(UroToday.com) In the second Hot Topics session of the Société Internationale D’Urologie (SIU) 2021 annual meeting focused on the role of prostate specific membrane antigen (PSMA) and theranostics in prostate cancer, Dr. Robert Reiter began with a presentation on the role of PSMA-based imaging as a diagnostic tool in the initial staging of patients with prostate cancer.
Dr. Reiter began his talk with an overview of the important role of imaging in prostate cancer, across the disease trajectory. In patients at the time of diagnosis of clinically localized disease, imaging is important in treatment planning and prognostication. This role evolves and arguably grows as patients progress through the disease trajectory.
He emphasized that PSMA is a cell surface membrane protein that is highly expressed in prostate cancer cells but is not entirely exclusive to these cells. Further, PSMA expression increases as disease advances, with increased levels in high-grade tumors, in hormone-refractory disease, and in metastatic disease. Functionally, following substrate binding to PSMA, there is enhanced uptake, deposit, and retention in the tumor cell. This results in high quality images for diagnosis and high dose localization in theranostics. While not entirely new, the targeting of PSMA is rapidly evolving.
He highlighted that the newly released 2022 NCCN Clinical Practice Guidelines for prostate cancer now include PSMA-PET imaging as a recommendation for patients with newly diagnosed unfavourable intermediate and high-risk prostate cancer, for investigation of patients with biochemical recurrence, and for staging of those with metastatic disease. Further, on the basis of the increased sensitivity and specificity of PSMA, the guideline panel did not feel that negative conventional imaging was a prerequisite to the use of PSMA-PET.
PSMA-PET was initially investigated in patients with biochemical recurrence following local therapy. In this setting, data from UCLA and UCSF have demonstrated much higher detection rates using 68Ga-PSMA-11 than was previously seen with conventional imaging, or other PET imaging approaches. This was particularly notable in patients with low PSA levels. Notably, even at PSA <0.5 ng/mL, disease could be localized in almost half of patients. In PSA up to 2 ng/mL, detection rates exceed 90 or 95%. Work from the CONDOR study demonstrated very comparable results with the use of 18F-DCFPyL-PET.
Interestingly, this work has changed our understanding of the disease. While it was previously assumed that most patients with low PSA levels at the time of biochemical recurrence had localized disease in the pelvis, work from the UCLA and UCSF group using 68Ga-PSMA-11 demonstrated that even in patients with PSA levels <0.5 ng/mL, local prostate bed recurrence was a minority of patients with imaging detectable disease and that extrapelvic nodal disease, bony disease, and multiple sites of disease were not uncommon. As PSA levels rise, an even greater proportion of patients have non-localized disease.
The question, Dr. Reiter emphasized, is how these imaging approaches change management. There have been a number of studies assessing this question with results ranging from 29% to 76% of patients having management change following PSMA-PET imaging. In general, this manifests with a decreased use of salvage radiotherapy to the prostate fossa and an increased used of salvage nodal dissection, stereotactic radiotherapy, and androgen deprivation therapy (ADT). However, whether this results in improved patient outcomes is somewhat unclear. Certainly, Dr. Reiter highlighted a number of potential benefits resulting from the use of PSMA-PET imaging among patients with biochemical recurrence following prostatectomy.
At UCLA, a phase III trial is ongoing assessing whether salvage radiotherapy planning should be based on PSMA imaging. Among 270 patients, 52 (19%) had recurrence outside the standard salvage radiotherapy template. The author hypothesized a 20% improvement in progression-free survival with the use of a PSMA-PET informed salvage treatment approach. Accrual has been completed for this trial and data is currently maturing with an expected readout in the coming years.
The question of how to approach patients with oligometastatic disease is, somewhat uncertain and the topic of another presentation in this session. Thus, Dr. Reiter transitioned to discussing the role of PSMA-PET at the time of diagnosis for the staging of men with high-risk prostate cancer. The first question he considered is whether PSMA-PET should replace conventional imaging in this setting. Highlighting data from the proPSMA trial, he demonstrated that 68-Ga-PSMA has significantly higher accuracy, sensitivity, and specificity for the identification of metastatic disease in these patients, both overall and with respect to specific metastatic sites. Thus, he concluded that, largely, PSMA-PET could replace conventional imaging. A retrospective analysis of the UCLA cohort similarly demonstrated that PSMA-PET has both higher sensitivity and specificity than conventional imaging. As a result, there are fewer equivocal lesions and false positive results.
Second, he considered whether we should be using PSMA-PET in the local staging of disease and whether it adds to multi-parametric MRI in this context. Citing data from Drs. Emmett, Stricker, and colleagues, highlighted that the addition of PSMA-PET adds to the sensitivity (and negative predictive value) of mpMRI at the expense of decreased specificity for the localization of cancer. This is likely due to the expression of PSMA in non-cancerous prostate tissue. However, it may be useful in patients with recurrence following radiotherapy in which local failure is suspected despite a negative MRI. He suggested, therefore, that we should not be routinely combining these approaches but that there may be circumstances where it is appropriate and helpful and that further data will be both necessary and useful.
Third, Dr. Reiter considered the role of PSMA-PET for the staging of pelvic nodal metastasis in the planning of local therapy. Again citing data from UCLA and UCSF, the authors assessed the sensitivity of PSMA-PET for the detection of nodal disease using radical prostatectomy and pelvic lymph node dissection as a gold standard. Notably, many patients with positive PSMA-PET did not undergo surgery. Thus, these results may underestimate the true sensitivity. However, overall sensitivity was approximately 0.4, with a specificity of 0.95, based on the majority read by 3 independent reviewers. As may be expected, sensitivity was higher for lesions >1cm than those <1cm. In the same vein, the OSPREY study similarly assessed this question using 18F-DCFPyL, instead of 68Ga-PSMA-11, finding similar results with a sensitivity of 0.40 for all pelvic lymph nodes and 0.60 for pelvic lymph nodes >5mm. Thus, we cannot omit lymph node dissection on the basis of a negative PSMA-PET.
As in the setting of biochemical recurrence, the question arises as to what degree treatment can and should be modified on the basis of the results of PSMA-PET imaging. To date, we do not have the answer as to how we should act on the basis of these imaging results. He, therefore, emphasized that we have great technology that we don’t yet know how to best deploy. Many of these outstanding questions are actively being investigated.
In conclusion, Dr. Reiter emphasized that PSMA-PET imaging is revolutionizing the diagnosis or staging of prostate cancer. While sensitivity is much higher than conventional imaging (allowing it to likely replace conventional imaging for most patients), the moderate sensitivity of nodal metastasis may limit the actionability of negative studies. However, high sensitivity of biochemical recurrent disease is promising. Moving forward, there are many unresolved questions regarding how to best act on these data and new technologies.
Presented by: Robert Reiter, MD, Professor of Urologic Oncology, Chief of the Division of Urologic Oncology, Director of UCLA's Prostate Cancer Program, UCLA
Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 Société Internationale D’Urologie (SIU) Hybrid Annual Meeting, Wed, Nov 10 – Sun, Nov 14, 2021.