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New PET Imaging Tracers and Targets for the Staging Biochemically Recurrent Prostate Cancer

In December 2020, Gallium 68 PSMA-11 (68Ga PSMA-11) was approved by the U.S. Food and Drug Administration (FDA) for the staging of prostate cancer patients with suspected recurrence based on elevated serum prostate-specific antigen (PSA) levels.1 This was shortly followed by the FDA approval of 18F-DCFPyL (PYLARIFY®) in May 2021 for the same indication.2
  • Written by: Rashid K. Sayyid, MD MSc, University of Southern California, Los Angeles, CA & Zachary Klaassen, MD, MSc, Wellstar MCG Health, Georgia Cancer Center, Augusta, GA
  • References:
    1. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer. Accessed on December 12, 2024.
    2. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer#:~:text=FDA%20approved%20the%20first%20PSMA,at%20two%20sites%20in%20California. Accessed on December 12, 2024.
    3. U.S. FDA Approves Blue Earth Diagnostics’ POSLUMA® (Flotufolastat F 18) Injection, First Radiohybrid PSMA-targeted PET Imaging Agent for Prostate Cancer. https://www.businesswire.com/news/home/20230530005180/en/U.S.-FDA-Approves-Blue-Earth-Diagnostics%E2%80%99-POSLUMA%C2%AE-Flotufolastat-F-18-Injection-First-Radiohybrid-PSMA-targeted-PET-Imaging-Agent-for-Prostate-Cancer. Access on December 13, 2024.
    4. Afshar-Oromieh A, da Cunha ML, Wagner J, et al. Performance of [68Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients. Eur J Nucl Med Mol Imaging. 2021; 48(9):2925-34.
    5. Vlachostergios PJ, Niaz MJ, Sun M, et al. Prostate-Specific Membrane Antigen Uptake and Survival in Metastatic Castration-Resistant Prostate Cancer. Front Oncol. 2021; 11:630589.
    6. Huynh TT, van Dam EM, Sreekumar S, et al. Copper-67-Labeled Bombesin Peptide for Targeted Radionuclide Therapy of Prostate Cancer. Pharmaceuticals (Basel). 2022; 15(6):728.
    7. Tolvanen T, Kalliokoski K, Malaspina S, et al. Safety, Biodistribution, and Radiation Dosimetry of 18F-rhPSMA-7.3 in Healthy Adult Volunteers. J Nucl Med. 2021; 62(5):679-84.
    8. Wurzer A, Di Caro D, Schmidt A, et al. Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA-inhibitors. J Nucl Med. 2020; 61(5):735-42.
    9. Wurzer A, Parzinger M, Konrad M, et al. Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereo configuration on pharmacokinetics. EJNMMI Res. 2020; 10(1):149.
    10. Wurzer A, Kunert J, Fischer s, et al. Synthesis and preclinical evaluation of 177Lu-labeled radiohybrid PSMA ligands (rhPSMAs) for endoradiotherapy of prostate cancer. J Nucl Med. 2022; 63(10):1489-95.
    11. Jani AB, Ravizzini GC, Gartrell BA, et al. Diagnostic Performance and Safety of 18F-rhPSMA-7.3 Positron Emission Tomography in Men With Suspected Prostate Cancer Recurrence: Results From a Phase 3, Prospective, Multicenter Study (SPOTLIGHT). J Urol. 2023; 210(2):299-311.
    12. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clin Cancer Res. 2021;27(13):3674-82.
    13. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer. JAMA Oncol. 2019; 5(6):856-63.
    14. Fleming MT, Hermsen R, Purysko AS, et al. True-Positive 18F-Flotufolastat Lesions in Patients with Prostate Cancer Recurrence with Baseline-Negative Conventional Imaging: Results from the Prospective, Phase 3, Multicenter SPOTLIGHT Study. J Nucl Med. 2024; 65(7):1080-6.
    15. Nordquist L, Lengyelova E, Saltzstein D, et al. COBRA: Assessment of safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy. J Clin Oncol. 2024; 42:Number 16_suppl.
    16. Baratto L, Jadvar H, Iagaru A. Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors. Mol Imaging Biol. 2018; 20(4):501-9.
    17. Beer M, Montani M, Gerhardt J, et al. Profiling gastrin-releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. Prostate. 2012; 72(3):318-25.
    18. Faviana P, Boldrini L, Erba PA, et al. Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen? Front Oncol. 2021; 11:650249.
    19. Mapelli P, Ghezzo S, Gajate AMS, et al. 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in Recurrent Prostate Cancer: Diagnostic Performance and Association with Clinical and Histopathological Data. Cancers (Basel). 2022; 14(2):334.
    20. Kurth J, Krause B, Joksch M, et al. Intraindividual comparison of [68Ga]Ga-RM2 and [68Ga]Ga-PSMA PET/CT in patients with mCRPC in a theranostic setting. J Nucl Med. 2023; 64(Supplement 1):1089.
    21. Nordquist LT, Lengyelova E, Iagaru A, et al. SABRE: Assessment of safety and efficacy of 64Cu-SAR-BBN in patients with PSMA-negative biochemical recurrent prostate cancer. J Clin Oncol. 2024; 42:Number 4_suppl.

New PET Imaging Tracers for the Primary Staging of Unfavorable Intermediate and High-Risk Prostate Cancer

Introduction

In December 2020, Gallium 68 PSMA-11 (68Ga PSMA-11) was approved by the U.S. Food and Drug Administration (FDA) for the initial staging of prostate cancer patients at high risk of metastases,1 and this was shortly followed by the FDA approval of 18F-DCFPyL (PYLARIFY®) in May 2021.2 These positron emission tomography (PET) imaging modalities have since been endorsed by numerous international guidelines and have been widely adopted in clinical practice for the primary staging of unfavorable intermediate- and high-risk prostate cancer patients.

PSMA PET Imaging in Prostate Cancer: Staging for Unfavorable Intermediate and High-Risk Disease

Conventional imaging using CT and bone scan has limited sensitivity when staging men with high-risk localized prostate cancer. Findings of extraprostatic spread in the form of extraprostatic extension and/or lymph node, visceral, or bone metastasis can influence treatment planning, and thus, potentially, patient outcomes.
  • Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
  • References:

     

    1. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216.
    2. De Feria Cardet RE, Hofman MS, Segard T, et a. Is Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging Cost-effective in Prostate Cancer: An Analysis Informed by the proPSMA Trial. Eur Urol. 2021;79(3):413-8.
    3. Hope TA, Eiber M, Armstrong WR, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase 3 Imaging Trial. JAMA Oncol. 2021;7(11):1635-42.
    4. Van Kalmthout LWM, van Melick HHE, Lavalaye J, et al. Prospective Validation of Gallium-68 Prostate Specific Membrane Antigen-Positron Emission Tomography/Computerized Tomography for Primary Staging of Prostate Cancer. J Urol. 2020;203(3):537-45.
    5. Pienta KJ, Gorin MA, Rowe SP, et al. 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.
    6. Jansen BHE, Bodar YJL, Zwezerijnen GJC, et al. Pelvic lymph-node staging with 18F-DCFPyL PET/CT prior to extended pelvic lymph-node dissection in primary prostate cancer - the SALT trial. Eur J Nucl Med Mol Imaging. 2021;48(2):509-20.
    7. Prostate Cancer. https://uroweb.org/guidelines/prostate-cancer. Accessed on Aug 14, 2022
    8. Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed on August 27, 2022.

The Current Landscape of PSMA PET Imaging in Prostate Cancer: Evaluating Men with Biochemical Recurrence

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
  • References:

     

    1. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-74.
    2. Jadvar H. Is There Utility for FDG PET in Prosate Cancer? Semin Nucl Med. 2016;46(6):502-506.
    3. Picchio M, Briganti A, Fanti S, et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol 2011;59:51-60.
    4. Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:18-23.
    5. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol. 2018;7(5):844-54.
    6. Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2013;40:486-95.
    7. Morigi JJ, Stricker PD, van Leewen PJ, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. 2015;56(8):1185-90.
    8. 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):1286-94.
    9. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer. JAMA Oncol. 2019; 5(6):856-63.
    10. Caroli P, Sandler I, Matteucci F, et al. 68 Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients. Eur J Nucl Med Mol Imaging. 2018;45(12):2035-44.
    11. Ceci F, Castellucci P, Graziani T, et al. 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy. Eur J Nucl Med. 2019;46:31-39.
    12. Mazrani W, Cook GJR, Bomanji J. Role of 68Ga and 18F PSMA PET/CT and PET/MRI in biochemical recurrence of prostate cancer: a systematic review of prospective studies. Nucl Med Commun. 2022;43(6):631-7.
    13. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clin Cancer Res. 2021;27(13):3674-82.
    14. Ong S, Pascoe C, Kelly BD, et al. PSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up. Cancers (Basel). 2022;14(11):2717.
    15. Emmett L , Tang R, Nandrukar R, et al. 3-Year Freedom from Progression After 68 Ga-PSMA PET/CT-Triaged Management in Men with Biochemical Recurrence After Radical Prostatectomy: Results of a Prospective Multicenter Trial. J Nucl Med. 2020;61(6):866-72.
    16. Pozdnyakov A, Kulanthaivelu R, Bauman G, et al. The impact of PSMA PET on the treatment and outcomes of men with biochemical recurrence of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2022.

The Current Landscape of PSMA PET Imaging in Prostate Cancer: Evolution of Next Generation Imaging & PSMA PET for Primary Tumor Evaluation

Imaging plays a significant role in the diagnosis and management of prostate cancer. While transrectal ultrasound and, subsequently, multiparametric magnetic resonance imaging (mpMRI) have become well-established modalities in the initial diagnosis of prostate cancer, numerous techniques for the distant staging of prostate cancer have all suffered from significant limitations.

  • Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
  • References:
    1. Macedo F, Ladeira K, Pinho F, et al. Bone metastases: an overview. Oncol Rev. 2017;11(1):321.
    2. Heindel W, Gübitz R, Vieth V, et al. The diagnostic imaging of bone metastases. Dtsch Arztebl Int. 2014;111(44):741-7.
    3. Jadvar H. Is There Utility for FDG PET in Prosate Cancer? Semin Nucl Med. 2016;46(6):502-506.
    4. Picchio M, Briganti A, Fanti S, et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol 2011;59:51-60.
    5. Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:18-23.
    6. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol. 2018;7(5):844-54.
    7. Schuste DM, Nieh PT, Jani AB, et al. Anti-3-[18F] FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191(5):!446-53.
    8. Wondergem M, van der Zant FM, van der Ploeg T, Knol RJJ. A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer. Nuclear medicine communications Nucl Med Commun. 2013;34(10):935-45.
    9. Nanni C, Zanoni L, Pultrone C, et al. 18 F-FACBC (anti1-amino-3-18 F-fluorocyclobutane-1-carboxylic acid) versus 11 C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43(9):1601-10.
    10. Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2013;40:486-95.
    11. Chang SS. Overview of Prostate-Specific Membrane Antigen. Rev Urol. 2004;6(Suppl 10):S13-S18.
    12. Farolfi A, Calderoni L, Mattana F, et al. Current and Emerging Clinical Applications of PSMA PET Diagnostic Imaging for Prostate Cancer. J Nucl Med. 2021;62:596-604.
    13. Prostate Cancer. https://uroweb.org/guidelines/prostate-cancer. Accessed on Aug 14, 2022
    14. Ahmed HU, Bosaily AE, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389(10071):815-822.
    15. Bodar YJL, Jansen BHE, van der Voorn JP, et al. Detection of prostate cancer with 18 F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial. World J Urol. 2021;39(7):2439-2446.
    16. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016;70(5):829-836.
    17. Emmett L, Buteau J, Papa N, et al. The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol. 2021;80(6):682-9.
    18. Lopci E, Saita A, Lazzeri M, et al. 68 Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study. J Urol. 2018;200(1):95-103.

     

Imaging in Prostate Cancer: An Update on a Rapidly Changing Space

An accurate assessment of the extent of disease is critical to the care of patients with cancer, across the natural history of disease including initial evaluation, following local treatment, and assessing response to systemic therapy. Thus, improvements in radiographic imaging may revolutionize the way we diagnose disease and the treatments we can offer.

The Rapidly Evolving Role of PSMA In Prostate Cancer Diagnostics And Therapeutics

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein which functions as a zinc metalloenzyme and is found on prostatic epithelium. In normal prostate tissue, PSMA expression and localization focuses on the cytoplasm and apical side of the epithelium surrounding prostatic ducts. However, during prostate carcinogenesis, PSMA is transferred to the luminal surface of the ducts. 

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