing enzalutamide treatment, suggesting that a combined approach might improve treatment outcomes without significantly increasing toxicity [56,57]. Similarly, the Lu-PARP trial addresses the intersection of DNA repair gene mutations and prostate cancer aggressiveness, highlighting the vulnerability of such cancers to PARP inhibitors. This approach leverages the interconnectedness of PARP-associated DNA repair pathways and androgen receptor signaling, suggesting that targeting these mechanisms concurrently could offer a more effective treatment strategy [58]. However, PARP inhibitors (such as olaparib and talazoparib) did not enhance the DNA-damaging effects of 177Lu-PSMA radioligand therapy in vitro, which indicates that further validation is required [59]. Both trials emphasize the critical role of MDT in integrating the latest treatment advances and selecting the most suitable therapy for individual patients. This approach not only ensures that patients receive the most up-to-date and effective treatments but also highlights the importance of tailoring therapy to the patient’s specific disease characteristics and genetic profile, thereby maximizing therapeutic efficacy while minimizing unnecessary toxicity.

CONCLUSION

In conclusion, the integration of the MDT approach with PSMA theranostics in prostate cancer treatment highlights the importance of further investigation. There are unanswered questions regarding how the high sensitivity of PSMA imaging in detecting more lesions impacts patient outcomes, the identification of predictive markers for patient selection in PSMA-targeted radioligand therapy, and the potential benefits of combination therapies. Addressing these areas through focused research within the MDT framework is essential to ensure that the clinical application of PSMA theranostics leads to improved patient care and outcomes. This effort requires collaboration among clinicians, researchers, and patient advocacy groups to advance prostate cancer management.

NOTES

Funding/Support

This work was supported by grants from the National Research Foundation of Korea (NRF-2020R1A2C2011428).

Conflicts of Interest

The authors have nothing to disclose.

Author Contribution

Conceptualization: MS, GJC; Visualization: MS, GJC; Writing - original draft: MS, GJC; Writing - review & editing: MS, GJC.

Fig. 1.
A 69-year-old patient with metastatic castration-resistant prostate cancer involving the left pelvis. Initial management included leuprorelin therapy, followed by a combination of triptorelin and bicalutamide. Despite these treatments, the patient exhibited a gradual increase in serum prostate-specific antigen (PSA) levels from 0.074 ng/mL to 0.212 ng/mL within 8 months. (A, B) Prostate-specific membrane antigen (PSMA) positron emission tomography identified a focal PSMA-avid lesion in the right pubic bone. (C) Subsequently, the patient underwent stereotactic ablative radiotherapy to the right pubis with a single fraction of 22 Gy, leading to a reduction in PSA levels from 0.212 ng/mL to 0.053 ng/mL.
juo-244600200010f1.jpg
Fig. 2.
Theranostic process in a 64-yearold male patient with metastatic prostate cancer who underwent hormone therapy followed by 2 cycles of chemotherapy. Despite these treatments, the patient continued to develop metastatic lesions, prompting referral for radioligand therapy. Pretreatment prostate-specific membrane antigen (PSMA) positron emission tomography (PET) showed multiple PSMA-avid metastases. Following PSMA radioligand therapy, prostate-specific antigen levels dramatically decreased from 823.8 ng/mL to 0.53 ng/mL, indicating a substantial response to treatment.
juo-244600200010f2.jpg
Table 1.
Ongoing clinical trials employing PSMA PET
Study Trial phase Definition of oligometastasis Intervention Outcome
NCT05352178 Phase III 1-5 extracranial metastases in any organ, detected on PSMA PET SBRT/surgery vs. SBRT/surgery + 1 month of ADT vs. Poly-metastatic free survival
NCT04619069 Phase I/II 1-3 PSMA-avid areas of metastatic disease SBRT/surgery + 6 months of ADT + anzalutamide Hormone therapy vs. SBRT + hormone therapy Proportion of eligible patients who enroll onto the study
NCT04983095 Phase III 1-3 skeletal or extra pelvic lymph node metastases detected by PSMA PET ADT + local radiotherapy vs. SBRT + ADT + local radiotherapy Failure-free survival
NCT04302454 Phase III 1-4 lesions (bone + lymph nodes) in total, without evidence of visceral metastases detected by PSMA PET Radiotherapy vs. radiotherapy + hormonal therapy Metastases progression-free survival

PSMA, prostate-specific membrane antigen; PET, positron emission tomography; SBRT, stereotactic body radiation therapy, ADT, androgen deprivation therapy.

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