Prostate-Specific Membrane Antigen (PSMA) PET for Initial Staging of Prostate Cancer – Now That It’s Regulatory Approved, What’s Next?

PSMA PET imaging has now achieved regulatory approval in the United States.  On December 1, 2020, the United States (US) Food and Drug Administration (FDA) granted a limited approval to the University of California, Los Angeles and the University of California, San Francisco, for 68Ga-PSMA-11 PET imaging for patients “with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy” and for patients with “suspected prostate cancer recurrence based on elevated serum PSA levels.”1  More recently, on May 27, 2021, a second PSMA imaging agent, PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL), received FDA approval for the exact same indication.2  Although neither 68Ga-PSMA-11 and PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL) are widely available yet, both likely soon will be, and they will change how we think about and treat patients with prostate cancer and both high-risk localized disease and biochemical recurrence.

For the purposes of this article, I will focus on the initial staging of prostate cancer.  This is the disease state where there is going to be likely to be a little less controversy, as neither oligometastatic site-directed therapy nor early introduction of systemic therapy with androgen deprivation therapy with or without treatment intensification for PSMA PET detected disease in the biochemically-recurrent disease state is proven to definitively improve patients outcomes.  However, in the setting of initial staging, it is clear that confidence in PSMA PET findings may alter health care provider plans for surgery or radiation, and these alterations could have both efficacy and quality of life considerations.

The proPSMA study was a multi-center, Australian, two-arm, randomized trial that included patients with biopsy-proven prostate cancer and high-risk features.3  Patients were randomly assigned to CT and bone scan conventional imaging or 68Ga-PSMA-11 PET/CT.  Of 295 evaluable men, 87 (30%) had pelvic nodal or distant metastatic disease identified by 68Ga-PSMA-11 PET/CT.  Accuracy was 27% (95% CI 23-31) greater by 68Ga-PSMA-11 PET/CT over conventional imaging (92% [88-95] vs 65% [60-69]; p<0.0001).  Additionally, sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) were both inferior for conventional imaging compared with 68Ga-PSMA-11 PET/CT.  Management changes occurred less frequently with conventional imaging compared with 68Ga-PSMA-11 PET/CT (23 [15%] men [10-22] vs. 41 [28%] men [21-36]; p=0.008).  Interestingly, radiation exposure was 10.9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for 68Ga-PSMA-11 PET/CT (19.2 mSv vs 8.4 mSv; p<0.001).  This implied a potential refinement of radiation treatment planning with 68Ga-PSMA-11 PET/CT imaging. 

The OSPREY (US and Canadian) trial evaluated PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL) PET/CT in patients with high-risk localized prostate cancer planning on radical prostatectomy and pelvic lymph node dissection (Cohort A) and patients with suspected recurrence of prostate cancer on conventional imaging (Cohort B).4  For purposes of this staging discussion, Cohort A had a focused primary endpoint on sensitivity and specificity of detection of pelvic nodal and distant metastatic disease.  Of 252 evaluable patients, median sensitivity was 40.3% (95% CI: 28.1-52.5%), and this did not meet the study prespecified endpoint for success.  However, median specificity, positive predictive value and negative predictive value, were all high at 97.9% (95% CI: 94.5-99.4%), 86.7% (95% CI: 69.7-95.3%), and 83.2% (95% CI: 78.2-88.1%), respectively.  One of the most helpful pieces of data from this trial is that 72 of the original 268 (26.9%) patients presented at the ASCO 2020 Genitourinary Cancers Symposium had either nodal or distant metastatic disease detected by PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL) PET/CT.5  This information obviously has potential to change pre-operative surgical planning.

When it comes to the initial staging of high-risk localized prostate cancer, it is clear that PSMA targeted PET/CT imaging has advantages, and it is anticipated that the uptake will be significant.  Yet, this is the tip of the iceberg when it comes to potential uses for this early stage of disease.  Can PSMA PET help guide prostate needle biopsies?  Might there be utility for this diagnostic tool for lower-risk prostate cancer?  Is there potential to combine with magnetic resonance imaging or spectroscopy to improve detection and anatomic definition?  Most importantly, do the findings on PSMA PET and changes in treatment lead to improved clinical efficacy outcomes for patients?  Below, I have selected some interesting trials that are ongoing that will add new information and answer some of the questions that I pose above.

Clinical trials with PSMA PET imaging prior to definitive therapy for localized prostate cancer

  • 68Ga-PSMA-11 PET for prostate biopsy for low and intermediate-risk localized prostate cancer (NCT03429244)
  • 68Ga-PSMA-11 PET for intermediate and high-risk localized prostate cancer (NCT04462926)
  • 68Ga-PSMA-11 PET for determining extraprostatic extension prior to radical prostatectomy (NCT04936334)
  • 68Ga-PSMA-11 PET/CT and fluciclovine PET/CT comparison prior to radiation therapy (NCT03762759)
  • 68Ga-PSMA-11 PET/MRI for prostate needle biopsy guidance (NCT03809078)
  • 18F-DCFPyL PSMA PET with multiparametric MRI (NCT04910425)
  • 18F-DCFPyL PSMA PET with multiparametric MRI and diffusion weighted imaging to detect high-grade prostate cancer prior to prostatectomy (NCT03232164)
  • 68Ga-HBED-CC-PSMA PET/MRI vs. 68Ga-HBED-CC-PSMA PET/CT vs. MRI alone for determination of prostate cancer (NCT03439033)
  • 68Ga-HBED-CC-PSMA PET/MRI for low and intermediate-risk prostate cancer and incorporation of stereotactic body radiation (NCT04243941)
  • 68Ga-HBED-CC-PSMA PET/MRI for radiation planning (NCT04176497)
  • 68Ga-PSMA-11 PET/MRI for delineation of prostate abnormalities (NCT04867603)
  • PSMA PET/MRI for high-risk prostate cancer prior to local therapy (NCT04790968)
  • 68Ga-PSMA-11 PET PET/MRI guided stereotactic body radiation for intermediate and high-risk localized prostate cancer to determine recurrence-free survival (NCT04402151)
  • 18F-DCFPyL PSMA PET with sodium MRI pre-prostatectomy (NCT04053842)
  • 68Ga-PSMA-11 PET/MR Spectroscopy across stages of prostate cancer (NCT04154280)
  • PATRON - 18F-DCFPyL PSMA PET to guide therapy intensification of high-risk localized prostate cancer and determine failure-free survival (NCT04557501)
  • 18F-DCFPyL PSMA PET/CT to guide therapy of high-risk localized prostate cancer and determine progression-free survival (NCT03976843)
  • Randomized phase 3 trial of radiation with or without 18F-DCFPyL PSMA PET/CT planning to determine progression-free survival (NCT04457245)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


  1. "FDA Approves First PSMA-Targeted PET Imaging Drug For Men With Prostate Cancer". 2021. U.S. Food And Drug Administration. 
  2. "FDA Approves PSMA-Targeted Imaging Drug For Men With Prostate Cancer". 2021. U.S. Food And Drug Administration. 
  3. Bander NH et al. "Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer," J Clin Oncol 2005; 23:4591-601.
  4. Hofman MS 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; 395:1208-16.
  5. Pienta KJ 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; 206:52-61.
  6. Pouliot F et al. "A prospective phase II/III multicenter study of PSMA-targeted 18F-DCFPyL PET/CT imaging in patients with prostate cancer (OSPREY): A sub-analysis of regional and distant metastases detection rates at initial staging by 18F-DCFPyL PET/CT." J Clin Oncol 38, no. 6_suppl (February 20, 2020) 9-9.