(UroToday.com) The Advanced Prostate Cancer Consensus Conference 2021 virtual meeting session discussing PSMA in diagnostics and therapy included a presentation by Dr. Charles Ryan discussing the best use of Lutetium-PSMA and where to place it when sequencing therapies, including treatment monitoring.
Dr. Ryan notes that 177Lu-PSMA-617 targeted radioligand therapy is a new method of treating mCRPC. According to Dr. Ryan, there are several important points that the recently published VISION1 trial told us. First, most patients (~87%) with advanced prostate cancer are PSMA positive:
Second, the overall survival (OS) (HR 0.63, 95% CI 0.51-0.79) and progression free survival (PFS) (HR 0.40, 95% CI 0.29-0.57) benefits of 177Lu-PSMA-617 targeted radioligand therapy extend across a wide variety of patient subtypes:
Dr. Ryan notes that given the results of VISION, for 177Lu-PSMA-617 targeted radioligand therapy it is no longer a question if we use it, but a question of when we used it and can we do even better? However, there are several important points that VISION does not tell us:
- Is 177Lu-PSMA-617 targeted radioligand therapy an alternative to chemotherapy?
- There was no direct comparison with individual therapies (ie. abiraterone, enzalutamide)
- Is therapy possible after 177Lu-PSMA-617 targeted radioligand therapy? This may include standard therapies, retreatment, or alternative radioligand therapy
- We do not know long-term post-treatment safety concerns
Furthermore, a majority of patients do not experience a PSA decline of >=50%, suggesting that not all patients will respond to therapy:
Dr. Ryan notes that the next step for 177Lu-PSMA-617 targeted radioligand therapy is to move earlier in the disease process. The TheraP trial is a phase III randomized controlled trial enrolling patients with mCRPC who had previously received docetaxel and were eligible to receive cabazitaxel . Patients were required to have progressive disease with a rising PSA with absolute PSA of 20 ng/mL or higher. All patients underwent both Ga-68-PSMA-PET/CT and F-18-FDG-PET/CT prior to randomization. To be eligible for inclusion, patients must have had a high avidity lesion on PSMA PET/CT (SUV max >20 at any site) with measurable disease with SUV max of 10 or greater. Further, there could be no sites of disease which were FDG positive but PSMA negative. Among 200 men at 11 sites in Australia who were eligible, randomization was performed in a 1:1 fashion to 177Lu-PSMA-617 or cabazitaxel. The primary study outcome was PSA response: Compared to those receiving cabazitaxel (37%, 95% CI 27 to 46%), responses were significantly higher among those who received Lu-PSMA (66%, 95% CI 56 to 75%) with an absolute difference of 29% (95% confidence interval 16 to 42%, p<0.0001). Furthermore, there was a modest improvement in PSA PFS:
The PSMAfore trial is also assessing 177Lu-PSMA-617 targeted radioligand therapy earlier in the disease course, randomizing mCRPC patients with disease progression on previous AR therapy and no prior taxane chemotherapy 1:1 to 177Lu-PSMA-617 targeted radioligand therapy versus a change in AR inhibitor therapy:
The PSMAddition trial is testing 177Lu-PSMA-617 targeted radioligand therapy even earlier in advanced prostate cancer, specifically metastatic castration-sensitive disease (mCSPC). This trial will randomize untreated or minimally treated patients appropriate for standard of care 1:1 to standard of care + 177Lu-PSMA-617 targeted radioligand therapy or to standard of care alone:
Dr. Ryan emphasizes that there are several aspects to watch in the mCSPC disease space:
- Does PSMA expression evolve, devolve or stay the same?
- In patients on ADT with a near universal response, is there concern over delivering radioligand to a tumor free bone marrow?
- What is the potential long-term toxicity?
Looking closer at the TheraP trial, Dr. Ryan notes that there are hints of heterogeneous biology and a potential opportunity for biomarker selection. As previously highlighted, all patients in this trial underwent both Ga-68-PSMA-PET/CT and F-18-FDG-PET/CT prior to randomization, and to be eligible for inclusion patients must have had a high avidity lesion on PSMA PET/CT (SUV max >20 at any site) with measurable disease with an SUV max of 10 or greater; there could be no sites of disease which were FDG positive but PSMA negative. By selecting patients that have PSMA/FDG PET concordance, perhaps we are able to select patients that will benefit most from 177Lu-PSMA-617 targeted radioligand therapy. Additionally, bone marrow suppression may be limiting for certain patients given that 23.4% of patients had grade 3-5 toxicity in the VISION trial.
The Lutectomy trial based in Australia is assessing 177Lu-PSMA-617 targeted radioligand therapy in high risk men, followed by prostatectomy + pelvic lymph node dissection to assess absorbed radiation dose (primary outcome) and several secondary outcomes as highlighted in the following schema:
Additionally, there is early evidence that there may be activity of alpha emitter therapy after beta therapy. Among patients receiving Actinium-225-PSMA-617 who had previously failed 177Lu-PSMA-617 targeted radioligand therapy, there was a high-rate of response (62%), but these responses were short-lived and toxicity was high (xerostomia, hematologic adverse events) .
Dr. Ryan concluded his presentation of the sequencing of 177Lu-PSMA-617 targeted radioligand therapy with the following take-home messages:
- There is a clear benefit of 177Lu-PSMA-617 targeted radioligand therapy in the post taxane population of patients
- There is a potential benefit compared to chemotherapy – it does not mean that we won’t give taxane chemotherapy, but it may give us an option
- There are still questions to answer in the ARSI naïve population
- The mCSPC disease space represents a significant opportunity for potential benefit
- At this point in time, utilization in localized disease is experimental only
- Looking ahead to radioligand therapy in 2030, Dr. Ryan forecasts there will be (i) combination approaches, (ii) castrate levels of testosterone may not be required (ie. in patients with mCSPC, PSA relapse), and (iii) utilization as adjuvant therapy in high-risk localized disease. However, we need long-term safety data first.
Presented by: Charles J. Ryan, MD, Department of Medicine, Division of Oncology, University of Minnesota, Minneapolis, MN; President and Chief Executive Officer, Prostate Cancer Foundation, Santa Monica, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.
- Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
- Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.
- Feuerecker B, Tauber R, Knorr K, et al. Activity and adverse events of Actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of Lutetium-177-PSMA. Eur Urol 2021 Mar;79(3):343-350.