Addressing Knowledge Gaps and Clinical Challenges of PSMA PET in Prostate Cancer

Phillip Koo | March 27, 2024

More than three years after the first FDA approval of a PSMA radiotracer for detecting prostate cancer (PCa), we are seeing an evolution and maturation of use in the clinic. The availability of PSMA PET with different tracers enables us to detect lesions that conventional imaging misses, identify disease recurrence at very low (<0.5 ng/mL) PSA levels, and distinguish between benign and malignant tissue.1-3 In some countries and regions, PSMA PET is now standard practice for initial PCa staging, treatment planning, and monitoring treatment response. However, questions persist about how to manage patients in the PSMA PET era, particularly because registrational trials of current therapies predated the widespread availability of PSMA PET and therefore used only conventional imaging (i.e., CT, bone scan). Here, I discuss current knowledge gaps pertaining to the use of PSMA PET in various scenarios and how we can best steward this resource.

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Phillip J. Koo, MD, FACS

Phillip J. Koo, MD is the Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona. Prior to this, he was Chief of Nuclear Medicine and Associate Professor of Radiology at the University of Colorado School of Medicine. He is a diplomate of both the American Board of Radiology (ABR) and American Board of Nuclear Medicine and is the Chair of the Quality and Evidence Committee for the Society of Nuclear Medicine and Molecular Imaging.

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Written by Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
October 19, 2022

Although definitive local therapy in the form of radical prostatectomy or radiation therapy with or without ADT offers excellent long-term outcomes for the majority of patients with clinically localized prostate cancer, patients with high-risk disease experience primary treatment failure rates approaching 65%.1 Disease persistence/recurrence in such patients may be restricted to the prostatic fossa, pelvic lymph nodes, non-regional lymph nodes (M1a), bones (M1b), or the viscera (M1c).

Written by Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
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The purpose of this document is to describe the appropriate use of imaging in the diagnostic evaluation of patients with BCR after definitive primary treatment. The imaging modalities that were considered included CT, bone scan, and the U.S. Food and Drug Administration (FDA)–approved PET radiotracers that track malignancy-induced lipogenesis (11C-choline) and amino acid metabolism (18F-fluciclovine). 
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Conference Highlights Written by Physician-Scientist
Presented by Daniela-Elena Oprea-Lager, MD, PhD
 The 2024 European Society of Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain was host to the session Biochemical failure post-local therapy: An opportunity for tailored treatment? Dr. Daniela E. Oprea-Lager discussed if PSMA PET could be a game changer for treatment decision-making in patients with biochemical failure post-local therapy.
Presented by  Michael S. Hofman, MBBS (Hons), FRACP, FAANMS
The 2024 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Michael Hofman discussing Prostate Cancer Working Group 4 (PCWG4) preliminary criteria using serial PSMA PET/CT for response evaluation.
Presented by Jiarou Wang, MD
At the 2024 SNMMI annual meeting Dr. Jiarou Wang discussed the diagnostic performance of 68Ga-P16-093 in newly diagnosed prostate cancer. 68Ga-P16-093 is a novel PSMA-targeted radiopharmaceutical that has a labeling reaction compatible with various Ge/Ga generators and has a simple labeling method of heating at 95 degrees Celsius for 5 minutes, leading to high radiochemical purity. As a targeting agent in prostate cancer patients,
Presented by Luke Nordquist, MD
(UroToday.com) The 2024 Society of Nuclear Medicine & Molecular Imaging (SNMMI) annual meeting featured a session on prostate cancer, and a presentation by Dr. Luke Nordquist discussing results of COBRA, an assessment of the safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy.
Presented by Jean-Mathieu Beauregard, MD, MSc, FRCPC
The 2024 SNMMI annual meeting featured a session on prostate cancer, and a presentation by Dr. Jean-Mathieu Beauregard discussing a sub-analysis of the 3TMPO study assessing eligibility for PSMA radioligand therapy based on dual FDG/PSMA-PET. Eligibility criteria for PSMA radioligand therapy are currently debated, particularly with respect to the role of FDG-PET in patient selection.
Presented by Linlin Li, PhD
The 2024 SNMMI annual meeting featured a session on prostate cancer, and a presentation by Dr. Linlin Li discussing the dosimetry and pilot therapy study of novel PSMA-targeting agents, 177Lu-P17-087 and 177Lu-P17-088, in metastatic castration-resistant prostate cancer patients. 
Presented by Thomas Hope, MD
The 2024 SNMMI annual meeting was host to the session Novel Approaches and Combination Therapies; Pre-Targeting Approaches. Dr. Thomas Hope discussed the combination treatment of prostate cancer using Pembrolizumab with PSMA-based radioligands.
Presented by Nat Lenzo, MD, EMBA, FRACP, FAANMS, GAICD
At the 2024 SNMMI annual meeting, Dr. Nat Lenzo presented preliminary results of ProstACT SELECT, specifically the safety, tolerability, and dosimetry of TLX591 with best standard of care in patients with PSMA-expressing metastatic castration resistant prostate cancer.
Presented by Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, FICI
The 2024 SNMMI annual meeting featured the Therapy Center of Excellence Saul Hertz Lecture and Award, and a presentation by Dr. Michael Hofman discussing bridging evidence-based medicine and precision oncology. Saul Hertz (1905-1950) conceived and brought from bench to bedside radioactive iodine for medical uses based on the 1936 question “Could iodine be made radioactive artificially?” This was followed by the 1937 radioactive iodine studies assessing thyroid physiology, tracer qualities, dosimetry, and thyroid carcinoma. 
Presented by James Buteau, MD, FRACP, FRCPC
Th SNMMI 2024 Annual Meeting was host to a prostate cancer novel approaches and combination therapies session. Dr. James Buteau discussed novel approaches of combination PSMA-based radiopharmaceutical treatments for prostate cancer.
Presented by David Chen, PhD
At the SNMMI 2024 Annual Meeting, David Chen presented the results of a prospective analysis of the ProsTIC registry evaluating the oncologic and quality-of-life outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients with a stable or poor initial PSA response to [177Lu]Lu-PSMA-617, and the prognostic value of baseline imaging biomarkers and dosimetry.
Presented by Meryam Losee, BS
At the SNMMI 2024 Annual Meeting, Dr. Meryam Losee presented the results of a study evaluating the effect of bone marrow disease on hematologic toxicity and PSA response to 177Lu-PSMA-617 therapy. 
Presented by Benjapa Khiewvan, MD
At the SNMMI 2024 Annual Meeting Dr. Benjapa Khiewvan presented the first Thai experience with Lu-177-PSMA-I&T treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC).
Presented by Fuad Novruzov, MD, PhD
At the SNMMI 2024 Annual Meeting Dr. Fuad Novruzov presented the results of a prospective phase 3 randomized study from Azerbaijan evaluating 225Ac-PSMA + 177Lu-PSMA tandem therapy for metastatic castration-resistant prostate cancer (mCRPC).
Presented by Vishnu Murthy
At the SNMMI 2024 Annual Meeting Vishnu Murthy presented the results of a US expanded access program evaluating the efficacy and toxicity of 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC) in a real-world setting and compared these results to those from the phase 3 VISION trial.
Presented by Oliver Sartor, MD
At the SNMMI 2024 Annual Meeting Dr. Oliver Sartor presented the updated results of PSMAfore, a phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Oliver Sartor, MD
The SNMMI 2024 Annual Meeting was host to a prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) tumor board session. Dr. Oliver Sartor discussed whether earlier use of PSMA RLT in earlier settings is of clinical benefit.
Presented by Josef Zahner, PhD
At the SNMMI 2024 Annual Meeting, Dr. Josef Zahner presented the first dosimetry results of a study evaluating the influence of androgen receptor pathway inhibitors (ARPIs) on absorbed doses in metastatic castrate-resistant prostate cancer (mCRPC) patients undergoing 177Lu-PSMA-617 therapy.
Presented by  Michael Gorin, MD
The 2024 ASCO annual meeting was host to a presentation by Dr. Michael Gorin, who presented CLARIFY, a phase III diagnostic study of positron emission tomography (PET) using 64Cu-SAR-bisPSMA in patients with high-risk prostate cancer prior to radical prostatectomy.
Presented by Luke Nordquist, MD, FACP
The 2024 ASCO annual meeting featured a session on prostate cancer, and a presentation by Dr. Luke Nordquist discussing results of COBRA, an assessment of the safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy.
Presented by Rui M. Bernardino, MD
The 2024 European Association of Urology (EAU) annual meeting featured a session on adverse pathology and imaging for risk assessment and local staging, and a presentation by Dr. Rui Bernardino discussing intraductal prostate cancer affinity for lymphatic-predominant metastases through 18F-DCFPyL-PSMA-PET/CT scans in pre-treatment prostate cancer patients.
Presented by Ken Herrmann, MD
The 2024 European Association of Urology (EAU) annual congress held in Paris, France was host to a plenary session addressing imaging-related controversies for the staging of genitourinary cancers. Professor Ken Herrmann discussed the advantages and pitfalls of molecular imaging for prostate cancer characterization.
Presented by Henk G. van der Poel, MD, PhD
 The 2024 European Association of Urology (EAU) annual congress held in Paris, France was host to a plenary session addressing imaging-related controversies for the staging of genitourinary cancers. Professor Henk van der Poel discussed why patients with prostate-specific membrane antigen (PSMA)-detected M1a disease should be treated similarly to patients with conventional imaging-detected M0 disease.
Presented by Louise Emmett, MBChB, FRACP
In the Discussant session at the 2023 ASCO annual meeting, Dr. Louise Emmett discussed the current and future states of novel imaging modalities for advanced prostate cancer, highlighting three abstracts from this session.
Presented by Thomas A. Hope, MD
(UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, a breakout session assessing the best approaches and treatment updates in biochemically recurrent prostate cancer featured a presentation from Dr. Thomas A. Hope discussing the manner in which molecular-based imaging is defining the landscape of prostate cancer.
Presented by William J. Aronson, MD
In a podium presentation at the Friday morning plenary of the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. William Aronson presented a State-of-the-Art Lecture on prostate specific membrane antigen (PSMA) Diagnostics and Theranostics.
Presented by Michael Hofman, MBBS (Hons), FRACP, FAANMS, FICIS
The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on the management of metastatic hormone sensitive prostate cancer (mHSPC) and a presentation by Dr. Michael Hofman discussing how frequent low-volume disease on conventional imaging becomes high-volume on next-generation imaging. Dr. Hofman started his presentation by noting that there has been an explosion of PSMA PET publications per year from 2001 to 2021:
Presented by Michael Morris, MD
The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on the management of non-metastatic castrate-resistant prostate cancer (nmCRPC), and a presentation by Dr. Michael Morris discussing the advantages of using novel imaging in this disease space.
Presented by Ken Herrmann, MD, MBA
The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on high-risk and locally advanced prostate cancer and a presentation by Dr. Ken Herrmann discussing the impact of next generation imaging and the optimal tracer for PET-based imaging for staging.
Presented by Jason Efstathiou, MD
The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on high-risk and locally advanced prostate cancer and a presentation by Dr. Jason Efstathiou arguing for changes in management based on next-generation imaging.
Presented by Gerald L. Andriole, Jr, MD
The SUO annual meeting included a prostate cancer session and a presentation by Dr. Gerald Andriole discussing the impact of 18F-fluciclovine PET/CT on plans for ADT in patients with biochemical recurrence of prostate cancer. 
Presented by Robert Reiter, MD
The SIU 2021 annual meeting focused on the role of prostate-specific membrane antigen (PSMA) and theranostics in prostate cancer, Dr. Robert Reiter began with a presentation on the role of PSMA-based imaging as a diagnostic tool in the initial staging of patients with prostate cancer.
Presented by Ephraim E. Parent, MD
In a special session of the ASTRO and SNMMI held at the 2021 ASTRO Annual Congress, Dr. Parent presented on the role of molecular imaging and targeted radionuclide therapy using PSMA-based radiopharmaceuticals.
Presented by Bital Savir-Baruch, MD
In a special session of the American Society for Radiation Oncology (ASTRO) and Society of Nuclear Medicine and Molecular Imaging (SNMMI) held at the 2021 ASTRO Annual Congress, Dr. Baruch presented on the role of molecular imaging using Fluciclovine PET imaging.
Presented by Alberto Bossi, MD
Dr. Alberto Bossi discussed radiotherapy after radical prostatectomy in the PSMA-PET era. Adjuvant radiotherapy is defined as immediate postoperative radiation in the case of extraprostatic extension, positive margins, seminal vesicle infiltration, high Gleason score, or pN+ disease. Salvage radiotherapy is defined as a wait-and-see policy in that radiation is only given in the case of a rising postoperative PSA.
Presented by obias Maurer, MD
The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology 2021 Meeting included a presentation by Dr. Tobias Maurer discussing the role of imaging-guided surgical treatment for recurrent metastatic hormone sensitive prostate cancer (mHSPC).
Presented by Karim Fizazi, MD, Ph.D
Dr. Karim Fizazi finished off the thematic session of Treatment Sequencing in Metastatic Prostate Cancer with a presentation on the role of PSMA in diagnostics and treatment of metastatic prostate cancer.
Presented by Michael S. Hofman, MBBS (Hons), FRACP, FAANMS,
The game changing session of the European Association of Urology (EAU)’s 2021 annual meeting included a presentation by Dr. Michael Hofman from the Peter MacCallum Cancer Centre discussing the phase 2 trial of 177Lu-PSMA-617, TheraP, as well as important contrasts/differences between TheraP and VISION.
Presented by Johann De Bono, MD, MSc, Ph.D., FRCP, FMedSci
The EAU 2021 Annual Meeting included a presentation by Johann De Bono discussing the VISION trial, a phase 3 study of 177Lu-PSMA-617 in patients with mCRPC. As PSMA is highly expressed in prostate cancer and mCRPC lesions, the combination of PSMA-617 with the beta-emitter lutetium allows for the targeted delivery of ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment.
Presented by Mary-Ellen Taplin, MD
Following Micheal Morris’s presentation of the results of the phase III VISION trial of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer in the Plenary Session of the 2021 ASCO, Dr. Mary-Ellen Taplin from the Dana Farber Cancer Institute provided a discussant overview of these data and helped to contextualize how we may apply them to our practices.
Presented by Micheal Morris, MD
In a plenary presentation at the 2021 ASCO Annual Meeting, Dr. Morris presented the first results of the VISION trial, a phase III study assessing lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer.
Presented by Mike Machaba Sathekge, MD, Ph.D
In a plenary presentation in the Progress and Promise in Treatment Personalization for Advanced Prostate Cancer session at the 2021 American Society of Clinical Oncology Genitourinary (Cancers Symposium (ASCO GU), Dr. Sathekge provided a talk examining the role of Lutetium in prostate cancer.
Presented by James Wysock, MD, MSc
At the Society of Urologic Oncology (SUO) Annual Meeting, Dr. James Wysock gave an update on the imaging for primary prostate cancer. Dr. Wysock briefly touched on imaging strategies in both the screening and diagnosis of localized prostate cancer.
Presented by Matthew R. Cooperberg, MD, MPH and Tanya B. Dorff, MD
To conclude the advances in prostate cancer session Drs. Matthew Cooperberg and Tanya Dorff debated whether prostate-specific membrane antigen (PSMA) imaging should be routinely used in the clinical management of prostate cancer.
Presented by Declan Murphy, MB, BCH, BaO, FRACS, FRCS, Urol
At the 2020 virtual Society of Urologic Oncology's (SUO) prostate cancer session, Dr. Declan Murphy discussed the role of prostate-specific membrane antigen (PSMA) scanning in prostate cancer staging. Dr. Declan Murphy states that PSMA PET/CT is an obvious challenger to conventional imaging.
Presented by Declan Murphy, MB, BCH, BaO, FRACS, FRCS, Urol
(UroToday.com) During the Individualized Approach in Advanced Prostate Cancer session at the European Multidisciplinary Congress on Urological Cancers (EMUC) 2020 virtual meeting, Dr. Declan Murphy presents on using prostate-specific membrane antigen (PSMA) positron emission tomography (PET) for upfront staging in high-risk prostate cancer disease. Dr. Murphy states that PSMA PET/CT is an obvious challenger to conventional imaging.
Presented by Renu Eapen, MD
The Société Internationale d'Urologie (SIU) 2020 Virtual Annual Congress featured a debate discussing imaging definitions for oligometastatic prostate cancer. Dr. Renu Eapen from Australia argued that oligometastatic disease should be defined based on novel imaging modalities.
Presented by Noel William Clarke, MD
The Société Internationale d'Urologie (SIU) 2020 Virtual Annual Congress featured a debate discussing imaging definitions for oligometastatic prostate cancer. Dr. Noel Clarke from the United Kingdom argued that oligometastatic disease should be defined based on standard imaging modalities.
Presented by Michael S. Hofman, MBBS (Hons), FRACP, FAANMS,
(UroToday.com) As part of the “Game-Changing Session 1” plenary presentation at the 2020 European Association of Urology (EAU) Virtual Annual Meeting, Dr. Michael Hofman presented results of the proPSMA study which was recently published in the Lancet.1
Presented by Scott T. Tagawa, MD, MS, FACP
There are currently significant imaging deficiencies for men with prostate cancer (Figure 1), with the hope that PSMA imaging-based modalities will address a significant gap in this field. Prostate-specific membrane antigen PSMA is a transmembrane glycoprotein with folate hydrolase activity.
Presented by Michael J. Morris, MD
Men with biochemically recurrent prostate cancer after definitive local therapy currently have limited imaging modalities in the United States which are sensitive or specific enough to detect tumor recurrence. PSMA PET scans can improve on this detection by detecting cells expressing PSMA protein on their cell surface.
Presented by Charles J. Ryan, MD, & Markus Graefen, MD
San Francisco, California (UroToday.com)  The first case presented was that of a 54-year-old otherwise healthy man who underwent radical prostatectomy after biopsy-confirmed prostate cancer.
Presented by Jeremie Calais, MD
San Francisco, California (UroToday.com) Advanced imaging is increasingly being used across all stages of prostate cancer. Dr. Jeremie Calais from UCLA Medical Center discussed
Presented by Claire M. De La Calle, MD
Washington, DC (UroToday.com) While PSA screening has resulted in decreasing prostate cancer mortality, PSA is also known to be a poorly specific test for the detection of clinically
Presented by Renu Eapen, FRACS
Athens, Greece (UroToday.com) Dr. Renu Eapen gave an overview of the role of PET- prostate-specific membrane antigen (PSMA) in prostate cancer and gave a preview of what is to come
Presented by Sigrid Carlsson, MD, PhD, MPH
Athens, Greece (UroToday.com) Dr. Carlsson gave an encompassing presentation on prostate cancer screening from the perspective of an epidemiologist.
Presented by Cora Sternberg, MD
Barcelona, Spain (UroToday.com)  Dr. Cora Sternberg summarized the findings from several posters, including three immunotherapy phase 1 or 2 trials, a phase 2 trial of 177Lu-PSMA-617,
Presented by Scott T. Tagawa, MD, MS
Barcelona, Spain (UroToday.com) PSMA is overexpressed in prostate cancer with limited expression in other organs. Furthermore, prostate cancer is radiosensitive with dose-response (
Presented by Stefano Fanti, MD
Barcelona, Spain (UroToday.com) Theranostics is an emerging field of medicine which utilizes targeted cancer therapy based on specific molecular-targeted diagnostic tests. As part of the Imaging in Prostate Cancer plenary session at the 2019 European Association of Urology (EAU) annual meeting in Barcelona, Spain
Presented by Olivier Rouvière, MD, PhD
Barcelona, Spain (UroToday.com) Dr. Rouviere presented the imaging specialist’s perspective on MRI use in prostate cancer. According to the European Association of Urology (EAU) guidelines prostate multiparametric MRI (mpMRI) was originally recommended after a negative prostate biopsy
Presented by Michael Hofman, FRACP, MBBS

San Francisco, CA (UroToday.com) PSMA is over-expressed in all prostate tissue, including prostatic carcinoma. Lutetium-177 (177Lu)-PSMA617 (LuPSMA) is a small radiolabeled molecule which binds to PSMA

Presented by Jeremie Calais, MD, MSc
San Francisco, CA (UroToday.com)  Salvage radiotherapy (SRT) for prostate cancer biochemical recurrence after radical prostatectomy (RP) is commonly administered to patients with PSA < 1 ng/mL, a threshold at which standard-of-care imaging 
Presented by Paul L. Nguyen, MD
Prague, Czech Republic (UroToday.com) Dr. Paul Nguyen took the stance for radiation therapy in this much-anticipated debate regarding appropriate local treatment in men with high risk localized prostate cancer. Dr. Nguyen notes that high-quality radiation therapy for high-risk disease needs long-term ADT and a brachytherapy boost.