Prognostic value of PSMA PET in predicting long‐term biochemical control following curative intent treatment for prostate cancer - Ades - Journal of Medical Imaging and Radiation Oncology - Wiley Online Library

Summary of Multiple Sources on Prognostic Impact of PSMA PET/CT for Prostate Cancer Care

PSMA PET/CT scans can help predict post-treatment progress of prostate cancer in several ways:

1. Predicting biochemical recurrence and survival:

• - Patients with positive nodes (miN1) on PSMA PET have significantly shorter time to biochemical failure compared to node-negative patients after radical prostatectomy.
• - The number of PSMA-avid nodes is predictive of biochemical progression-free survival, with two or more nodes associated with worse outcomes.
• - PSMA PET-derived volumetric metrics like whole-body PSMA tumor volume (wbPSMA-TV) and total lesion PSMA (wbPSMA-TL) correlate with serum PSA, tumor Gleason score, and shorter progression-free survival.

2. Guiding salvage therapy decisions:

• - PSMA PET can localize recurrence to the prostate bed, pelvic lymph nodes, or distant sites, which impacts salvage therapy approaches.
• - Patients with negative PSMA PET prior to salvage radiotherapy have better odds of response and more favorable 3-year biochemical progression-free survival.
• - The presence of recurrence outside the prostate bed on PSMA PET predicts unfavorable response to salvage radiotherapy.

3. Predicting response to systemic therapies:

• - In metastatic castration-resistant prostate cancer, higher SUVmean (≥10) of lesions on baseline PSMA PET is associated with better PSA response and progression-free survival with PSMA-targeted radioligand therapy.
• - Whole-body PSMA-avid tumor burden metrics on baseline PET can predict response to androgen receptor-targeted therapies and taxane chemotherapy.

4. Assessing treatment response:

• - Changes in whole-body PSMA-avid tumor burden after cycles of therapy correlate with overall survival.
• - Complete response on PSMA PET during/after therapy is associated with longer overall survival.

5. Indicating tumor biology:

• - PSMA expression correlates with genomic risk scores, potentially serving as a non-invasive marker of genetic alterations and aggressive phenotypes.

In summary, PSMA PET/CT provides valuable prognostic information through assessment of disease extent, tumor burden quantification, and PSMA expression levels. This can help guide treatment decisions and predict outcomes across various stages of prostate cancer management. However, the authors note more research is still needed to fully establish the role of PSMA PET in predicting long-term survival outcomes in some scenarios.

Patient Oriented Summary

Here's a patient-oriented summary of how PSMA PET/CT scans can help in prostate cancer care:

What is a PSMA PET/CT scan?

A PSMA PET/CT scan is an advanced imaging test that combines two types of scans: PET (Positron Emission Tomography) and CT (Computed Tomography). It uses a special tracer that attaches to prostate cancer cells, making them visible on the scan.

How can PSMA PET/CT scans help me?

1. More accurate diagnosis:
- These scans can detect prostate cancer more accurately than traditional scans, even when it has spread to other parts of the body.
- This means your doctors can have a clearer picture of your cancer's extent, helping them choose the most appropriate treatment for you.

2. Better treatment planning:
- If you're newly diagnosed, the scan results can help decide if surgery, radiation, or other treatments are best for you.
- If your cancer has returned after initial treatment, the scan can pinpoint where it has come back, guiding decisions about further treatment.

3. Predicting treatment outcomes:
- The amount and intensity of cancer seen on the scan can give clues about how aggressive your cancer might be.
- This information helps doctors estimate how well different treatments might work for you.

4. Monitoring treatment effectiveness:
- PSMA PET/CT scans can show if your treatment is working by comparing scans before and after treatment.
- This allows your doctors to change your treatment plan if needed, rather than waiting for other signs that it might not be working.

5. Guiding specialized treatments:
- Some new treatments target the same protein (PSMA) that these scans detect. The scan results can show if you're likely to benefit from these treatments.

6. Avoiding unnecessary procedures:
- By providing detailed information, these scans might help you avoid unnecessary surgeries or treatments that are unlikely to help.

7. Personalizing your care:
- The scan results, combined with other tests, help create a more complete picture of your specific cancer, allowing for more personalized treatment plans.

What should I know about getting a PSMA PET/CT scan?
- It's a painless procedure that usually takes about 2 hours.
- You'll receive an injection of a small amount of radioactive tracer before the scan.
- Not all hospitals offer these scans yet, and they may not be covered by all insurance plans.
- While very helpful, these scans are not perfect. Your doctor will use the results along with other tests and examinations to make treatment decisions.

Remember, PSMA PET/CT scans are a powerful tool, but they're just one part of prostate cancer care. Always discuss the results and their implications with your healthcare team to understand how they apply to your specific situation.

Clinical Impact

The clinical impact of these PSMA PET/CT results on prostate cancer care is significant and multifaceted:

1. Improved risk stratification:
PSMA PET/CT provides more accurate staging and risk assessment compared to conventional imaging. This allows for better tailoring of treatment strategies to individual patients' risk levels. For example, patients with seemingly low-risk disease on biopsy but high PSMA uptake may be considered for more aggressive treatment approaches.

2. More informed treatment decisions:
- Initial staging: PSMA PET can detect metastases not visible on conventional imaging, potentially altering treatment from curative-intent to systemic therapy.
- Biochemical recurrence: The ability to localize recurrence sites guides salvage therapy decisions, such as whether to treat the prostate bed alone or include pelvic lymph nodes in radiation fields.
- Metastatic disease: PSMA PET findings can inform decisions about the extent of systemic therapy needed or whether to consider metastasis-directed therapy.

3. Prediction of treatment outcomes:
The prognostic information provided by PSMA PET allows clinicians to better counsel patients about their likely outcomes with different treatment options. This facilitates shared decision-making and setting of appropriate expectations.

4. Treatment response monitoring:
PSMA PET's ability to assess treatment response, particularly in metastatic disease, allows for earlier identification of treatment failure and timely switching to alternative therapies.

5. Patient selection for targeted therapies:
PSMA PET is crucial for selecting patients likely to benefit from PSMA-targeted radioligand therapies, which are becoming increasingly important in managing advanced prostate cancer.

6. Avoiding unnecessary procedures:
By providing more accurate staging, PSMA PET can help avoid futile surgeries or unnecessary extensive lymph node dissections in some patients.

7. Refinement of active surveillance protocols:
PSMA PET findings might help identify patients with apparently low-risk disease who are actually at higher risk of progression and thus not ideal candidates for active surveillance.

8. Potential for personalized medicine:
The correlation between PSMA expression and genomic risk scores suggests potential for PSMA PET to serve as a non-invasive biomarker of tumor biology, possibly guiding more personalized treatment approaches in the future.

9. Cost-effectiveness:
While PSMA PET/CT is more expensive than conventional imaging, its superior accuracy could lead to cost savings by avoiding futile treatments and allowing for earlier, more effective interventions.

10. Clinical trials:
PSMA PET is increasingly being incorporated into clinical trial designs, potentially leading to more refined patient selection and outcome assessment in prostate cancer research.

It's important to note that while these impacts are significant, some aspects of PSMA PET's role in prostate cancer management are still evolving. Ongoing research and clinical experience will further refine its optimal use in different clinical scenarios. Additionally, the availability and cost of PSMA PET/CT may limit its widespread adoption in some healthcare settings.

Q&A

Here's a list of potential questions and likely answers from an oncologist:

Q1: Why are you recommending this scan for me now?

A1: "Based on your recent PSA test showing a slight increase, we want to check if there's any detectable recurrence of your prostate cancer. The PSMA PET/CT scan can detect very small areas of cancer activity that might not show up on conventional scans."

Q2: What specific information do you hope to gain from this scan?

A2: "We're looking to see if there are any areas where cancer cells are active. This could be in the area where your prostate was, in nearby lymph nodes, or potentially in other parts of your body. This information will help us determine if your cancer has recurred and, if so, where exactly it's located."

Q3: How might the results of this scan change my treatment plan?

A3: "If the scan is negative, we might continue with close monitoring. If it shows localized recurrence, we might consider targeted radiation therapy. If it shows more widespread disease, we might need to discuss systemic treatments like hormone therapy. The scan results will help us tailor the best approach for your specific situation."

Q4: How accurate is this scan in detecting recurrent prostate cancer?

A4: "PSMA PET/CT is currently one of the most sensitive tools we have for detecting recurrent prostate cancer. It can detect cancer when PSA levels are as low as 0.2-0.5 ng/mL. However, like all tests, it's not perfect. Very small areas of cancer or those with low PSMA expression might be missed."

Q5: Are there any alternatives to this scan? If so, why do you prefer the PSMA PET/CT?

A5: "There are alternatives like conventional CT, bone scans, or MRI. However, PSMA PET/CT is more sensitive and can detect smaller areas of cancer activity. This gives us more precise information to guide treatment decisions."

Q6: What does the scan involve? How should I prepare for it?

A6: "The scan takes about 2 hours. You'll receive an injection of a radioactive tracer, then wait about an hour before the actual scan, which takes 30-45 minutes. You don't need to fast, but stay hydrated and avoid strenuous exercise 24 hours before the scan. We'll give you detailed instructions."

Q7: Are there any risks or side effects associated with this scan?

A7: "The risks are very low. The radiation exposure is minimal and the tracer is generally well-tolerated. Some people experience mild headache or nausea, but serious side effects are rare. You should tell us if you have any allergies or kidney problems."

Q8: How long will it take to get the results, and how will they be communicated to me?

A8: "We usually get the results within 1-2 days. I'll review them and then we'll schedule a follow-up appointment to discuss the findings in detail. If there's anything urgent, we'll contact you sooner."

Q9: If the scan shows no signs of cancer, how confident can we be that the cancer hasn't returned?

A9: "While PSMA PET/CT is very sensitive, no test is 100% perfect. A negative scan is reassuring, but we'll continue monitoring your PSA levels. If your PSA continues to rise despite a negative scan, we might consider additional testing."

Q10: If the scan does show cancer, what are my next treatment options?

A10: "That would depend on where the cancer is found and how extensive it is. Options could include salvage radiation therapy, hormone therapy, or in some cases, surgery. We'd discuss all appropriate options based on the specific findings."

Q11: Is this scan covered by my insurance? If not, what will be my out-of-pocket cost?

A11: "PSMA PET/CT is now covered by Medicare for certain indications. Many private insurers are following suit, but coverage can vary. Our billing department can check with your insurance and give you an estimate of any out-of-pocket costs."

Q12: How often might I need to repeat this scan in the future?

A12: "That depends on the results of this scan and your ongoing PSA levels. If we need to monitor treatment response, we might repeat it in 3-6 months. If it's negative, we might not need to repeat it unless your PSA rises again."

Q13: Are there any clinical trials related to PSMA PET/CT or treatments based on its results that I should consider?

A13: "There are ongoing trials looking at how to best use PSMA PET/CT results to guide treatment. Depending on your specific situation, you might be eligible for trials of new targeted therapies. We can discuss this further once we have your scan results."

Q14: How does my PSA level correlate with the decision to do this scan?

A14: "We typically consider PSMA PET/CT when PSA levels are rising after treatment, often when they reach about 0.2 ng/mL or higher after surgery, or when there's a significant rise after radiation. In your case, your PSA has risen to [specific level], which is why we're recommending this scan now."

Remember, these are general answers. Your oncologist's responses would be tailored to your specific medical history and current condition.

Prognostic value of PSMA PET in predicting long‐term biochemical control following curative intent treatment for prostate cancer - Ades - Journal of Medical Imaging and Radiation Oncology - Wiley Online Library

 

onlinelibrary.wiley.com

Angus Ades

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Radiation Oncology—Original Article

Corresponding Author

Angus Ades

• angusades@gmail.com

• orcid.org/0009-0006-9285-002X

Radiation Oncology Princess Alexandra Hospital Raymond Terrace, Brisbane, Queensland, Australia

First published: 11 October 2024

A Ades: BSc, MD; T Holt MBBS, FRANZCR; H Rhee MBBS, PhD; M Webb MBBS, FRACP, FAANMS; AM Mehdi BSc, MSc, PhD; G Ratnayake MBBS, MPhil, FRANZCR.

Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

doi: 10.1111/1754-9485.13787. Online ahead of print.

Angus Ades  ¹ , Tanya Holt  ^{1   2} , Handoo Rhee  ^{3   4} , Myles Webb  ⁵ , Ahmed M Mehdi  ⁶ , Gishan Ratnayake  ^{1   2}

Affiliations

• PMID: 39394722
• DOI: 10.1111/1754-9485.13787

Abstract

Introduction: The aim of this study is to investigate the prognostic value of ⁶⁸Ga-labelled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) metrics in predicting long-term biochemical failure-free survival (BFFS) following curative intent treatment for prostate cancer.

Methods: We completed a prospective study that followed men who had PSMA PET for staging of newly diagnosed prostate cancer between 2015 and 2017 who went on to have curative intent treatment with radiotherapy (RT) or radical prostatectomy (RP). PSMA PET CT imaging was reported and the intraprostatic maximum standardised uptake value (SUV_max) was recorded. The primary outcome was BFFS. Statistical analysis included descriptive statistics, Cox proportional hazards (PH) models, Kaplan-Meier survival analysis and a regression tree structured method.

Results: A total of 183 men were included in the analysis with a median age of 66 years and the majority of patients (55.2%) had ISUP grade 1-3 disease. All patients had PSMA PET staging prior to curative intent treatment with RP (66.1%) or external beam radiotherapy (33.9%). PSMA-avid pelvic nodes were present in 26 patients but were not associated with worse biochemical control. A PSMA SUV_max of the prostate primary greater than the median (>5.6) was associated with a lower BFFS (HR: 4.4, 95% CI 1.42-3.72, P = 0.01). A multivariate Cox model incorporating initial biopsy grade, age and PSMA SUV_max showed that PSMA SUV_max was an independent predictor of BFFS. The RT-structured method identified an optimal threshold of 6.8 for PSMA SUV_max, above which patients with ISUP 1-3 disease had a significantly worse BFFS.

Conclusion: PSMA SUV_max is a strong predictor of BFFS in patients with non-metastatic prostate cancer who underwent curative intent treatment. Patients with low-risk disease on biopsy (ISUP 1-3) but high PSMA SUV_max may have biochemical failure risk analogous to higher-risk disease (ISUP 4-5). These findings allow for further risk stratification and prognosis of patients with newly diagnosed prostate cancer planned for definitive treatment.

Keywords: 68Ga PSMA PET; biochemical failure‐free survival; prostate cancer.

© 2024 Royal Australian and New Zealand College of Radiologists.

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References

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3. Prostate Cancer NCCN Guideline. 2022. [Cited 1 Nov 2022.] Available from URL: https://www.nccn.org/guidelines/guidelines‐detail.
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5. Roach PJ, Francis R, Emmett L et al. The impact of 68Ga‐PSMA PET/CT on management intent in prostate cancer: results of an Australian prospective multicenter study. J Nucl Med 2018; 59: 82–88.
6. Hruby G, Eade T, Emmett L et al. 68Ga‐PSMA‐PET/CT staging prior to definitive radiation treatment for prostate cancer. Asia Pac J Clin Oncol 2018; 14: 343–346.
7. van Leeuwen PJ, Donswijk M, Nandurkar R et al. Gallium‐68‐prostate‐specific membrane antigen (68Ga‐PSMA) positron emission tomography (PET)/computed tomography (CT) predicts complete biochemical response from radical prostatectomy and lymph node dissection in intermediate‐and high‐risk prostate cancer. BJU Int 2019; 124: 62–68.
8. Dekalo S, Kuten J, Mintz I et al. Preoperative 68Ga‐PSMA PET/CT defines a subgroup of high‐risk prostate cancer patients with favorable outcomes after radical prostatectomy and lymph node dissection. Prostate Cancer Prostatic Dis 2021; 24: 910–916.
9. Uprimny C, Kroiss AS, Decristoforo C et al. 68 Ga‐PSMA‐11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging 2017; 44: 941–949.
10. Demirci E, Kabasakal L, Şahin OE et al. Can SUVmax values of Ga‐68‐PSMA PET/CT scan predict the clinically significant prostate cancer? Nucl Med Commun 2019; 40: 86–91.
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13. Wang Z, Zheng A, Li Y et al. 18F‐PSMA‐1007 PET/CT performance on risk stratification discrimination and distant metastases prediction in newly diagnosed prostate cancer. Front Oncol 2021; 11: 759053.
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15. Hoffmann MA, Miederer M, Wieler HJ, Ruf C, Jakobs FM, Schreckenberger M. Diagnostic performance of 68Gallium‐PSMA‐11 PET/CT to detect significant prostate cancer and comparison with 18FEC PET/CT. Oncotarget 2017; 8: 111073–111083.
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17. Roberts MJ, Morton A, Papa N et al. Primary tumour PSMA intensity is an independent prognostic biomarker for biochemical recurrence‐free survival following radical prostatectomy. Eur J Nucl Med Mol Imaging 2022; 49: 3289–3294.
18. Leow BYJ, Eade T, Hruby G et al. Prognostic impact of prostate‐specific membrane antigen positron emission tomography (PSMA PET) staging for clinically node‐positive prostate cancer. J Med Imaging Radiat Oncol 2024. https://doi.org/10.1111/1754‐9485.13655.

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Prognostic Value of PSMA PET/CT in Prostate Cancer - ScienceDirect

sciencedirect.com

AB Jani

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Introduction

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with a large catalytic extracellular domain that allows for ligand binding.^1,2 There is a low-level PSMA expression in different tissues in the body, including salivary glands, duodenal epithelial lining, and cells of the proximal convoluted tubules of the kidney.³ PSMA expression is low in normal and hyperplastic prostate glands.⁴ However, PSMA is over-expressed in prostate cancer (PCa) tissue.⁵ The level of its expression in PCa is higher in castration-resistant PCa compared to metastatic hormone-sensitive PCa, which in turn shows a higher level of PSMA expression compared with localized PCa. This differential PSMA expression in different phases of PCa progression suggests that its level of expression is proportional to the tumor aggressiveness and patient outcome.⁶ One of the catalytic roles of PSMA in PCa is conferred by its folate hydrolase 1 function, which cleaves folate off poly-γ-glutamated folate making folate available for cellular metabolism.⁷ High folate concentration is associated with increased tumor growth and invasiveness.⁸ Beyond its catalytic roles, PSMA also internalizes ligands bound to it, in this way helping to traffic folate into the cell.⁸ Intracellular folate activates major oncologic signaling pathways that modulate aggressive tumor phenotypes.^9,10 For example, increased PSMA level is related to the modulation of mTOR transcription and the phosphorylation of 4EBP1, a downstream target in the mTOR signaling pathway.⁹ Similarly, PSMA expression increases the phosphorylation of Akt and its downstream targets, S6K and 4EBP1, while the inhibition of PSMA activity with 2-PMPA is associated with reduced phosphorylation of these molecular targets.⁹

Imaging plays a vital role in the management of PCa. Molecular imaging has played critical role in PCa management owing to the possibility of targeting different molecular targets and metabolic pathways in the tumor. Earlier molecular imaging probes targeting amino acid, fatty acid, and glucose metabolism in PCa show important limitations in their clinical applications. The first attempt at targeting PSMA for molecular imaging of PCa utilized a monoclonal antibody targeting the intracellular epitopes of PSMA with limited sensitivity and specificity for lesion detection.¹¹ In the last decade, two molecular targets have been explored for the improved detection of PCa lesions, ¹⁸F-fluciclovine targeting amino acid trapping by PCa12, 13, 14 and PSMA ligands targeting the extracellular domain of PCA membrane-bound PSMA.^15,16 Several small molecular ligands targeting PSMA have been synthesized and labeled with diagnostic and therapeutic radionuclides for imaging and therapy of PCa. The list of the radioligand PSMA for imaging and therapy of PCa is long and growing. The most successful radioligand in widespread clinical utilization across the world includes ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL, ¹⁸F-PSMA-1007, ⁶⁸Ga-PSMA-I&T, and ¹⁸F-rhPSMA-7.3.17, 18, 19, 20 Recently, the excellent performance of ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL, and ¹⁸F-rhPSMA-7.3 for PET imaging of PCa have been reported in phase 3 clinical trials leading to their approval by the United States FDA (Federal Drug Administration) and other regulatory authorities for the initial staging and detection of recurrence of PCa.21, 22, 23, 24, 25, 26, 27

Due to the central role that PCa cell membrane-expressed PSMA plays in tumor metabolism and progression, evidence supporting the prognostic information derivable from positron emission tomography (PET) imaging of PCa with radiolabeled PSMA ligands is increasingly being reported. In this review article, we will appraise the literature reporting the prognostic value of PSMA PET imaging in the different phases of PCa progression.

Men with suspected PCa based on clinical symptoms, clinical examination findings, and elevated serum prostate-specific antigen (PSA) undergo prostate biopsy for histological confirmation. Prostate biopsy, previously done blind, is now guided by imaging to improve the yield for disease detection. Transrectal ultrasound (TRUS)-guided biopsy has now been replaced by multiparametric magnetic resonance imaging (mpMRI)-guided biopsy of the prostate gland due to the lower sensitivity and specificity of the former.^28,29 Primary PCa has varying aggressiveness, with tumor aggressiveness graded with the Gleason score or, more recently, the International Society of Urological Pathology (ISUP) grading system. ISUP grade group 1 PCa are indolent and are often treated with a surveillance or watchful waiting approach. The goal of image-guided prostate biopsy is, therefore, not only the accurate detection of PCa lesions but prevent unnecessary biopsy and over-diagnosis of ISUP grade group 1 lesions while improving the detection of clinically significant PCa (csPCa) defined as ISUP grade group 2 to 5 (Gleason score ≥ 7). PCa lesion assessed on mpMRI is graded using the Prostate Image-Reporting and Data System (PI-RADS), which assigned a score of 1 to 5 to lesions based on their likelihood of malignancy. The pooled prevalence of csPCa in lesions assigned PI-RADS score of ≥3 is 45%.³⁰ The percentage of csPCa in lesions with PI-RADS scores 1 or 2, 3, 4, and 5 on mpMRI are 6%, 12%, 48%, and 72%, respectively.³⁰ These data show that about half of all patients had unnecessary prostate biopsies based on mpMRI findings and a significant proportion of patients with csPCa are missed, indicating the need for improvement in detecting and predicting csPCa in men with suspected PCa.

Evidence is emerging to support the clinical utility of PSMA PET imaging for improved prediction of csPCa on prostate biopsy pathology.³¹ The PRIMARY trial is a prospective multicenter study that investigated the superiority of combined ⁶⁸Ga-PSMA-11 PET/CT plus mpMRI over mpMRI alone for predicting csPCa on histology.³² In a cohort 291 men, PSMA PET was positive in 211 men (73%), mpMRI was positive (PI-RADS 3-5) in 196 men (67%), and combined PSMA PET plus mpMRI positivity in 235 men (81%). csPCa was confirmed in 162 (56%) patients on histology. PSMA PET had a superior sensitivity for csPCa compared with mpMRI, and the combination of both had better sensitivity than either alone (sensitivity of 90%, 83%, and 97% for PSMA PET, mpMRI, and combined PSMA PET and mpMRI, respectively). The negative predictive value (NPV) showed a similar trend, 80%, 72%, and 91% for PSMA PET, mpMRI, and combined PSMA PET plus mpMRI, respectively. In contrast, there was no improvement in specificity when PSMA PET was added to mpMRI in the prediction of csPCa, 50%, 53%, and 40%, for PSMA PET, mpMRI, and PSMA PET plus mpMRI, respectively.³² A similar improved performance of PSMA PET and combined PSMA PET plus mpMRI for csPCa had been previously reported by Eiber et al. ³³ in a smaller cohort of patients.

Maximum standardized uptake value (SUVmax) is a semi-quantitative metric with high intra- and inter-reader reproducibility. Varying criteria have been used to define PSMA PET positivity across studies contributing to the differences in the reported predictive ability of PSMA PET for csPCa on histology.34, 35, 36 The PRIMARY trial used a SUVmax cutoff of 4 to define PSMA PET positivity.³² In the prospective study of 99 patients by Margel et al.,³⁷ a SUVmax cutoff of 2.5 was used to define PSMA PET positivity. This lower SUVmax cutoff led an improved specificity of PSMA PET/MR compared with mpMRI alone (76% vs 49%, p < 0.001) but not the sensitivity (88% for PSMA PET/MR vs 92% for mpMRI, p > 0.99) and a similar NPV of 93% for each modality.³⁷ Beyond the patient- and technical-related factors that may cause differences in SUVmax obtained from different scanners, the prevalence of csPCa in the study population is another important factor that may contribute to the variability in the performance of PSMA PET imaging.³¹ The NPV of PSMA PET will be improved when the study population has a low prevalence of csPCa but reduced when the study population has a high proportion of patients with csPCa. In line with the pathophysiologic role of PSMA in PCa, SUVmax of PSMA radioligand directly correlates with tumor grade.^38,39 In a retrospective review of 200 patients, 162 of whom had csPCa, the median SUVmax of PCa lesion was 3.58 (Interquartile range, IQR: 2.74-5.60).⁴⁰ At different SUVmax thresholds of 3.0 to 5.0, PSMA PET showed decreasing sensitivity for detecting csPCa (ISUP grade group 2-5) of 84.6% (IQR: 78.1-89.9) at SUVmax threshold of 3%-50% (IQR: 42.1-57.9) at SUVmax of 5.0. On the contrary, the specificity of PSMA PET for predicting csPCA improved from 21.1% (IQR: 9.6-37.3) at a SUVmax threshold of 3%-92.1% (IQR: 78.6-98.3) at SUVmax threshold of 5.0.⁴⁰

The prostate gland has traditionally been divided into three anatomic zones (peripheral, transitional, and central zones) with varying proportions of stromal and glandular elements in each zone. PCa most commonly arises from the peripheral zone. Using the data from the PRIMARY trial, Emmett et al.,⁴¹ investigated the value of incorporating patterns of PSMA avidity and its location within the prostate gland (analogous to the PI-RADS) in predicting csPCa. They described a five-point PRIMARY scoring system of 1 to 5. The proportion of cSPCa confirmed on histology were 8.5% (4/47), 27% (15/55), 38% (11/29), 76% (89/117), and 100% (43/43) for PRIMARY scores 1, 2, 3, 4, and 5, respectively. The overall estimated area under the curve (accuracy) of the 5-point PRIMARY scoring system was 85% (95% CI: 81-89). Interestingly, the performance of this PSMA PET-based novel scoring system surpassed that of PI-RADS, which was 76% (95% CI: 71-81) for the PRIMARY trial cohort (p = 0.003).⁴¹ This scoring is promising with the potential to standardize reporting of PSMA PET findings in the prostate gland and accurately predict the probability of csPCa. To achieve these objectives, more work is needed to validate these findings in a different and larger cohort of patients and its inter-rater consistency evaluated further.

A significant proportion of csPCa may still be missed despite prior mpMRI with transrectal/transperineal ultrasound targeting mpMRI-identified csPCa for biopsy (mpMRI/TRUS fusion biopsy). In one study of 100 consecutive patients, 16% of csPCa (ISUP grade group 2-5) identified on radical prostatectomy specimens were missed on mpMRI.⁴² To address the area of clinical need, a prospective study of 97 patients with suspected PCa but with contraindications to mpMRI or negative biopsy has investigated the performance of PSMA PET/TRUS fusion biopsy to detect PCa in this population.⁴³ In the study, 64/97 (66%) of patients had positive PSMA PET findings and underwent PSMA PET/TRUS fusion biopsy. 23/64 (36%) of patients had histologically confirmed PCa with a Gleason score of 6 or higher. In 40 patients with 70 foci of focal avidity on PSMA PET, mpMRI prior to study enrollment were either negative or positive but with negative targeted biopsy. PCa (Gleason 7) were identified in four foci of PSMA avidity in patients with prior negative mpMRI and 14 foci among patients with prior positive mpMRI but a negative biopsy (Gleason 6 in 3 and Gleason 7 in 11). This study provided initial evidence supporting the performance of PSMA PET imaging for prebiopsy identification of csPCa and targeted biopsy using PSMA PET/TRUS fusion technique in patients with contraindication to MRI or with prior non-diagnostic mpMRI despite high clinical suspicion for csPCa. To advance this further, the same group is investigating the comparative performance of PSMA PET/TRUS fusion biopsy vs mpMRI/TRUS fusion biopsy for identifying csPCa in men suspected of PCa but with a prior negative biopsy in the PROSPET-BX trial.⁴⁴

Prior to the widespread application of mpMRI for prebiopsy prediction of csPCa, risk calculators that incorporate clinical information of the patients were used for risk stratification of patients.⁴⁵ Newer risk calculators that include information available on mpMRI have been validated and are in common use to select patients for TRUS-targeted prostate biopsy.^46,47 A novel risk calculator that incorporated prebiopsy PSMA PET findings, mpMRI findings, and patients’ clinical parameters has reported improvement of the novel MRI-PSMA risk calculator over the European Randomized Study of Screening for PCa (ERSPC-MRI) risk calculator alone for predicting csPCa.⁴⁸ In the cohort of patients, the novel MRI-PSMA calculator showed an AUC of 87.6% (95% CI: 75.5-86.9) for predicting csPCa compared with 80.5% (95% CI: 74.6-86.3) for ERSPC-MRI risk calculator (p = 0.001). This novel risk calculator further validates the added utility of prebiopsy PSMA PET imaging for predicting csPCa in men with suspected PCa.

Radical prostatectomy (RP) is offered to men with clinically localized PCa. Accurate preoperative staging is vital to exclude patients with distant metastatic PCa from undergoing RP. Morphologic imaging modalities alone have not been accurate enough to exclude nodal or distant metastasis in patients with clinically localized PCa. The proPSMA study showed the superiority of ⁶⁸Ga-PSMA-11 PET/CT over combined CT and bone scan in the initial staging of patients with high-risk PCa.²⁴ Despite its superiority over conventional imaging for PCa staging, with a true sensitivity (with histological validation) of only about 40% for detecting lymph node metastasis, the absence of lymph node metastases on PSMA PET is insufficient to preclude lymph node dissection in patients.^23,25 This limitation in the sensitivity of PSMA PET for the detection of lymph node metastasis is related to the low spatial resolution of clinical PET system for sub-centimeter nodes. Positive nodes on histology but negative on PSMA PET are significantly smaller (2 to 3 mm) than positive nodes on histology that are positive on PSMA PET/CT imaging (4-10 mm).⁴⁹ The risk of false negative PSMA PET is increased in patients with high-risk PCa. Patients with negative PSMA PET with an ISUP grade group 5 and mpMRI 5 have a high probability of lymph node metastasis on histology following extended pelvic lymph node dissection (ePLND).⁵⁰

Society clinical guidelines recommend the use of nomograms for preoperative prediction of lymph node metastasis in men with clinically localized PCa.⁵¹ Extended pelvic lymph node dissection (ePLND) is the gold standard procedure for lymph node staging. Due to the morbidity associated with the extensive tissue dissection at ePLND, only patients with >7% risk of nodal metastases based on novel predictive nomograms are recommended to undergo Eplnd.^51,52 With the widespread application of PSMA PET imaging for the preoperative staging of PCa, further modifications have been made to the currently applied nomograms in routine clinical practice to improve their performance in avoiding unnecessary ePLND and improving the lymph node staging among patients with clinically localized PCa. Including PSMA PET positivity information in all the currently used predictive nomograms have been reported to show an improvement in the abilities of these risk tools in predicting patients with lymph node invasion at RP,^53,54 thereby improving the preoperative selection of the best candidates to undergo ePLND.

Overall, PSMA PET remains the most sensitive imaging modality for the pretherapy whole-body staging of PCa.⁵⁵ The value of PSMA PET for the initial staging of PCa lies in its ability to detect metastatic disease and reduce futile surgery.55, 56, 57 Based on the superiority of PSMA PET over conventional imaging, the National Comprehensive Cancer Network (NCCN) now recommends PSMA PET imaging for the initial staging of PCa without the need for patients to first undergo conventional imaging⁵⁸. Others have expressed uncertainty on the impact of the improved lesion detection rate by PSMA PET on the survival of patients in which treatment approach was altered based on the additional lesions seen on PSMA PET imaging.⁵⁹ The mortality benefit of altering management decision based solely on additional lesions seen on PSMA PET remains unknown at this time. It is in view of this that the European Association of Urology, unlike the NCCN, is yet to recommend PSMA PET for the initial staging of patients with clinically localized PCa.⁵¹ A need, therefore, exists for studies investigating the survival benefit of changing management decisions based on additional lesions demonstrated on PSMA PET during the preoperative staging of PCa.

Radical prostatectomy plus ePLND offer good long-term disease control for PCa. The institution of radical local prostate therapy in patients with disseminated disease is a cause of PSA persistence post treatment. PSA persistence is associated with a higher risk of clinical recurrence and cancer-specific mortality compared with patients who achieved complete biochemical response post radical local therapy.^60,61 Patients with positive nodes (miN1) on PSMA PET have significantly shorter time to biochemical failure compared with patients who have node-negative PSMA PET findings, suggesting that node positivity on PSMA PET/CT is predictive of poor treatment outcome in patients treated with RP plus ePLND.^49,62, 63, 64 MiN1 status on PSMA PET may be a stronger predictor of PSA persistence than traditional risk factors, including the clinical T-stage, pre-RP PSA level, and tumor Gleason score.⁶⁵ Beyond its ability to predict PSA persistence, miN1 disease status on PSMA PET is also predictive of biochemical progression-free survival (bPFS), with Odds ratio of 5.70 (95% CI: 3.61-9.00, p < 0.001) for bPFS in patients with two or more PSMA-avid nodes vs patients with miN0 disease.⁶⁶ The number of PSMA-avid nodes also matters in patients with miN1 disease, with a shorter median bPFS in patients with two or more PSMA-avid nodes compared with those with one PSMA-avid node (4.1 vs 12.0 months).⁶⁶

PET imaging allows for the quantification of the whole-body burden of disease. Metabolic tumor volume and total lesion glycolysis initially developed and validated for FDG PET imaging with prognostic value in different solid tumors are increasingly being investigated in oncologic imaging with other tracers such as radiolabeled PSMA.67, 68, 69 Zou et al. ⁷⁰ showed a strong correlation between PSMA PET-derived volumetric metrics using whole-body PSMA tumor volume (wbPSMA-TV) and whole-body total lesion PSMA (wbPSMA-TL) with the serum PSA and tumor Gleason score. Also, higher tumor burden was reported to be associated with shorter progression-free survival. The impact of PSMA PET-derived derived volumetric metric on patient survival has been further investigated in a large cohort of patients. Using data from PSMA PET imaging done for initial staging in 1348 patients, the PSMA PET-derived local tumor volume, metastatic lymph node volume, metastatic bone volume, and visceral metastatic tumor volume were all negatively associated with overall survival⁷¹. This study confirms the prognostic role of tumor volume assessed on PSMA PET imaging on patients’ overall survival (Fig. 1). The investigation of the impact of PSMA PET on treatment outcome and patients’ survival is a research area with profound impact to shape the future of the application of PSMA PET for guiding radical therapy of PCa, especially in Europe.

Following initial radical local therapy of PCa, a significant proportion of patients will eventually experience disease recurrence that manifests as rising PSA in the long-term during follow-up. The goal of treatment of patients experiencing biochemical recurrence of prostate cancer (BCR) is the prompt and accurate localization of the site of recurrence followed by salvage therapy, mostly radiotherapy.^72,73 The institution of salvage therapy early, before serum PSA rises above 0.25 ng/mL, has survival benefit.⁷⁴ At this level, PSMA PET imaging has a good positivity rate,⁷⁵ with a performance superior to conventional imaging.⁷⁶ PSMA PET imaging is, therefore, the recommended imaging modality for re-staging of PCa prior to salvage therapy.^58,77,78

PSMA PET localizes recurrence to the prostate bed, pelvic lymph nodes, or distant metastatic sites. The likelihood of PSMA PET positivity for localizing the site of recurrence increases with the serum PSA level. Different patterns of PSMA PET findings have prognostic implications on post salvage therapy bPFS and time to the occurrence of metastatic disease progression. Patients with a negative PSMA PET at the time of salvage radiotherapy (sRT) and receive radiation to the prostate bed have better odds of response to treatment and a more favorable 3-year Bpfs.^79,80 Metastasis-free survival (time to the appearance of M1 disease post sRT) and the time to attaining castration-resistant status are equally longer in patients with negative PSMA PET compared with those with positive localization of PCa recurrence on PSMA PET.⁸¹ A negative PSMA PET is likely to occur in patients with low PSA. At this time, the majority of PCa recurrence occurs in the prostate bed, with a higher likelihood of the intense urinary PSMA activity obscuring its visualization on PET imaging. This explains the higher likelihood of response following sRT to the prostate bed in these patients despite negative PSMA PET imaging. A second reason may relate to the biological significance of PSMA avidity in PCa lesions. PSMA-avidity is a marker of aggressive disease. Hence, lesion without avidity on PSMA PET imaging may represent a more indolent disease with a more favorable outcome with or without treatment.

The presence of recurrence outside the prostate bed (PB) is an identified strong predictor of unfavorable response to sRT in patients treated for BCR of PCa, with PSMA PET finding outperforming serum PSA level in predicting 3-year bPFS⁸⁰. There is a higher chance of response to sRT therapy in patients with recurrence disease confined to the PB compared with patients who show nodal recurrence on PSMA.⁷⁹ The presence of pelvic lymph node recurrence on PSMA PET increases the risk of developing metastatic disease after sRT (hazard ratio [HR]: 2.39; 95% CI: 1.3 - 3.6).⁸² The proportion of patients with disease control at 3-years is higher when PSMA PET is negative or show recurrent disease confined to the PD (81%) than when PSMA PET imaging shows disease extension outside of the pelvis.⁸⁰ Using the pattern of lesion recurrence demonstrated on PSMA PET imaging obtained for re-staging, different risk categories of patients with varying chances of response to treatment and post-treatment survival can be established. It remains to be seen how these different disease phenotypes seen on PSMA PET imaging at PCa recurrence will influence therapy approach, viz-a-viz adding androgen-deprivation therapy and other lines of systemic therapy to sRT, redefining the standard sRT field template, radiation boosting, among others.

Salvage lymph node dissection is a therapy option in men who experience nodal recurrence of PCa. For salvage lymph node dissection (sLND) to effectively eradicate disease, a sensitive imaging probe must be used for the preoperative localization of the recurrent nodes. PSMA PET imaging, being the most sensitive imaging modality for lymph node metastasis is, therefore, a reasonable choice of imaging for preoperative planning. In patients who had PSMA PET imaging followed by PSMA-targeted radio-guided sLND for nodal recurrence of PCa, a single lesion on PSMA PET was predictive of complete biochemical response to treatment (PSA <0.2 ng/mL) (HR: 0.57, 95% CI: 0.27-0.8, p = 0.06).⁸³ In another study, tracer-avid retroperitoneal nodes (M1a disease) and the presence of three or more avid nodes on either PSMA PET or radiolabeled choline PET imaging were predictive of clinical recurrence after sLND for PCa recurrence.⁸⁴ Put together, these studies show that the extent of recurrent PCa as demonstrated on PSMA PET imaging is prognostic for post-sLND treatment outcome in patients with PCa recurrence.^83,84

Salvage therapy for PCa recurrence aims to eradicate disease and delay the institution of systemic therapy. Eventually, disease progression occurs with PCa spread to distant sites in the lymph nodes, bones, and visceral organs. In the initial phase of the disease progression, metastatic PCa is hormone-sensitive, requiring androgen for growth. PCa eventually becomes castration-resistant when tumor growth occurs independent of androgen drive. This phase of metastatic castration-resistant PCa (mCRPC) is the lethal phase of the disease. PSMA radioligand therapy (PRLT) with ¹⁷⁷Lu-PSMA-617 was recently approved for the treatment of mCRPC following remarkable response and survival benefits demonstrated in several retrospective studies and landmark clinical trials.85, 86, 87, 88, 89 PSMA PET imaging is recommended prior to treatment with ¹⁷⁷Lu-PSMA-617 to demonstrate target expression (PSMA), a predictor of response to treatment.^90,91 In recent years, many studies have been published reporting various parameters derivable from PSMA PET imaging obtained prior to or during PRLT with ¹⁷⁷Lu-PSMA-617.⁹²

SUV is the most common PET-derived metric to quantify lesion radiotracer avidity. A higher SUV connotes higher expression of PSMA in the tumor with a potential for improved ¹⁷⁷Lu-PSMA-617 trapping and dose delivery to the tumor.⁹³ SUVmax of the most intense lesion has not been shown to have significant prognostic importance in predicting PRLT outcome.^94,95 SUVmax reflects the level of radiotracer uptake in the single most intense voxel in a given lesion (Fig. 2). This may limit its ability to predict the overall response to treatment when patients have multiple lesions with varying PSMA avidity. SUVmean averages radiotracer avidity in all voxels within a volume of interest (VOI). The prognostic significance of SUVmean of PCa lesion on PRLT outcome has been investigated by several groups. A retrospective study of 103 men with mCRPC who were treated with ¹⁷⁷Lu-PSMA I&T showed that SUVmean of lesions on the baseline PSMA-1007 PET imaging was predictive of PSA response (≥50 decline in serum PSA) at 8 weeks post-PRLT and overall survival (OS).⁹⁵ The impact of SUVmean on response to PRLT has been investigated in the TheraP cohort using a threshold SUVmean of ≥ 10 to define high PSMA expression.⁹⁶ PSA response was more frequent in patients who had SUVmean of ≥10 (32 of 35 men, 91%) compared to men with SUVmean of <10 (33 of 64 men, 52%). There was also an association between SUVmean of ≥10 and progression-free survival benefits (radiographic and biochemical).⁹⁶ Similar survival advantages (radiographic progression-free survival and OS) have been reported for the VISION cohort of patients who had high SUVmean of mCRPC lesions compared with those who did not.⁹⁷ Nomograms have now been created that include tumor SUVmean, number of PSMA-avid metastatic lesions, and the sites of lesions on PSMA PET to predict PSA response, PSA progression-free survival, and overall survival in patients treated with ¹⁷⁷Lu-PSMA for mCRPC, establishing the integral role of PSMA PET imaging as a gatekeeper to selecting patients to undergo PRLT.⁹⁸

Other PSMA PET-derived lesion quantification metrics have been investigated for their predictive roles in ¹⁷⁷Lu-PSMA PRLT. Whole-body quantification of PSMA-avid tumor volume, in theory, should outperform SUVmean in predicting response to PRLT. Results from the literature have however been inconsistent in supporting a prognostic value for wbPSMA-TL or wbPSMA-TV derived from baseline PSMA PET in mCRPC patients treated with ¹⁷⁷Lu-PSMA.95, 96, 97^,99 There is a high level of variability in the SUV threshold set for computing these volumetric variables which may impact their consistency across studies. Also, the computation of wbPSMA-TL and wbPSMA-TV requires the drawing of VOI to encompass all PSMA-avid lesions. It is technically demanding to accurately delineate all metastatic lesions and exclude foci of physiologic PSMA uptake. This may contribute to the lack of consistency in the predictive ability of these PSMA volumetric indices.

PSMA PET imaging may be used for molecular imaging-based response assessment during PRLT. Rosar and colleagues recently reported the prognostic significance of the change in the whole-body PSMA-avid tumor burden after two cycles of ¹⁷⁷Lu-PSMA compared with baseline volume of disease in mCRPC patients.¹⁰⁰ Patients who achieved partial response based on PSMA PET imaging findings after two cycles of ¹⁷⁷Lu-PSMA had significantly longer OS compared with patients who had stable or progressive disease (24.6 months, 95% CI: 15.4-33.8 vs. 10.7 months, 95% CI: 0-21.8). In a multivariate analysis, lack of demonstrable response to PRLT on PSMA PET was an independent predictor of OS with a hazard ratio of 2.76 (95% CI: 1.45-5.26, p = 0.002).¹⁰⁰

Evidence is emerging supporting the application of Actinium-225 PSMA (²²⁵Ac-PSMA) for targeted alpha therapy (TAT) of metastatic PCa.¹⁰¹ TAT exploits the highly energetic alpha particles released by ²²⁵Ac for effective tumor killing. ²²⁵Ac-PSMA induces longer or comparable duration of tumor control in relation to therapy agents applied prior to it.¹⁰² Its safety and efficacy have also been reported in many clinical scenarios, including in patients who experienced disease progression while on ¹⁷⁷Lu-PSMA,¹⁰³ patients with extensive skeletal metastasis in whom response to ¹⁷⁷Lu-PSMA may be sub-optimal or induce severe bone marrow depression,¹⁰⁴ and in patients with de novo hormone-sensitive metastatic PCa.¹⁰⁵ Like PRLT with ¹⁷⁷Lu-PSMA, TAT with ²²⁵Ac-PSMA is preceded with PSMA PET patient for optimum patient selection.^101,106 However, there is a paucity in evidence to support the prognostic value of PSMA PET in TAT of PCa with ²²⁵Ac-PSMA. In two separate works from Pretoria, Sathekge et al. Showed that patients who achieved a complete response to therapy on PSMA PET imaging obtained during or after ²²⁵Ac-PSMA therapy achieved longer OS compared to patients who did not.^107,108 There is a need to understudy the prognostic value of baseline PSMA PET imaging volumetric indices on response to TAT. While response to TAT is expected to be improved with lesion avidity for PSMA as demonstrated for ¹⁷⁷Lu-PSMA, there is an important difference in the kinetics of emitted particles between ¹⁷⁷Lu and ²²⁵Ac that may result in significant differences. Alpha particles emitted by ²²⁵Ac are very energetic but have a short pathlength in tissues. There is significant intra-lesion and inter-lesion heterogeneity in PSMA expression in PCa lesions.¹⁰⁹ Therefore, a higher intensity of avidity and a more homogeneous expression of PSMA expression may be more important for effective tumor kill needed to achieve a survival benefit in patients treated with ²²⁵Ac-PSMA compared with ¹⁷⁷Lu-PSMA.

¹⁷⁷Lu-PSMA is approved for the treatment of mCRPC in patients who have failed at least one line of novel androgen receptor signaling targeted therapies (enzalutamide or arbiraterone) and/or taxane chemotherapy. PSMA expression is not required for the effectiveness of these therapies. PSMA expression is, however, a marker of PCa biology indicating that its level of expression may predict response to these conventional therapeutic agents. In a group of 44 men treated with enzalutamide or abiraterone for mCRPC, the whole-body tumor volume on baseline PSMA PET scan quantified by wbPSMA-TV and wbPSMA-TL were significantly associated with response to therapy.¹¹⁰ Similarly, a higher reduction in wbPSMA-TV and wbPSMA-TL between baseline and post-treatment PSMA PET was significantly associated with a longer survival.¹¹⁰ Pan et al.¹¹¹ have also investigated the impact of the heterogeneity of SUVmean between mCRPC lesions in patients treated with abiraterone. Patients whose lesions show a higher rate of SUVmean heterogeneity demonstrated significantly less response to treatment compared with patients with less heterogeneity. In the context of mCRPC disease, PSMA expression may be down-regulated, especially after several lines of therapy. This down-regulation of PSMA expression has been shown in patients treated with PSMA-targeted radionuclide therapy and is commonly associated with de-differentiation of tumor.^112,113 At this stage of the disease, fluorodeoxyglucose (FDG) PET becomes the appropriate imaging modality for evaluating the extent of the disease.

The prognostic value of PSMA PET has also been investigated in patients treated with taxane chemotherapy for mCRPC. In a total of 71 men treated with one or more lines of taxane chemotherapy, wbPSMA-TV ≥ 78.5 and wbPSMA-TL ≥ 278.8 were significantly associated with a shorter OS on univariate but not on multivariate analysis compared with men who had a lower total-body burden of disease.¹¹⁴ Other authors have also reported the prognostic significance of PSMA PET metrics in unselected population of patients treated with taxane chemotherapy or next-generation androgen signaling axis inhibitors.^115,116 Among patients who had baseline PSMA PET imaging and subsequently received treatment for mCRPC with a first line agent (docetaxel or a next-generation androgen signaling axis inhibitor), wbPSMA-TL and wbPSMA-TV were significantly lower among patients who were alive at follow-up (22.2 and 192.4) vs patients who were dead (61.7 and 455.1, respectively).¹¹⁶

Genetic mutations are a major driver for oncogenesis, including PCa. During cancer progression, additional somatic mutations are acquired to give the cancer cells a survival advantage with implications for aggressive tumor biology, resistance to treatment, and unfavorable disease outcomes. Molecular biomarkers of deleterious genetic mutations can be assayed from tumor biopsy specimens using services available from different commercial vendors such as Decipher. The Decipher scoring system quantifies the genetic mutation burden in a tumor and a higher score is predictive of aggressive tumor phenotype.¹¹⁷ In a study of 95 primary PCa tumors, PSMA expression was positively correlated with a higher Decipher genomic risk score (OR: 1.51, 95%CI: 1.45-1.56).¹¹⁸ A positive linear correlation between PSMA expression and Decipher genomic risk score was reported (r = 0.19, p < 0.001). This study shows the potential for the use of PSMA PET imaging as a non-invasive surrogate marker of deleterious genetic cancer mutations in PCa patients. This potential of PSMA PET to identify lesions with genetic alterations has been investigated in a small number of patients. The study reported intense PSMA avidity in sites corresponding to the genomic index lesions, which were the lesions harboring higher chromosomal copy number alterations.¹¹⁹ Acquired somatic mutations abound during cancer progression giving rise to tumor heterogeneity, especially common in advanced disease (Fig. 3). PSMA PET may, therefore, serve as a noninvasive tool for interrogating inter-lesion differences in disease phenotypes that are driven by differences in acquired somatic mutations.

After two decades of decline in PCa incidence, the number of new PCa diagnoses is on the increase again,¹²⁰ primarily due to new diagnoses of metastatic PCa disease among Black men. PCa mortality is also two to four times higher for Black men compared to men of other races.¹²⁰ In addition to socio-economic factors that predispose Black men to unfavorable outcomes of PCa treatment, men of African ancestry are known to be at increased risk of harboring deleterious genetic mutations with implications for aggressive disease phenotype and unfavorable treatment outcomes.¹²¹ The predictive role of PSMA PET in investigating the differences in disease phenotypes between Black and Caucasian men has been investigated in cohorts of South African men with PCa.122, 123, 124 In cohorts of patients who received PSMA PET imaging for the initial staging of PCa, there were no significant differences in the Gleason grade group distribution and the proportions of patients with lymph node and distant metastasis between the Caucasian and Black patients.¹²² In contrast, serum PSA levels and SUVmax of the primary tumor were significantly higher among the Black men compared to their Caucasian counterparts.^122,123 Gleason score normalized to the median SUVmax was 2.5 times higher in the Black patients compared with Caucasian patients with PCa.¹²² Despite a lack of significant differences in the Gleason grade group distribution between the two populations, Black men had significantly larger primary tumor volume than Caucasians.¹²³ These findings provide molecular imaging-based evidence with PSMA PET to support the more aggressive tumor phenotypes among Black patients compared to Caucasians. In a cohort of patients who received PSMA PET imaging for the localization of PCa recurrence, no significant differences were found between Black and Caucasian patients with respect to disease characteristics (serum PSA and tumor Gleason score) and PSMA PET findings (PSMA PET positivity rate and miM1 disease rates).¹²⁴ More work is needed to further advance the role of PSMA PET imaging in interrogating the aggressive tumor biology among Black men in different settings.

There is a large and growing body of evidence reporting the potential prognostic utility of artificial intelligence (AI) applied to PSMA PET images in different settings among PCa patients.¹²⁵ In patients with suspected PCa, radiomic models have been found useful in identifying csPCa.¹²⁶ This application has the potential to improve the yield of identifying csPCa for targeted biopsy while reducing unnecessary biopsies of clinically insignificant lesions.¹²⁷ It also has a potential application for guiding focal therapy of primary PCa.¹²⁸ PSMA is expressed in about 90% of PCa lesions leaving a significant 10% of lesions that can be missed on PSMA PET imaging due to lack of significant PSMA expression. The capability of machine learning algorithm to identify PCa lesions in patients with negative PSMA PET imaging has been reported.^129,130 This application may improve overall primary tumor detection rates, especially in the context of low or no PSMA expression. Despite its clear superiority for pelvic lymph nodes and distant metastatic detection above conventional imaging techniques, PSMA PET still underperforms in the detection of metastasis in small lymph nodes (<4 mm). AI algorithm applied to the primary PCa lesion has the potential to predict the presence of lymph node invasion with acceptable accuracy.^131,132 This may help improve the selection of patients who may benefit from ePLND with improved nodal staging while avoiding unnecessary ePLND and its associated morbidities in patients with a low risk for lymph node invasion. Patients with metastatic disease are treated with systemic therapy including ADT, chemotherapy, and ¹⁷⁷Lu-PSMA. Radiomic features extracted from pretherapy PSMA PET have been found useful in predicting response to systemic therapy in patients with metastatic PCa.^133,134

AI applied to PSMA PET images holds a lot of promise for prognostication in PCa. There is, however, a lot of challenges that need to be surmounted to actualize these potentials. Many of the studies reporting favorable prognostic utility of AI in PCa management are single-institution small studies that use limited data set for training and validation of the AI models. This limits the external validity of the performance of these so-derived models. Machine learning algorithms are very sensitive to errors, such that when these errors are not identified and corrected, they are propagated leading to inaccurate output function. The European Association recently published a position paper detailing some of the crucial problems with AI and providing recommendations for standardization.¹³⁵

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