Practical Applications and Clinical Utility of PSMA PET/CT Imaging in the Management of Prostate Cancer

The continuing expansion of the role and utility of imaging using novel prostate-specific membrane antigen (PSMA) PET-CT agents in the management of prostate cancer were reviewed by Phillip J. Koo, MD, Chief of Diagnostic Imaging and Oncology Physician Executive at Banner MD Anderson Cancer Center, Gilbert, AZ.

Conventional imaging techniques for prostate cancer, including bone scintigraphy, computed tomography (CT) and multiparametric or standard MRI, are of limited use in patients with biochemical recurrence with lesions <1 cm in size and PSA <2 ng/mL, Dr. Koo noted. Typically, these patients often have a negative bone scan or CT. Bone scans are rarely positive in asymptomatic patients or in the absence of high PSA, he stressed.

Bone scintigraphy has the advantages of being an established procedure and, widely available, a whole-body scan of where bony metastasis might be occurring. CT is of limited use for detecting tumor recurrence within the surgical bed and is dependent mainly on size and morphology for nodal evaluation, which leads to poor sensitivity. Its usefulness is in following treatment response of known enlarged metastatic lymphadenopathy and it can detect sclerotic bone metastasis and visceral metastatic disease. mpMRI is used in initial characterization of disease and detecting local recurrence post radiotherapy, but it is limited to the pelvis and relies on size criteria to determine metastasis. Whole body MRI techniques have been developed to stage distant metastasis, but they are not widely used in the US.

Next-generation imaging, particularly PET/CT, makes use of acquisition of high resolution imaging and specialized techniques to more accurately detect disease burden at lower PSA levels, which creates new opportunities for the management of prostate cancer. However, there is currently a lack of standardization and practical applications for this technology across the prostate disease state, Dr. Koo pointed out.

Next-generation imaging takes advantage of unique biological aspects of prostate cancer carcinogenesis, he continued. Several types of molecular imaging probes are in clinical use of currently undergoing clinical evaluation . They can be divided into probes, can image increased cell metabolism, target prostate-specific membrane proteins and receptor molecules, or bind to bone matrix adjacent to bone. Increased metabolism and vascular changes in prostate cancer cells can be evaluated with radiolabeled analogs of choline, acetate, glucose, amino acids, and nucleotides.

Several next-generation PET/CT imaging options have already been approved by the US Food and Drug Administration (FDA), Dr Koo noted, beginning in 1972 with the approval of sodium fluoride F 18 for diagnostic PET imaging of bone to defined areas of altered osteogenic activity. Interest in sodium fluoride F 18 has declined, since it is no longer reimbursed by the Centers for Medicare and Medicaid Services (CMS) under the National Oncologic PET Registry, Dr Koo noted.1

In 2012, choline C 11 was approved for PET imaging of patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, CT or MRI, at the Mayo Clinic in Rochester, MN.2 Access to choline C 11 was limited for most patients because of its short half-life.

In 2016, fluciclovine F 18 was granted FDA approval for PET imaging in men with suspected prostate cancer recurrence based on elevated blood PSA following prior treatment.3 Fluciclovine F 18 is a synthetic amino acid, 18F-labeled PET imaging agent that has been shown to be recognized and taken up by amino acid transporters that are upregulated in many cancer cells, including prostate cancer.4,5 Fluciclovine F 18 is not metabolized, or incorporated into newly synthesized proteins, suggesting that it may not interfere with normal protein synthesis.4 Its performance improves as the PSA level rises, which is intuitive because there is a higher disease burden, Dr Koo commented. In a study of around 600 men with biological recurrence after initial therapy for prostate cancer (BED-001), whole body detection rate at the lowest PSA level (:<,;0.79 ng/mL) was 41.4%.6 “This was better than anything we had before for imaging and it created a lot of excitement in the prostate cancer field, being able to do a better job at detecting recurrent disease in patients with biochemical recurrence,” Dr. Koo recalled.

PSMA PET takes advantage of prostate cancer-specific markers, Dr. Koo explained. Because of overexpression of PSMA in prostate cells in patients with prostate cancer, high quality imaging can be achieved by uptake of ligand- binding PSMA into tumor cells.7,8 In December 2020, the first PSMA-targeted PET imaging agent for men with prostate cancer, gallium (Ga) 68 PSMA-11, was approved by the FDA for PET of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer.9 It was approved for use at only a small number of academic centers, so access was limited.

In May 2021, the FDA approved piflufolastat F 18, the first and, to date, only commercially available approved PSMA PET imaging agent for prostate cancer.13 It is indicated for PET imaging of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum PSA. The recommended dosage is 333 MBq administered as a bolus intravenous injection, with imaging to be initiated within 1 hour of administration.

Regulatory approval was based on data from the pivotal OSPREY and CONDOR trials. In the phase 2/3 OSPREY trial (cohort A), improvements were seen in specificity and positive predictive value (PPV) of piflufolastat F 18 PET imaging over conventional imaging in men at risk for metastatic prostate cancer prior to initial therapy.14

In the phase 3 CONDOR trial, piflufolastat F 18 PET imaging detected and localized metastatic lesions with high positive PPV, regardless of anatomic region in men with biochemically recurrent prostate cancer and low PSA values (median 0.8 ng/mL) where standard imaging was uninformative.15 A separate study with in 130 men with localized or oligometastatic disease showed a 92% lesion detection rate in patients with PSA ≥2.0 ng/ml, Dr Koo added.16 In future, next-generation imaging will lead to change in the diagnostic approach and management of prostate cancer, Dr Koo predicted. “A landscape change is imminent” due to the advent of innovative modalities targeting PSMA, he believes. He called for guidelines for the use of imaging to be optimized “so that they can provide succinct practical information for decision making.” PSMA PET/CT should be considered in patients with negative conventional imaging and at high suspicion for metastatic disease, he urged. He stressed that with current standard of care negative conventional imaging should be done prior to PET/CT, but in the future, perhaps we may just go straight to PSMA PET/CT in certain patient subgroups, he suggested. “At biochemical recurrence, every single patient should get PSMA PET/CT,” Dr Koo declared.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU on- cology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.


  1. Kux L. Food and Drug Administration, HHS. Determination That sodium fluoride F 18 (sodium fluoride F-18) Injection, 10 to 200 millicuries per milliliter, was not withdrawn from sale for reasons of safety or effectiveness. Fed Reg. 201176(122):37129. Available at Federal Register:: Determination That SODIUM FLUORIDE F 18 (Sodium Fluoride F-18) Injection, 10 to 200 Millicuries per Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness
  2. Choline C 11 injection, for intravenous use. Prescribing information. 2012. Mayo Clinic PET Radiochemistry Facility; 2012.. label/2012/203155s000lbl.pdf
  3. Axumin (fluciclovine F 18) injection, for intravenous use. Prescribing information. Blue Earth Diagnostics; 2016, revised 2021.
  4. Schuster DM, Nanni C, Fanti S, et al. Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid: physiologic uptake patterns, incidental findings, and variants that may simulate disease J Nucl Med. 2014;55(12):1986-1992. DOI: 10.2967/jnumed.114.143628
  5. Schuster DM, Nanni C, Fanti S. Evaluation of prostate cancer with radiolabeled amino acid analogs. J Nucl Med. 2016;57:61S-66S. DOI: 10.2967/jnumed.115.170209
  6. Bach-Gansmo T, Nanni C, Nieh PT, et al. Multisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) positron emission tomography/ computerized tomography imaging in the staging of biochemically recurrent prostate cancer. J Urol. 2017;197(3 Pt 1):676-683. DOI: 10.1016/j.juro.2016.09.117
  7. Haberkorn U, Eder M, Kopka K, Babich JW, Eisenhut M. New strategies in prostate cancer: prostate-specific membrane antigen (PSMA) ligands for diagnosis and therapy. Clin Cancer Res. 2016;22(1):9-15. DOI: 10.1158/1078-0432.CCR-15-0820
  8. Lenzo NP, Meyrick D, Turner JH. Review of gallium-68 PSMA PET/CT imaging in the management of prostate cancer. Diagnostics (Basel). 2018;8(1):16. DOI: 10.3390/diagnostics8010016
  9. Gallium Ga 68 PSMA-11 Injection, for intravenous use. Prescribing information. 12/2020. University of California, Los Angeles label/2020/212642s000lbl.pdf
  10. Grabmüller B, Baltzer P, D’Andrea D, et al. 68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy – diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imag. 2018;45(2):235-242. DOI: 10.1007/s00259-017-3858-2
  11. Calais J, Ceci F, Eiber M, et. al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single- centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286-1294. DOI: 10.1016/S1470-2045(19)30415-2
  12. Hofman MS, Lawrentschuk N, Francis RJ, et al; proPSMA Study Group Collaborators . Prostatespecific membrane antigen PET-CT in patients with high-risk prostate cancer before curative intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicenter study.” Lancet. 2020;395(10231):1208-1216. DOI: 10.1016/S0140-6736(20)30314-7
  13. PYLARIFY® (piflufolastat F 18) injection, for intravenous use. Prescribing information. Progenics Pharmaceuticals; 2021.
  14. Pienta KJ, Gorin MA, Rowe SP, et al; OSPREY Study Group. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/ CT with 18 F-DCFPyL in prostate cancer patients (OSPREY). J Urol. 2021;206(1):52-61. DOI: 10.1097/JU.0000000000001698
  15. Gorin MA, Siegel BA, Rowe SP, et al.. A multicenter phase 3 study of PSMA-targeted 18F-DCFPYL PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR trial. J Urol. 2020;203(4S Suppl):e1119-e1120. Abstract LBA02-12. DOI: 10.1097/ JU.0000000000000958.012
  16. Rousseau E, Wilson D, Lacroix-Poisson F, et al. A prospective study on 18 F-DCFPyL PSMA PET/CT imaging in biochemical recurrence of prostate cancer. J Nucl Med. 2019;60(11):1587-1593. DOI: 10.2967/jnumed.119.226381