Phase 3 VISION Trial in mCRPC
Scott T. Tagawa, MD, FACP, reviews the phase 3 VISION trial evaluating the use of 177Lu-PSMA-617 therapy in patients with mCRPC.
Scott T. Tagawa, MD, FACP: PSMA [prostate-specific membrane antigen]-targeted radionuclide therapy means directing a radionuclide, which is either generally a beta or alpha emitter. People are familiar with alpha emitters, as in the approved radium-223, and may remember some beta emitters. Certainly, everyone’s familiar with iodine-131 for thyroid cancer. But in the older days, we used strontium and samarium to palliate painful bone metastasis. Lutetium-177 is an approved agent targeting somatostatin for GI [gastrointestinal] neuroendocrine tumors, and is one of the leading agents in a number of tumor types, including prostate cancer. We can target or aim these radionuclides against PSMA using either small molecules or antibodies. I’m not going to go into great details about these other than to say that they have different properties and kinetics. Both are given intravenously or systemically and wind up in the tumor. The small molecules wind up in some other PSMA-positive areas, and I do think that’s important to know in terms of the toxicity or adverse event profile.
One of the specific agents, lutetium-PSMA-617, has been initially used anecdotally as part of expanded access programs, and then more recently in prospective single-arm trials. There are now 2 completed and published randomized clinical trials. The potentially registration phase 3 trial is called VISION. This was a trial that was designed to enroll men with castration-resistant prostate cancer who had no other options. They were supposed to receive all the hormonal therapy, targeted therapy, and chemotherapy that was appropriate for them. They were required to have at least 1 prior modern AR [androgen receptor] pathway inhibitor and at least 1 prior taxane. But if they were appropriate for radium, a PARP inhibitor, and a second taxane, they should have received that first. That was the overall intent of the study design.
For the treatments among that population of men, there was another selection besides the general selection criteria that we use for clinical trials, such as intact performance status and organ function: PSMA positivity. This was defined for the protocol, and for those who are interested in the details, most protocols are not the same. The other randomized trial is called TheraP. It has much different PSMA imaging inclusion criteria than the VISION study. Basically, the VISION study said that all of the soft tissue lesions needed to be PSMA-positive. None of them that were evident on CT—at least defined by the study—could be negative, with negative designed by uptake less than liver.
These patients were enrolled and started on whatever the most appropriate standard of care per the protocol allowed. Then they were randomized 2:1 with or without lutetium-PSMA-617. Because of the way the study was designed, that they were supposed to receive all the drugs before, and with the limited amount of safety information for combinations, there were 2 main types of drugs that were excluded in terms of standard of care: chemotherapy and radium. Those were supposed to be given prior to the study. Patients were enrolled on this standard of care alone or standard of care plus lutetium-PSMA-617 with an alternative primary end point of radiographic progression-free survival. Those of you who have seen prostate cancer clinical trials understand what that is. It also looked at overall survival. Alternative primary end points means that if only one of those is positive and the other one’s negative, then the study is seen as positive overall.
These men were enrolled at a number of different centers across the world. The type of the standard-of-care agent was declared up front. That was a stratification factor, specifically modern-day AR pathway inhibitor or not. They had PSMA-PET [positron emission tomography] scans and then were treated. On PSMA-PET imaging, approximately 95% were PSMA-positive as defined by having at least 1 PSMA-positive lesion. But then an overlapping 8.7%, which equals about 13% overall, weren’t included. Overall, 87% were included by the study definition of PSMA positivity.
Patients were treated, and as all of you know from the ASCO [American Society of Clinical Oncology] plenary presentation followed by the New England Journal of Medicine publication, both primary alternative end points were positive. There was a nearly 40% improvement in overall survival. The hazard ratio was 0.62 with confidence intervals that didn’t come close to 1. The radiographic progression-free survival was even bigger, with a hazard ratio of 0.4, or a 60% improvement in radiographic progression-free survival. Generally speaking, both of these were positive across all individual subgroups. The secondary end points were also generally positive, while some analysis is ongoing for some of them. That included PSA [prostate-specific antigen] declines as well as objective RECIST responses in measurable disease.
The patients who were included in the VISION trial were fairly typical of those who have received a number of different therapies. It may not be exactly the same thing as the “real world” because they have to qualify for a clinical trial and be at a center for the clinical trial, so clinical trial data aren’t always the same as real-world data. That being said, as we’d expect for someone with 1 to 2 lines of potent AR pathway inhibitors and 1 to 2 lines of chemotherapy plus others, most had bone metastasis and a lot had soft tissue disease, including both nodal and visceral disease, with visceral disease including both lung and liver. All had to have an intact performance status enough to qualify for a clinical trial, as well as organ function, such as laboratory tests and blood count enough for clinical trial. But that’s not so different than we’d expect for most clinical trials.
Transcript Edited for Clarity
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