The session highlighted the advantages, pitfalls, and challenges of molecular imaging for prostate cancer. Several highly accurate PSMA PET tracers are available, each demonstrating strong tumor uptake and minimal background uptake. Three PSMA tracers are FDA-approved, including Gallium PSMA 11, Fluor 18 PYL, and Rh PSMA, with two EMA-approved and PSMA 1007 receiving market authorizations in European countries. The approval of tracers for imaging was achieved through landmark studies focused on detecting lymph node metastasis. Two key studies were pivotal: one featuring gallium PSMA11 on the left and PYL on the right. Both exhibited a sensitivity of 40% and impressive specificities of 95% and 98%, respectively. Inter-reader reliability was notably positive, establishing this as the premier imaging test. Despite the 40% sensitivity, an improvement over prior methods, the standout support came from the pro-PSMA study out of Australia. This phase 3 study randomized patients to receive conventional imaging (CT and bone scan) or PSMA PET, with patients crossing over to the other modality if no metastasis was found. The results decisively favored PSMA PET for accuracy, both in sensitivity and specificity, across all types of metastatic disease, including pelvic nodal detection and distant metastasis. In a recent study from Switzerland, the PSMA tracer 1007, known for its efficacy, has been found to present a challenge with unspecific bone uptake, particularly evident in digital, novel, and modern scanners. Conversely, research from Essen indicates that this uptake may be resolved with alternative imaging methods, with most cases not detected on gallium PSMA 11. Although challenges persist, advancements such as AI offer potential solutions. Another hurdle lies in interpreting the significance of more sensitive imaging tests, which could redefine disease volume and affect prognosis. Despite retrospective limitations, there are promising findings regarding PSMA PET's prognostic value in non-metastatic CIPC. The presence of <5 lesions on nmRCPC-PET indicates a significantly better overall survival prognosis than patients with >5 lesions. Incorporating modern imaging into future prostate cancer clinical trials is crucial, exemplified by ongoing studies like the promoting and ARASTEP studies. These trials include PSMA PET imaging and explore PSMA-based endpoints, potentially impacting regulatory approval processes. Standardizing reporting methods for PSMA PET scans is essential, prompting collaboration between EAU, ASCO, and EANM under the SPARC project. Despite challenges like unspecific bone uptake, addressing these pitfalls through training and data accumulation is vital for the long-term success of PSMA PET imaging. In summary, PSMA PET emerges as the premier imaging test for prostate cancer, particularly in primary staging. Challenges such as ambiguous bone uptake persist but can be mitigated through training and data augmentation. Standardization is imperative for sustained success, necessitating open dialogue. SPARC, introduced as a prototype, aims to unify classification stakeholders and establish a new gold standard for the future. Collaboration is essential to ensure PSMA PET integration in all forthcoming clinical trials. 

Controversies on GU Cancer Staging: Is it Only Imaging? Are Biomarkers Better? By BF. Chapin

In the realm of prostate cancer staging for newly diagnosed patients, the debate between biomarkers and imaging techniques takes center stage. In the staging of prostate cancer in newly diagnosed patients, biomarkers and imaging play significant roles. Biomarkers, which include genomic markers and artificial intelligence (AI) arterial imaging, are increasingly used to compartmentalize patients based on their disease characteristics, including stage, aggressiveness, and responsiveness to therapies. This compartmentalization helps in clinical trial balancing, retrospective studies, and minimizing biases. The spectrum of biomarkers in prostate cancer encompasses various types used or considered for diagnosis and management. The focus areas for newly diagnosed cases include genomic markers and artificial intelligence (AI) imaging. However, according to the EAU, these biomarkers should not be routinely offered but should be selectively used in subsets of patients where they can provide clinically actionable information. This approach can influence treatment decisions, such as shifting patients from a favourable intermediate-risk category to a more aggressive or less aggressive consideration, particularly in active surveillance. 

The updated NCCN guidelines focused on gene expression markers, their predictive or prognostic significance, and their endpoints. Biomarkers for staging and risk stratification are discussed, particularly for newly diagnosed patients categorized as low, intermediate, and high risk, as well as clinically known positive or metastatic cases. PSMA PET imaging is highlighted for its potential to refine staging, possibly reducing the number of patients. Researchers have conducted studies utilizing genomic information in clinical settings, such as the one led by Dan Spratt on a 22-gene classifier's performance in intermediate-risk prostate cancer. This study, part of the NRG trial, compared low and higher doses of radiation without using a DT (dose-escalation technique) in 215 patients. The genomic classifier was found to be prognostic for distant metastasis and prostate cancer-specific mortality through multivariable analysis. Particularly, the risk of distant metastasis was 4% with a low genomic classifier and 16% with a high one. This raises questions about the benefit of using a DT in patients with low-risk genomic classifier levels and intermediate disease who undergo radiation therapy. A study, NRG GU010, examines treatment intensity balance in cancer care, akin to GU009, focusing on Artera AI's role in predicting the need for Androgen Deprivation Therapy (ADT) alongside radiation. The AI model, drawing from various NRG studies, emphasizes the importance of the Gleason score, primary factors, and imaging. A validation study underscores the model's efficacy in predicting outcomes for intermediate-risk patients with or without four months of hormone treatment, showing improved survival rates and distant metastasis-free survival with ADT. However, biomarkers have minimal impact on surgical decisions, though efforts to integrate Decipher for lymph node assessment exist. Radiation therapy considerations in prostate cancer now include Decipher or Artera AI, especially when combined with hormone therapy, aligning with guidelines from organizations like EAU and NCCN for clinically node-positive cases. A notable clinical trial, NRG-GU009 (PREDICT-RT), focuses on high-risk prostate cancer patients who undergo Decipher testing. Those with lower Decipher scores are randomized to standard treatment: radiation with 24 months of ADT, while those with higher scores may receive enhanced ADT with apalutamide. This study aims to assess the prognostic value of Decipher rather than its predictive capabilities, offering insights into its potential role in patient care. 

The GUNS trial focused on high-risk prostate cancer patients preparing for surgery. Participants undergo genomic profiling while receiving LHRH and apalutamide, then are grouped based on genomic findings into four categories. This trial allows for additional arms in the future, with 20 patients per arm initially, and potential expansion based on high complete response rates (above 15%). The importance lies in distinguishing between prognostic and predictive markers, with prospective trials like this vital for validating current and new biomarkers' prognostic value and assessing their predictive potential in therapeutic outcomes. Skeptical optimism is warranted until these markers are fully validated through trials like GUNS. 

The PSMA M1a Positive Patient: Treat as M0

The M1a prostate cancer (PCa) classification, according to the TNM system, denotes the presence of non-regional lymph nodes above the bifurcation of the common iliac artery and other metastases like inguinal or pararectal without specified details. Between 2010 and 2018, de novo M1a prostate cancer (PCa) incidence in the Netherlands increased from 0.47 to 1.89 cases per 100,000. Treatment guidelines recommend androgen deprivation therapy (ADT) with radiotherapy up to 72 Gy for low-volume M1a PCa per CHAARTED criteria. Systemic treatments combined with local interventions are advised, especially in PrePSMA PET. Recent data show better outcomes for patients with only non-regional lymph nodes. Nodal involvement significantly affects outcomes even in low-volume disease. PSMA PET imaging reveals M1A disease prevalence and location, with up to 40-50% of intermediate and high-risk PCa patients having M1A disease, often in common iliac and paraortocaval regions. Mediastinal nodes detected exclusively on M1a scans, notably on PSMA PET scans, can pose false positive concerns, similar to intra-abdominal ganglia. Accurate interpretation by experienced nuclear physicians is crucial. Despite multiple studies, evidence supporting ADT escalation benefits for M1a disease patients remains limited. Recent findings from the PEACE-1 study suggest limited efficacy of ADT escalation like Abiraterone in this context. Treatment advances for metastatic prostate cancer have shown little improvement for M1a cases, likely due to unique genetic traits. Stampede study indicates that adding radiotherapy to the prostate can improve failure-free survival in M1a patients. Additionally, studies suggest potential benefits from local radiotherapy to nodes in the pelvis and M1a disease. Surgical approaches also show promise, with up to 40% of patients achieving recurrence-free survival when receiving local therapy to both the prostate and nodes. Expert opinions at the APCC show divergence without consensus on treatment approaches, emphasizing the importance of local therapy for M1a disease. Metastasis-directed therapy (MDT) is considered viable but recommended primarily in clinical trials. The heterogeneity of M1a disease complicates treatment decisions, especially regarding nodal metastasis locations identified on PSMA PET scans. While systemic therapies are common, non-systemic approaches like local therapies for the prostate or metastases are gaining attention for their potential efficacy. M1a disease is complex and underexplored, increasingly diagnosed with advanced imaging. Conventional systemic treatments may be less effective; localized therapies could offer better outcomes.

Controversies In Initial Staging for Prostate Cancer-The Patient With PSMA M1a Positive Disease: Treat As M1 By C. Sweeney

A 68-year-old man presented with typical symptoms. He had a PSA level of 45. The biopsy identified 8 glycinate, and PSMA PET imaging showed 5 lymph nodes (<1cm). A vivid M1 lesion indicative of systemic disease was observed. The focus shifted from whether to administer systemic therapy to determining the optimal systemic treatment plan. Traditional imaging would have classified the patient as having high-risk localized disease (M0) or possibly low-volume node-only disease if the node was slightly larger. However, recent findings suggest that intensifying systemic therapy for very high-risk localized prostate cancer (M0) through the addition of Abiraterone to ADT and radiation can substantially decrease the risk of mortality by 40%. The PEACE study data underscores shifts in standard care, notably with radiation's efficacy in improving survival for low-volume disease patients. PSMA PET CT imaging outperforms traditional methods, requiring cut points for effective treatment guidance. Personalized plans, including triple therapy, hinge on these thresholds. CT and bone scans highlight disease bulk and advanced issues, aiding in systemic therapy decisions. PSMA reporting detects smaller, less resistant cancer volumes with eradication potential for M1A PSMA PET-positive lesions. Cutoff points for scans determine disease severity, aiding in treatment decisions, with intact prostates potentially benefiting from radiation therapy as per current protocols. The session discussed management strategies for high-risk localized disease, emphasizing using PSMA PET imaging to identify disease extent beyond conventional imaging limits.

The combination of systemic therapy with local control yields better results than systemic therapy alone, particularly evident with intensified hormonal therapy (ADT and Abiraterone) alongside radiation. Notably, the many patients potentially identified as M1A by PSMA PET could benefit from combined treatments. An analysis of HORRAD and STAMPEDE studies suggests prostate radiation benefits patients with four or fewer bony metastases. PSMON study findings highlight improved RPFS with Abiraterone plus radiation. However, caution is advised against docetaxel use. High-volume synchronous disease shows the most significant benefit, while low-volume disease offers diminishing benefits. Meta-analysis supports a modest benefit from adding prostate radiation. Tailored treatment based on disease volume and PSMA PET findings is recommended, advocating ADT and radical therapy for De NOVO PSMA PET M1a patients and comprehensive treatment for PSMA PET CT M1a negative patients, including ADT, radical therapy, and prostate radiation.

Discussion

The conversation encompassed several key themes regarding using PSMA PET scans and biomarkers in prostate cancer diagnostics and treatment stratification. One topic addressed the variability in PSMA PET SUV thresholds, influenced by factors like scanner type and timing, which complicates establishing standardized cutoffs. Efforts like the SPARK project aim to address this, but consensus suggests that a singular numerical cutoff may not be sufficient. Another focus was on ongoing trials using PSMA and biomarkers to guide treatment intensity, exploring the potential synergy of combining these approaches. Challenges were acknowledged in retrospectively evaluating widely used technologies without comprehensive prospective assessment.

Additionally, discussions emphasized adapting PSMA PET scans and biomarkers into future trials to align with clinical practices, drawing parallels to successful approaches in lymphoma diagnostics with FDG PET. However, concerns were raised about the cost of biomarker testing, particularly for low and intermediate-risk cases, highlighting the selective use of biomarkers to guide surveillance strategies. Ongoing studies, notably one led by Todd Morgan and the Michigan group, are assessing the utility of decipher in radiation therapy selection, stressing the importance of demonstrating tangible patient benefits. Challenges related to false positives in PSMA imaging, especially with PSMA 10 or 7, underscored the complexity of distinguishing metastases from other conditions. Decision-making relies on evaluating the complete clinical context, including PSA levels, biopsy outcomes, and lesion characteristics, with multidisciplinary teams playing a crucial role in navigating these complexities. 

European Association of Urology (EAU) Annual Congress 2024, 5th April - 8th April 2024, Paris, France