Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) Diagnostics

PSMA PET CT (PSMA PET) imaging has led to a profound transformation in prostate cancer diagnosis and management. PSMA PET imaging is superior to conventional imaging for initial staging in men with newly diagnosed prostate cancer, and is superior to conventional imaging for patients with biochemical recurrence. In 2020 the U.S. Food and Drug Administration (FDA) approved the radiotracer ⁶⁸Ga-PSMA-11 based on pivotal clinical trials done at the University of California, Los An­geles and University of California, San Francisco,^1,2 and in 2021 the FDA approved the radiotracer ¹⁸F-DCFPyL based on results of the CONDOR and OSPREY trials.^{3,4 68}Ga-PSMA-11 and ¹⁸F-DCFPyL have similar performance characteristics and are superior to the fluciclovine scan.⁵ PSMA is overexpressed 100 to 1,000 times in prostate cancer cells. Given low PSMA levels in bone and lymph nodes, there is a favorable signal-to-background ratio allowing for excellent visualization of PSMA PET positive lesions at these sites.

Details of the sensitivity, specificity, and positive and negative predictive values for PSMA PET imaging are in the references below. Several aspects deserve special mention. For initial staging in men with newly diagnosed prostate cancer, we need to be well aware of the limitations of PSMA PET imaging for lesions less than 6 mm. For example, Cohort A in the OSPREY trial enrolled patients scheduled for radical prostatectomy with pelvic lymph node dissection with a Gleason score ≥8, PSA >20, and clinical stage ≥T3a.⁴ The sensitivity of detecting prostate cancer in histologically positive lymph nodes was low (40%). In a post-hoc analysis the sensitivity improved to 60% when excluding histologically positive nodes less than 6 mm. Thus, it is important not to exclude doing a pelvic lymph node dissection based on a negative PSMA PET scan. Another aspect of PSMA PET imaging that deserves special attention is the correlation between PSA levels and detection of PSMA PET positive lesions in patients with biochemical recurrence following primary therapy. As seen in the Figure, the higher the PSA, the higher the detection rate. Once the PSA reaches levels of 1 or higher detection rates are high, ranging from 75% to 95%.⁶

Although results from PSMA PET imaging are known to change management decisions, such as radiation therapy planning, there are no high-level data demonstrating improved patient outcomes. That being said, in a subset analysis of 35 patients from the ORIOLE trial, a phase 2 randomized trial examining stereotactic body radiation therapy for oligometastatic prostate cancer in which the radiation oncologists were blinded to PSMA PET findings, there was improved progression-free survival in patients who had all PSMA PET positive lesions treated as compared to patients who did not have all the PSMA PET lesions treated.⁷ Prospective randomized trials evaluating therapy of PSMA PET detected lesions that are negative on conventional imaging are ongoing and we should make every effort to enroll our patients in these trials.

PSMA-Based Theranostics

The term “theranostics” refers to combining diagnostics with tumor directed therapy. In the VISION trial, lutetium-177 (emits beta particles causing single-stranded DNA breaks) linked with PSMA-617 (Lu-177-PSMA-617) was proven to be an effective treatment for men with metastatic castration resistant prostate cancer (mCRPC). This was a prospective, randomized trial in men with mCRPC that failed an androgen receptor pathway inhibitor and docetaxel chemotherapy. Lu-177-PSMA-617 improved progression-free survival and overall survival, and had favorable findings for quality of life and pain scores relative to the control group.⁸ The infusion is given by a nuclear medicine physician every 6 weeks for up to 6 doses. These findings represent a major advancement for our patients with mCRPC. Trials are ongoing evaluating radioligand-PSMA based therapies for earlier stages of disease.

Figure. ⁶⁸Ga-PSMA and ¹⁸F-DCFPyL PSMA scanning detection rates increase with increasing PSA in patients with biochemical recurrence.

Future Directions

There are numerous future directions for PSMA PET imaging and theranostics. Benign prostate tissue has a low uptake of PSMA as compared to prostate cancer, and prior studies suggest combining multiparametric MRI with PSMA PET may improve our ability to diagnose prostate cancer.^9,10 Combining PSMA PET and magnetic resonance imaging into one imaging modality to be used for fusion biopsy is also under development. The role for PSMA PET imaging to monitor treatment response and outcomes is also under investigation. Artificial intelligence image analysis may also play a role in understanding the disease biology and for risk stratification. Research is also underway evaluating intraoperative detection of prostate cancer in lymph nodes using probes that detect radiolabeled PSMA. In addition, new “formulations” of PSMA targeting for imaging and treatment are also being evaluated in prospective trials.

Challenges Moving Forward and Take Home Messages

PSMA PET CT can be considered a “disruptive” technology in that we need to rethink how we image and manage all stages of prostate cancer, and reconsider what is best for our patients in the setting of insufficient outcomes data. Although it seems intuitive that earlier detection of metastatic disease will result in improved outcomes for our patients, prospective randomized trials are required. To date, all the FDA-approved therapies for metastatic castration sensitive and castration resistant prostate cancer were done with conventional ­
imaging. There exists a risk of overtreatment with increased long-term adverse events and financial toxicity if we prescribe therapies for advanced disease based on positive PSMA PET imaging with negative conventional imaging.

Take home messages are as follows: 1) PSMA PET CT imaging is superior to conventional imaging for initial staging and biochemical recurrence for our patients with prostate cancer. 2) A negative PSMA PET CT of pelvic lymph nodes should not exclude performing a pelvic lymph node dissection at the time of radical prostatectomy. 3) As per the present National Comprehensive Cancer Network® guidelines, for patients who progress while on androgen deprivation therapy, PSMA PET can be considered as an alternative to conventional imaging for bone and soft tissue. 4) Lutetium-177 linked to PSMA-617 is an effective therapy for patients with mCRPC that failed an androgen receptor pathway inhibitor and docetaxel chemotherapy. 5) When possible, we should enroll our patients in clinical trials to better define the role of PSMA based diagnostics and theranostics.