The Evolution of Prostate Cancer Imaging: Embracing the Power of PSMA PET/CT

Advancements in diagnostic imagining for prostate cancer, a prevalent malignancy in men, may redefine the way clinicians manage this disease.^1,2,3 This article explores some of the limitations of conventional prostate cancer imaging and highlights the emergence of prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) to improve the diagnosis and staging of prostate cancer.^2-4

Although PET/CT has been accessible for some time, its efficacy in prostate cancer has remained limited. The introduction of PSMA PET-CT has dramatically altered this landscape and it is quickly becoming the preferred choice for clinicians, especially when they suspect the patient has metastatic disease or there is potential metastatic likelihood.^1,3,5

Conventional prostate cancer imaging

Conventional imaging modalities for prostate cancer typically include CT and bone scans.^1,5 In the last decade, multiparametric MRI (mpMRI) has been used commonly in the evaluation of the prostate gland and for MRI-directed tissue sampling for the initial diagnosis of prostate cancer.⁶ When there is a concern, a biopsy-proven cancer, or need for complete staging, a diagnostic CT scan of the abdomen and pelvis is typically used. Bone scans typically are used for the evaluation of metastasis because the bones are a common site of metastases for prostate cancer. Although clinicians continue to utilize these conventional imaging methods in the diagnosis and management of prostate cancer, limitations and challenges do exist.^1,5

Limitations and clinical challenges

Image quality, challenges in interpreting results, and low sensitivity and/or specificity are some of the common limitations and challenges associated with conventional imaging.^1-4,7,8 For example, because bone scans have low sensitivity, they may not detect a prostate cancer recurrence in which the patient has low prostate-specific antigen (PSA) levels.⁷ A CT scan can detect lesions in the bones and lymph nodes, but detection of lesions in soft tissue is difficult because CT scans exhibit low sensitivity and specificity.⁴ Additionally, CT, bone scans, and MRI may not detect small lymph nodal lesions or bone lesions or be able to differentiate metastatic vs nonmetastatic lesions in patients with high-risk and intermediate-risk disease.9 These limitations with conventional imaging have paved the way for next-generation imaging with PSMA PET/CT.^2,3,5,10

Emergence of PSMA PET/CT in prostate cancer imaging

In many ways, PSMA PET/CT imaging has overcome the challenges inherent in conventional imaging; it offers superior image quality, interpretation, sensitivity, and specificity.¹⁰ PSMA is a transmembrane protein highly expressed on prostate cancer cells, distinguishing it from normal tissue. This unique characteristic has paved the way for the development of radiolabeled PSMA ligands that can be visualized through PSMA PET/CT. PSMA is not entirely specific and may be found in other tissues, such as salivary glands, the small intestine, and the kidneys, which can lead to some nonspecific uptake on imaging. However, prostate cancer cells express PSMA at levels 100 to 1000 times higher than other cells. About 90% to 95% of prostate cancers have PSMA expression, and higher-grade cancers tend to express even more PSMA.^11-12

PSMA PET/CT imaging utilizes radiolabeled tracers that bind specifically to PSMA. The introduction of PSMA PET/CT with gallium and fluorine agents in 2020 and 2021, respectively, has led to improved detection of disease, including both small lesions and disease recurrence at very low PSA levels.^13-15 It has also allowed for increased specificity in distinguishing benign vs malignant tissue.

PSMA PET/CT has been shown to be beneficial particularly for evaluation and staging of patients with unfavorable intermediate-risk or high-risk disease features, such as a Gleason score of 4+3 or greater and a PSA of 10 ng/mL or higher. Furthermore, PSMA PET/CT has proven valuable in detecting disease earlier and with greater precision in patients with biochemical recurrence after definitive treatment.¹⁰

Compared to conventional imaging, PSMA PET/CT can detect disease recurrence at very low PSA levels after prostate cancer treatment. The sensitivity of the test at PSA levels from 0.5 ng/mL to 1 ng/mL is approximately 50% to 60%.⁹

FDA-approved PSMA PET/CT imaging tracers available

In the United Sates, FDA-approved PSMA tracers include gallium 68 (⁶⁸Ga) PSMA-11 (also known as Ga 68 gozetotide), fluorine 18 (¹⁸F)- DCFPyL (also known as piflufolastat F-18), and ¹⁸F-rhPSMA-7.3 (also known as flotufolastat F-18).^1,14-16 These FDA-approved agents are similar in use and detection efficacy for primary and metastatic disease.

68Ga-PSMA-11

⁶⁸Ga-PSMA-11 was approved by the FDA as the first drug for PET-imaging of PSMA-positive lesions in men with prostate cancer.¹³ In 2021, the FDA approved ⁶⁸Ga-labeled PSMA-11, which is currently indicated for PET of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy, with suspected recurrence based on elevated serum PSA level, and for selection of patients with metastatic prostate cancer for whom lutetium ¹⁷⁷Lu vipivotide tetraxetan PSMA-directed therapy is indicated.¹⁷ In 2022, the FDA also approved a kit for the preparation of ⁶⁸Ga gozetotide injection; it is approved for the same indications.^18,19

The phase 3 proPSMA trial (ANZCTR12617000005358) evaluated ⁶⁸Ga-PSMA-11 PET/CT compared with conventional CT and bone scan imaging for staging high-risk prostate cancer before curative surgery or radiotherapy.² The study found that 68Ga-PSMA PET/CT demonstrated greater accuracy (92% vs 65%), sensitivity (85% vs 38%), and specificity (98% vs 91%) than conventional imaging. Study results also showed that ⁶⁸Ga-PSMA PET/CT demonstrated greater sensitivity and specificity for detecting nodal and distant metastatic disease. First-line PSMA PET/CT led to management change with a high or medium effect for 28% of patients vs 15% of patients who underwent conventional imaging. Additionally, second-line imaging with ⁶⁸Ga-PSMA PET/CT management change occurred in 27% of men versus 5% with conventional imaging.² No adverse events (AEs) to ⁶⁸Ga-PSMA-11 were reported.

A large, prospective study evaluated the efficacy of ⁶⁸Ga-PSMA-11 PET for detecting prostate adenocarcinoma in 2005 patients with elevated PSA after initial therapy with radical prostatectomy, definitive radiation therapy, or radical prostatectomy with postoperative radiational therapy. This study evaluated combined prospective data from clinical studies that assessed ⁶⁸Ga-PSMA-11 PET in the accuracy of detecting disease in patients with biochemical recurrence of prostate cancer at 3 institutions—the University of Michigan (NCT03396874), UCLA (NCT02940262), and the University of California San Francisco (NCT03803475). Researchers reported that ⁶⁸Ga-PSMA-11 PET had a high positive predictive value in this setting with PSA level as the main predictor of scan positivity.²⁰

Additionally, a retrospective analysis evaluated 2 academic institutions’ experience with ⁶⁸Ga-PSMA-11 PET/CT in 115 men with a history of radical prostatectomy and with biochemical recurrence of prostate cancer marked by increasing (but very low) PSA levels (≤ 0.2 ng/mL). The analysis determined that ⁶⁸Ga-PSMA-11 PET/CT is a useful tool in this setting; 44 suspicious lesions were found in 29 of 115 men, and multiple lesions were detected at PSA concentrations as low as 0.03 ng/ML in 9 of those men.²¹

¹⁸F DCFPyL/PyL PSMA

F-18–labeled piflufolastat F 18 was approved in 2021 and is indicated for PET of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or who have a suspected recurrence based on their elevated serum PSA levels.^15,21

The phase 2/3 OSPREY (Cohort A) trial (NCT02981368) demonstrated improvement in specificity and positive predictive value with ¹⁸F-DCFPyL PET/CT imaging over conventional imaging in men at risk for metastatic prostate cancer prior to initial therapy. Results for ¹⁸F-DCFPyL PET/CT in detecting disease in pelvic lymph nodes showed a median specificity of 97.9% and a median positive predictive value (PPV) of 86.7%.²² Safety results showed ¹⁸F-DCFPyL was well tolerated; the most frequent AEs reported included dysgeusia (2.6%), headache (1.8%), and fatigue (1.3%).

In the phase 3 CONDOR study (NCT03739684), which evaluated ¹⁸F-DCFPyL PET/CT in men with biochemical recurrent prostate cancer, the imaging demonstrated high accuracy of localization and detection rates, including in patients who had low PSA values (median PSA, 0.8 ng/mL); 63.9% of evaluable patients had a change in their intended management after the scan.²³ Safety results showed it was well tolerated. Headache was the most frequently reported AE (N = 4, 1.9%). One patient reported serious AEs of hypersensitivity, headache, and paresthesia to the study drug. This patient had a history of allergic reactions; all of the patient’s AEs resolved.

¹⁸F-rhPSMA-7.3

The flotufolastat F-18 injection, formerly ¹⁸F-rhPSMA-7.3, was approved in May 2023 for PET of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or who have suspected recurrence based on elevated serum PSA level.^16,24

The phase 3 LIGHTHOUSE study (NCT04186845) evaluated flotufolastat F-18 injection as a PET imaging product in unfavorable intermediate-, high-, and very high-risk patients who were scheduled for radical prostatectomy plus pelvic lymph node dissection. Results demonstrated that the imaging agent had high specificity (93% to 97% as assessed by blinded readers) for identifying pelvic lymph nodes compared with histopathology standard of truth in patients who had PSMA-positive lesions before undergoing radical prostatectomy.²⁵ Data from the phase 3 SPOTLIGHT (NCT04186845) study evaluating flotufolastat F-18 PET in men who had suspected prostate cancer recurrence based on elevated PSA levels after previous therapy showed high detection rates, even in men with low PSA levels.²⁶ No serious AEs were reported with the agent; 4.1% of participants experienced at least 1 treatment-emergent AE that could possibly be attributed to the agent.

PSMA PET/CT: A promising future

The shift towards PSMA PET/CT imaging from conventional imaging methods is evident with agreement from leading guideline recommendations on the utility of PSMA PET/CT in the diagnosis and staging of prostate cancer.^3,5,10 The potential of next-generation imaging with PSMA PET/CT is exciting, and its impact on patient care is just beginning to emerge.

References

1. American Cancer Society. Tests to Diagnose and Stage Prostate Cancer. Revised May 31, 2023. Accessed September 26, 2023. https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/how-diagnosed.html

2. 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. doi:10.1016/S0140-6736(20)30314-7

3. Fendler WP, Eiber M, Beheshti M, et al. PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0. Eur J Nucl Med Mol Imaging. 2023;50(5):1466-1486. doi:10.1007/s00259-022-06089-w

4 Briganti A, Abdollah F, Nini A, et al. Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. Eur Urol. 2012;61(6):1132-1138. doi:10.1016/j.eururo.2011.11.008

5. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2023. Accessed October 3, 2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

6. Demirel HC, Davis JW. Multiparametric magnetic resonance imaging: overview of the technique, clinical applications in prostate biopsy and future directions. Turk J Urol. 2018;44(2):93-102. doi:10.5152/tud.2018.56056

7. Cook GJ, Azad G, Padhani AR. Bone imaging in prostate cancer: the evolving roles of nuclear medicine and radiology. Clin Transl Imaging. 2016;4(6):439-447. doi:10.1007/s40336-016-0196-5

8. Hofman MS. ProPSMA: A callout to the nuclear medicine community to change practices with prospective, high-quality data. J Nucl Med. 2020;61(5):676-677. doi:10.2967/jnumed.120.245647

9. Tsechelidis I, Vrachimis A. PSMA PET in imaging prostate cancer. Front Oncol. 2022;12:831429. doi:10.3389/fonc.2022.831429

10. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol. 2023;209(6):1082-1090. doi:10.1097/JU.0000000000003452

11. Houshmand S, Lawhn-Heath C, Behr S. PSMA PET imaging in the diagnosis and management of prostate cancer. Abdom Radiol (NY). 2023;10.1007/s00261-023-04002-z. doi:10.1007/s00261-023-04002-z

12. Lauri C, Chiurchioni L, Russo VM, Zannini L, Signore A. PSMA expression in solid tumors beyond the prostate gland: ready for theranostic applications? J Clin Med. 2022;11(21):6590. doi:10.3390/jcm11216590

13. FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. News release. FDA. December 1, 2020. Accessed October 5, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer

14. FDA approves Telix’s prostate cancer imaging product, Illuccix. Published online December 20, 2021. Accessed October 5, 2023. https://telixpharma.com/news-views/fda-approves-telixs-prostate-cancer-imaging-product-illuccix/

15. Lantheus receives U.S. FDA approval of PYLARIFY® (piflufolastat F 18) injection, the first and only commercially available PSMA PET imaging agent for prostate cancer. Published online May 27, 2021. Accessed October 5, 2023. https://investor.lantheus.com/news-releases/news-release-details/lantheus-receives-us-fda-approval-pylarifyr-piflufolastat-f-18

16. US FDA approves Blue Earth Diagnostics’ Posluma (flotufolastat F-18 injection, first radiohybrid PSMA-targeted PET imaging agent for prostate cancer. News release. Blue Earth Diagnostics. May 30, 2023. Accessed October 5, 2023. 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

18. Novartis Pluvicto™ approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. Press release. Novartis. March 23, 2022. Accessed October 5, 2023. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer

19. Locametz. Prescribing Information. Novartis; 2023. Accessed October 12, 2023. https://www.novartis.com/us-en/sites/novartis_us/files/locametz.pdf

20. Abghari-Gerst M, Armstrong WR, Nguyen K, et al. A comprehensive assessment of 68Ga-PSMA-11 PET in biochemically recurrent prostate cancer: results from a prospective multicenter study on 2,005 patients. J Nucl Med. 2022;63(4):567-572. doi:10.2967/jnumed.121.262412

21. Burgard C, Hoffmann MA, Frei M, et al. Detection efficacy of 68Ga-PSMA-11 PET/CT in biochemical recurrence of prostate cancer with very low PSA levels: a 7-year, two-center “real-world” experience. Cancers (Basel). 2023;15(5):1376. doi:10.3390/cancers15051376

21. Pylarify. Prescribing Information. Progenics Pharmaceuticals; 2023. Accessed October 12, 2023. https://www.pylarify.com/sites/default/files/resources/prescribing-information.pdf

22. 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 18F-DCFPyL in prostate cancer patients (OSPREY). J Urol. 2021;206(1):52-61. doi:10.1097/JU.0000000000001698

23. 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 III, multicenter study. Clin Cancer Res. 2021;27(13):3674-3682. doi:10.1158/1078-0432.CCR-20-4573

24. Posluma. Prescribing Information. Blue Earth Diagnostics; 2023. Accessed October 12, 2023. https://www.posluma.com/prescribing-information.pdf

25. Surasi DS, Eiber M, Maurer T, et al. Diagnostic performance and safety of positron emission tomography with 18F-rhPSMA-7.3 in Patients with newly diagnosed unfavourable intermediate- to very-high-risk prostate cancer: Results from a phase 3, prospective, multicentre study (LIGHTHOUSE). Eur Urol. 2023;84(4):361-370. doi:10.1016/j.eururo.2023.06.018

26. 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. doi:10.1097/JU.0000000000003493