The Latest Updates in PSMA Diagnostics and Theranostics From AUA 2022

At the American Urological Association (AUA) 2022 meeting in New Orleans, the Friday plenary session consisted of several high-yield discussions.

One important topic covered by William Aronson, MD, professor of urology at University of California, Los Angeles (UCLA), was the “latest and greatest” in the realm of prostate-specific membrane antigen (PSMA) diagnostics and theranostics.

Dr Aronson began his presentation by providing an overview of the history of PSMA, citing preclinical studies conducted at Johns Hopkins and Weill Cornell Medical Center in the early 1990s.1 He explained, however, that it was not until 2 decades later that clinical use of PSMA began to make a footprint, when a group in Heidelberg, Germany, reported the first patient with prostate cancer to be imaged with gallium-68 (68Ga)-PSMA.1 Since then, the prostate cancer community has become increasingly interested in PSMA, owing to its ability to serve as a reliable diagnostic and therapeutic target.

The Biology of PSMA

For example, one study, the proPSMA trial, demonstrated greater accuracy (92% vs 65%) and sensitivity (85% vs 38%) with PSMA, compared with conventional imaging, in identifying nodal metastatic prostate cancer in the diagnostic setting.2 Dr Aronson went on to explain that the US Food and Drug Administration (FDA) approved 68Ga-PSMA positron emission tomography/computed tomography (PET/CT; 68Ga-PSMA-11) based on clinical trials reported from UCLA and UCSF (University of California San Francisco); it approved use of fluorine-18 (18F)-PSMA PET/CT (18F-DCFPyL) based on results from the CONDOR3 and OSPREY4 clinical trials.

Next, Dr Aronson spoke about the biology of PSMA. He explained that PSMA is found to have 100 to 1000 times greater overexpression in prostate cancer cells compared to benign prostatic tissue.5 He explained that the PSMA peptide is primarily expressed along the extracellular surface of the prostate cancer cell, allowing for small molecule binding. This binding site is used by the 68Ga- and 18F-based radiotracers. He reminded the audience that the true biological function of PSMA is still unknown. Comparing the 2 radiotracers, he explained that they have similar performance characteristics and that the process for reporting these imaging studies involves various grading algorithms that are subject to radiologist interpretation. Dr Aronson further highlighted that the combination of low PSMA expression in benign prostatic tissue, as well as in bone and lymph nodes, allows for a high signal-to-background ratio that facilitates targeted visualization of prostate cancer cells.

PSMA-Based Modalities

Switching gears to discuss patients with biochemical recurrence, Dr Aronson explained that both 68Ga- and 18F-PSMA PET/CT scans are superior to conventional imaging for diagnosing patients with biochemical recurrence (BCR) after primary treatment. For example, he cited the CONDOR trial3 in which patients with BCR after primary radiotherapy or radical prostatectomy were enrolled and received 18F-PSMA PET/CT after negative findings with conventional imaging. Of these patients, 63.9% experienced a change in management based on the results of the 18F-PSMA PET/CT scan. 3  

In the BCR setting, Dr Aronson explained that both PSMA-based modalities have similar rates of detection, especially as PSA levels rise. However, despite better detection rates compared with conventional imaging, the question of improved outcomes remains. In a prelude to ongoing clinical trials that are yet to be fully reported, Dr Aronson cited a study by Phillips et al6 of the ORIOLE phase 2 trial, in which patients with oligometastatic prostate cancer after primary therapy were randomized to stereotactic body radiation therapy (SBRT) or no SBRT to all PSMA avid lesions. The authors demonstrated that patients receiving therapy to all PSMA avid lesions had significant improvements in progression-free survival (hazard ratio, 0.26).6

Next, Dr Aronson discussed the utility of PSMA PET/CT in pre-primary treatment staging of prostate cancer. He cited data presented in reports of the OSPREY trial,4  specifically mentioning the cohort A population of patients with high-risk prostate cancer (Gleason grade group >4, PSA >20 ng/mL, clinical stage ≥T3a). He explained that the results of the trial demonstrated that PSMA PET/CT was superior to conventional cross-sectional imaging, although the findings were limited by low sensitivity levels (40%), owing to the inability to detect small pelvic lymph nodes. He noted that the take-home point from OSPREY was to not exclude performing a pelvic lymph node dissection during radical prostatectomy despite a negative PSMA PET/CT result. 4 To emphasize the utility of PSMA PET/CT, he presented an example patient case where a 77-year-old man with Gleason grade 4+5 prostate cancer had a negative finding with conventional imaging, whereas PSMA PET/CT revealed 2 PSMA avid pelvic lymph nodes and 1 site of metastatic disease in the sacrum.

Discussing PSMA Theranostics

Moving from diagnosis to therapeutics, Dr Aronson spoke about the emerging field of PSMA “theranostics” (diagnostics plus therapy). He explained that earlier this year, the FDA approved Lu-177-PSMA-617 (177Lu) for use in patients with metastatic castration-resistant prostate cancer (mCRPC) in whom hormonal therapy plus docetaxel has failed. This approval was based on the results of the VISION trial, presented in 2021, which demonstrated that 6 cycles of 177Lu plus standard of care (SOC) versus SOC alone prolonged overall survival (15.3 vs 11.3 months) and extended radiographic progression-free survival (8.7 vs 3.4 months).7 Dr Aronson remarked that  177Lu functions by emitting β-particles within a 2-mm radius of PSMA avid lesions, causing single-stranded DNA breaks. To highlight this promising new therapy, he demonstrated a case report in which a septuagenarian man with treatment-refractory mCRPC underwent 4 cycles of 177Lu, which resulted in a substantial decrease in disease burden appreciable on imaging.8 As of early May 2022, Novartis was experiencing production issues with 177Lu, but Dr Aronson said he expects resolution of these issues within 6 weeks.

At the end of his presentation, Dr Aronson spoke about the future utility of PSMA PET/CT for patients with elevated PSA levels, as well as the future direction for use of PSMA PET/CT overall. He presented the case of septuagenarian man with an elevated PSA level, negative prostate MRI results, and systematic biopsies utilizing PSMA PET/CT that demonstrated focal grade group 3 lesion on targeted biopsy. He explained that combining PSMA PET/CT with prostate MRI may improve the diagnostic accuracy of prostate MRI. Looking toward the future, he remarked on several exciting developments within the PSMA sphere, including nascent clinical trials exploring PSMA theranostics in patients with early-stage prostate cancer and intraoperative detection of PSMA avid prostate cancer lesions. Dr Aronson remarked that it is too soon to determine if earlier detection of prostate cancer with PSMA PET/CT will improve patient outcomes or if doing so will run the risk of overtreating patients.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

  1. Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68Ga] Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging. 2012;39(6):1085-1086. doi: 1007/s00259-012-2069-0
  2. Hofman MS, Lawrentschuk N, Francis RJ, et al; for the proPSMA Study Group Collaborators. 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. 2020;395(10231):1208-1216. doi: 10.1016/S0140-6736(20)30314-7
  3. Morris MJ, Rowe SP, Gorin MA, et al; for the CONDOR Study Group. 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: 1158/1078-0432.CCR-20-4573
  4. 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: 1097/JU.0000000000001698
  5. Jones W, Griffiths K, Barata PC, Paller CJ. PSMA theranostics: review of the current status of PSMA-targeted imaging and radioligand therapy. Cancers (Basel). 2020;12(6):1367. doi: 3390/cancers12061367
  6. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659. doi: 1001/jamaoncol.2020.0147
  7. Sartor O, de Bono J, Chi KN, et al; for the VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi: 1056/NEJMoa2107322
  8. Kuppermann D, Calais J, Marks LS. Imaging prostate cancer: clinical utility of prostate-specific membrane antigen. J Urol. 2022;207(4):769-778. doi: 1097/JU.0000000000002457