Las Vegas, Nevada (UroToday.com) In his talk at SNMMI 2019, Phillip Kuo, MD, Ph.D., described the current status of late-stage clinical trials, and the future landscape of 177-Lutetium-PSMA targeted therapies.
The prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate cancer and tends to increase with disease aggressiveness (Figure 1). There has been a significant increase in research related to PSMA in the last several years (Figure 2).
Figure 1 – PSMA transmembrane protein:
Figure 2 – Increase in PSMA-related research in recent years:
Lutetium-177 PSMA therapy uses a molecule that attaches itself to the PSMA receptors on cancer cells. Before it is administered, the PSMA molecule is bound with Lutetium-177, which emits beta radiation, a destructive type of radiation that damages the cancer cells when it is near them (Figure 3). Over time, it destroys the prostate cancer cells. The PSMA molecule acts as a means of transporting the radiation to the tumor site so that the whole body does not get exposed to the radiation. This is often referred to as Peptide Receptor Radionuclide Therapy (PRRT).
Figure 3 – PSMA-targeted radiotherapeutic:
The Lutetium-177 PSMA was originally developed by the German Cancer Research Center and University Hospital Heidelberg. It has high PSMA binding affinity, prolonged tumor uptake, high tumor to background ratio and rapid kidney clearance. There have been multiple clinical trials at multiple sites in Germany. The biodistribution and clearance of this compound are in the renal, gastrointestinal, salivary and lacrimal glands, and very little normal marrow uptake (Figure 4).
Figure 4 – Normal biodistribution and clearance of PSMA-LUTETIUM:
There is currently only one phase 3 trial assessing 177-Lutetium-PSMA targeted therapy. This is the VISION trial, assessing the role of this radionuclide in metastatic castrate-resistant prostate cancer (mCRPC) patients (Figure 5). In this trial, 750 men have been recruited, and the recruitment has been completed. Men were randomized 2:1 to receive either 177 Lutetium-PSMA 617 plus best supportive/best standard of care or best supportive/best standard of care only. The recruited patients all needed to have:
- Progressive mCRPC and have received at least one novel androgen axis drug (NAAD) such as enzalutamide or abiraterone, and have been previously treated with 1-2 taxane regimens
- Positive PSMA scans
The intervention was 7.4 GBq (200 mCi) of 177-Lutetium-PSMA-617 (not weight-based and no use of dosimetry based on imaging). This was given every 6 weeks intravenously for a maximum of 6 cycles.
The primary objective of this trial is to compare overall survival in patients with progressive PSMA-positive mCRPC who receive 177-Lutetium-PSMA-617 in addition to the best supportive/ best standard of care vs. patients treated with best supportive/best standard of care alone. The secondary objectives included:
- Radiographic progression-free survival (rPFS)
- Response evaluation criteria in solid tumors (RECIST) response
- Time to a first symptomatic skeletal event (SSE)
- Safety and tolerability
- Health-related quality of life
- Health economics
- Progression-free survival
- Biochemical response as measured by PSA, alkaline phosphatase levels and lactate dehydrogenase levels
Figure 5- VISION trial design:
Dr. Kuo moved on to discuss several of the ongoing phase 2 trials. One of these is the LuPSMA trial, which is a single-center, single-arm, phase 2 study (Figure 6). This trial had shown an incredible PSA response as seen in Figure 7. There are currently at least 8 other phase 1 or 2 clinical trials involving 177-Lutetium-PSMA, of which five trials are open for recruitment. Most studies are taking place in Australia, Germany, Italy, The Netherlands, and USA.
Figure 6 – LuPSMA trial flow chart:
Figure 7 – PSA response in the LuPSMA trial:
The role of Lutetium-177-PSMA-617 in combination with other treatments was also discussed. Optional combinations include immunotherapy (pembrolizumab), and the PARP inhibitor Olaparib. Future relevant trials will provide us with more data regarding the role of these treatment combinations.
In the near future, we will also see studies assessing treatment given with Iodine-131-1095, which is a small molecule inhibitor of PSMA. There is currently an ongoing phase 2 trial (ARROW - NCT03939689) which is assessing radiotherapy in combination with enzalutamide in mCRPC patients who are chemotherapy-naïve and have progressed on abiraterone. The primary outcome of this study is the proportion of patients with PSA response according to PCWG3 criteria defined as the first occurrence of a 50% or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later. The patient population will be PSMA-avid mCRPC patients whose disease has progressed despite abiraterone, and who are planned for treatment with enzalutamide.
Dr. Kuo concluded his talk mentioning the several open questions that hopefully will be answered in the near future, assessing the role of Lutetium-177-PSMA-677 and other radiopharmaceuticals. Specific important questions include defining the role of imaging prior to therapy, understanding whether dosimetry is necessary for safety or useful for optimization of dose, ascertaining the role of imaging in the post-therapy setting, and figuring the role of combination with other therapies.
Presented by: Phillip Kuo, MD, PhD, Professor, Medical Imaging, Biomedical Engineering and Medicine, Division Chief, Nuclear Medicine, and Director of PET/CT, Director of the Nuclear Medicine Fellowship Program, College of Medicine Tucson Medical Imaging, The University of Arizona Health Sciences
Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019 SNMMI Therapeutics Conference: Therapies, Theranostics, and Building Your Radionuclide Clinical Practice, October 25-27, 2019 in Las Vegas, Nevada.