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Why is PSMA a Key Phenotypic Biomarker
in Advanced Prostate Cancer?

PSMA is a transmembrane protein that is anchored in the cell membrane of prostate cancer epithelial cells.1-3 PSMA has been used as a phenotypic biomarker with positron emission tomography (PET) imaging approaches.4-6

PSMA is highly expressed in metastatic prostate cancer relative to normal tissue and is present in >80% of men with prostate cancer.7-14

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PSMA has been shown to have potential utility at multiple points within the prostate cancer care spectrum.6,10,15-17

Diagnosis
Prognosis
Clinical Management
CT, computed tomography; nmCRPC, nonmetastatic castration-resistant prostate cancer; PET, positron emission tomography; PSMA, prostate-specific membrane antigen.
*The ProPSMA study was a prospective, multicenter, randomised, controlled trial of men with high-risk apparently localised prostate cancer. A total of 302 men were randomly assigned to receive either CT and bone scan (conventional imaging) or PSMA PET/CT. First-line imaging was done within 21 days of randomisation. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up.6

PSMA and Prognosis

PSMA expression level in tumours has been negatively correlated with survival outcomes.10

The 5-year recurrence-free survival rates are 88.2%, 74.2%, 67.7%, and 26.8% for patients exhibiting no, low, medium, or high PSMA expression on preoperative biopsy, respectively.10

PSMA_and_Prognosis
IHC, immunohistochemistry; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen.
aPSMA expression was assessed in a retrospective study by immunohistochemistry in 294 preoperative biopsies, 621 primary tumour foci from 242 radical prostatectomies, 43 locally advanced or recurrent tumours obtained from transurethral prostate resection, 34 lymph node metastases, 78 distant metastases, and 52 benign prostatic samples from patients who underwent surgery. PSMA expression was categorised as no expression (score of 0), low expression (1), medium expression (2), or high expression (3). Expression was correlated to recurrence-free survival as the primary end point measure.10
bDisease recurrence was defined as biochemical recurrence (PSA increase above the postoperative nadir following radical prostatectomy) and used as the end point for survival analysis.10
cBy univariate analysis for PSMA negative vs PSMA high expression.10

Because of their utility in prognostics, PSMA PET/CT results may be used to guide management decisions in clinical practice.16

PSMA and Clinical Management

The results of a retrospective, real-world, single-institution study showed that PSMA PET/CT after conventional imaging may lead to management changes in up to 60% of patients.15,16

PSMA_and_Clinical_Management PSMA_and_Clinical_Management
Reproduced by permission from Springer Nature: Eur J Nucl Med Mol Imaging. Müller J et al. Copyright 2019.
ADT, androgen deprivation therapy; chemo, chemotherapy; CT, computed tomography; PET, positron emission tomography; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; RP, radical prostatectomy; RT, radiotherapy.
aThe aim of the retrospective study from Switzerland was to assess the effect of PSMA PET/CT on management and outcome in all patients imaged during the first year after its introduction into clinical practice. The rate of detection of recurrence was determined from review of patient charts. In the 203 patients with follow-up 6 months after PSMA PET/CT, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/mL representing a complete response and a decrease in PSA value of at least 50% from baseline at the time of the scan representing a partial response.16
bMultimodal included surgery, salvage RT, ADT, and/or chemotherapy combined.16

Furthermore, based on preclinical data, PSMA has been shown to affect several key oncogenic pathways* and is being evaluated as a relevant therapeutic target.18-23

Cell proliferation and survival

Cell proliferation and survival18-21

Cell migration

Cell migration21

Angiogenesis

Angiogenesis22,23

Many of these outcomes are driven by the role of PSMA in the PI3K/Akt pathway.18

illustration image
Reproduced with permission of Rockefeller University Press, from: Prostate-specific membrane antigen cleavage of vitamin 89 stimulates oncogenic signaling through metabotropic glutamate receptors. Kaittanis C et al. J Exp Med. 2018;215(1):159-175; permission conveyed through Copyright Clearance Center, Inc.
*In in vitro and animal studies.

PSMA is a diagnostic biomarker and potential therapeutic target, enabling a phenotypic precision medicine approach to help guide patient selection for therapy in advanced prostate cancer.6,10,15,16,24,25

References 1. Israeli RS et al. Cancer Res. 1993;53(2):227-230. 2. Mesters JR et al. EMBO J. 2006;25(6):1375-1384. 3. Bařinka C et al. Curr Med Chem. 2012;19(6):856-870. 4. Kratochwil C et al. J Nucl Med. 2016;57(8):1170-1176. 5. Calais J et al. Lancet Oncol. 2019;20(9):1286-1294. 6. Hofman MS et al. Lancet. 2020;395(10231):1208-1216. 7. Wright GL et al. Urology. 1996;48(2):326-334. 8. Sweat SD et al. Urology. 1998;52(4):637-640. 9. Perner S et al. Hum Pathol. 2007;38(5):696-701. 10. Hupe MC et al. Front Oncol. 2018;8:623. 11. Hope TA et al. J Nucl Med. 2017;58(12):1956-1961. 12. Pomykala KL et al. J Nucl Med. 2020;61(3):405-411. 13. Minner S et al. Prostate. 2011;71(3):281-288. 14. Bostwick DG et al. Cancer. 1998;82(11):2256-2261. 15. Calais J et al. J Nucl Med. 2018;59(3):434-441. 16. Müller J et al. Eur J Nucl Med Mol Imaging. 2019;46(4):889-900. 17. Fendler WP et al. Clin Cancer Res. 2019;25(24):7448-7454. 18. Kaittanis C et al. J Exp Med. 2018;215(1):159-175. 19. Colombatti M et al. PLoS One. 2009;4(2):e4608. 20. Perico ME et al. Oncotarget. 2016;7(45):74189-74202. 21. Zhang Y et al. Prostate. 2013;73(8):835-841. 22. Conway RE et al. Mol Cell Biol. 2006;26(14):5310-5324. 23. Conway RE et al. Angiogenesis. 2016;19(4):487-500. 24. Hofman MS et al. Lancet Oncol. 2018;19(6):825-833. 25. Zang S et al. Oncotarget. 2017;8(7):12247-12258.
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