Multidisciplinary Team Approach in Prostate-Specific Membrane Antigen Theranostics for Prostate Cancer: A Narrative Review

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.

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.

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.

Table 1.

Ongoing clinical trials employing PSMA PET

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.

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.