(UroToday.com) In the second Hot Topics session of the 2021 SIU Annual Congress focused on the role of prostate specific membrane antigen (PSMA) and theranostics in prostate cancer, Dr. Fleshner closed the session discussing the role of PSMA-PET imaging in metastatic castration-resistant prostate cancer (mCRPC) and PSMA-radioligand therapy (RLT).
Dr. Fleshner began with an overview of both positron emission tomography (PET) scans and PSMA-based PET imaging in practice. He highlighted that PSMA is significantly overexpressed in prostate cancer, with further increased expression in high-grade tumors and in those with advanced disease (metastatic disease and CRPC). The two commonly available agents, 68-Ga-PSMA-HBED and 18F-DCFPyL, have comparable sensitivity at the extremes of PSA (<0.5 ng/mL and > 3.5 ng/mL). However, in the intermediate range (0.5-3.5 ng/mL), Dr. Fleshner highlighted that 18F-DCFPyL has higher sensitivity (88% vs 66%). Further, the 18F-labelled tracer has an increased production yield, longer half-life, and increased image resolution.
He then transitioned to the discussion of the role of this imaging approach in CRPC, beginning with patients who have non-metastatic disease. He first highlighted the definition: patients with risk PSA and castrate levels of testosterone who have a normal CT and bone scan. However, he questioned whether this disease state really exists? Citing data from Weber and colleagues published this year, approximately half of patients (45-57%) with nmCRPC show evidence of metastasis of PSMA-PET imaging. Further, a shorter PSA doubling time is associated with a higher likelihood of metastatic disease. Notably, a low-volume of metastasis (oligometastatic disease) may be found in 6 to 28%.
In the context of mCRPC, Dr. Fleshner highlighted that PSMA-PET imaging is much more sensitive for measuring the extent of disease that conventional imaging. However, the effect on systemic therapy treatment selection is somewhat unclear. On example where it may be relevant is radium-223 which is only indicated where patients have exclusively bony metastatic disease. Use of PSMA-PET imaging is likely to detect visceral or nodal disease in many of these patients who would be otherwise eligible for radium-223. It is therefore somewhat unclear as to how this should affect treatment selection.
Dr. Fleshner then transitioned to the question of oligo-progression and the principle of making advanced prostate cancer a chronic disease, using the analogy of “weeding the garden”. This treatment approach has shown some potential in delaying the initiation of systemic therapy in patients with recurrent hormone sensitive prostate cancer. In this disease space, PSMA-PET imaging is a critical component of the paradigm due to its higher sensitivity compared with conventional imaging. However, data supporting this principle in mCRPC are much more scarce and controversial. However, the premise would be to treat “rogue clones” at oligoprogressive sites to delay the switch to the next line of systemic therapy. He cited three relatively small studies supporting this approach, emphasizing a paper from Dr. Henkenberens and colleagues. These authors showed that PSMA-PET guided radiotherapy of oligometastatic CRPC could delay further disease progression. Notably, a large proportion of patients experience a PSA response with this approach. In a more recent paper from Dr. Deek and colleagues, PSA responses were seen in 70-80% of patients and the median time to next intervention exceeded 12 months. However, Dr. Fleshner emphasized that these represent highly selected patient cohorts and the lack of a comparator group make it hard to assess the value of this treatment approach.
Dr. Fleshner then transitioned to discussing radioligand therapy, emphasizing that there are two key roles for PSMA-PET imaging in this space: first, as a prognostic marker to predict who will do poorly overall and, second, as a predictive marker to identify those patients who will respond (or respond better) to radioligand therapy.
Addressing first the prognostic role of PSMA-PET imaging, he emphasized that patients with non-PSMA-avid lesions or with discordant PSMA avid/non-avid tumors do worse overall. These tumors are less likely to be driven by the androgen axis and are more likely to have neuroendocrine features (particularly those that are FDG avid).
However, it is the predictive potential of this paradigm that offers the potential for precision medicine in advanced prostate cancer with the use of medical isotopes. Citing first the data from TheraP, he emphasized that 177-Lu-PSMA-617 radioligand therapy has better efficacy in the third line treatment space (following docetaxel and androgen-axis inhibition) than cabazitaxel based on randomized phase II data. Further, the VISION trial provides phase III randomized data demonstrating the benefit of 177-Lu-PSMA-617 in addition to standard of care, compared to standard of care alone, in patients who had essentially exhausted treatment options with proven survival benefit. Median overall survival was improved by 4 months (at 38% relative benefit).
Despite these promising data for radioligand therapy, Dr. Fleshner emphasized that there are PSMA-PET imaging-based markers of a poor response to therapy. These include discordant lesions, DG avidity, and lower PSMA-PET SUV max (eg. >15). This fits with our understanding of the disease biology and treatment mechanism as those with higher PSMA expression would be expected to receive a higher dose of radiotherapy. As a result, Dr. Fleshner emphasized that these imaging criteria for the basis of inclusion and exclusion criteria in many of the trials. In TheraP, FDG discordance was an exclusion criterion. Further, in VISION, patients had to have PSMA uptake in the metastatic lesion which exceeded that of the liver and could not have evidence of PSMA-negative metastatic lesions. However, these criteria excluded a relatively small proportion of screened patients from inclusion in VISION (12.6%) suggesting that most patients in this disease state fit these criteria. He noted further that VISION did not include FDG PET, in part because it is difficult to get access to this technology in the US for patients with prostate cancer.
He suggested that, as radioligand therapy moves earlier in the disease process, we may see the omission of PSMA-PET scanning prior to therapy as such a high proportion of patients will be expected to be suitable candidates.
Moving forward, he emphasized investigation of PSMA-617 and PSMA-I&T earlier in the prostate cancer trajectory, assessment of novel PSMA ligands and isotopes, as well as combination approaches. He highlighted the SPLASH trial examining PNT2002 as a PSMA-targeted radioligand therapy in patients with mCRPC following progression on androgen axis targeted agents, prior to chemotherapy. Further, while radioligand therapy so far has relied on 177-lutetium, he emphasized the growing role of actinium-225. Actinium-225 is an alpha-emitter, rather than the beta-emission from 177-lutetium.
Concluding, Dr. Fleshner emphasized that PSMA-PET imaging is here to stay and will have an evolving role in advanced prostate cancer. While it is helpful for staging patients with CRPC, the added value is unclear. Further, the role in defining patients with oligoprogression is promising but will require further evaluation to better understand its benefit. In patients being considered for radioligand therapy, PSMA-PET imaging has an important role in prognostication and patient selection.
Presented by: Neil Fleshner, MD, MPH, FRCSC, Chair and Professor at the Division of Urology, University of Toronto
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.