Radioligand Therapy 177Lu-PSMA-617 in Patients With Progressive PSMA-positive mCRPC - Episode 2
Dr Evan Y. Yu reviews the use of 177Lu-PSMA-617 therapy in patients with progressive PSMA-positive mCRPC as seen in the phase 3 VISION trial.
Evan Y. Yu, MD: Very recently, the randomized phase 3 VISION trial read out and was presented at ASCO [American Society of Clinical Oncology annual meeting] 2021. Now, this was a large, randomized controlled trial of best supportive care versus lutetium-177 PSMA [prostate-specific membrane antigen]-617, which is a small molecule that brings lutetium, a beta-emitting radiopharmaceutical, directly to PSMA expressing cells. It was the best standard of care plus that agent versus the best standard of care alone. Now, that best standard of care generally was the androgen receptor axis inhibitors, but glucocorticoids could be used, etc. The key eligibility criteria that defined the population were that patients had to receive 1 or more prior androgen receptor-targeted agents like abiraterone or enzalutamide, etc. They also had to receive 1 or 2 prior taxane chemotherapies, and that could include agents like docetaxel or cabazitaxel. They had to have a reasonable performance status, but patients with an ECOG performance status of 2 were allowed on the study. The interesting key criterion is that, since this is a precision therapy, PSMA PET [positron emission tomography] had to be positive. Now, in this study, they used Gallium-68 PSMA PET. You had to have a positive PSMA PET, and you couldn't have a negative lesion that was reasonably large. For example, if you had a soft tissue lesion that was PSMA PET negative and was greater than or equal to 1 cm, or if you had a lymph node that was PSMA PET negative that was greater than or equal to 2.5 cm, you were excluded.
I can only assume that is because there was concern that those patients might have lineage plasticity inaction that might be developing, or neuroendocrine, ovarian, or prostate cancers. If it does not express PSMA, those clones might take off and be problematic, so those patients were excluded from the trial. Again, I mentioned the standard of care was the control arm, and of course, the best standard of care was combined with lutetium-177 PSMA-617 in the therapeutic or experimental arm. Just to mention again, the standard of care was generally the hormonal agents. Chemotherapy, immunotherapies, radium-223, investigational agents, these were all excluded. The key finding is that the dual primary end points of overall survival and radiographic progression-free survival were very positive. For overall survival, the hazard ratio was 0.62 in favor of the lutetium arm. There was a very statistically significant P value, less than .001.
The median overall survival was 15.3 months versus 11.3 months. The radiographic progression-free survival had an even better hazard ratio; I think it was 0.4. Also, there was a very significant P value. Median progression-free survival was 8.7 versus 3.4 months. This was all very, very impressive. In regard to PSA [prostate-specific antigen] findings, one of the nice things about this radiopharmaceutical is it does decrease PSA. What we saw was that the 50% or greater PSA decline rate was seen in 46% of those receiving lutetium-177 PSMA-617 and 7.1% for the standard of care arm only. I think this is a really important point to bring up, that there are other agents in metastatic castration-resistant prostate cancer that we find are more niche drugs. When I say niche drugs, it means that smaller populations of patients receive it, and I think a lot of that has to do with PSA being a convincing mechanism to patients and providers. For instance, with agents like abiraterone and enzalutamide, clearly PSA declines. Those are agents that get used very widely. I think lutetium-177 PSMA-617 has that potential as well, since we noticed the survival benefit, radiographic progression-free survival benefit, and significant PSA decline.
One could argue that this patient population, in general, was heavily pretreated. They already had received 1 or more potent AR [androgen receptor]-targeted therapies, and they already received 1 or more prior chemotherapies. This was a very, very much a heavily pretreated population. They are patients that received abiraterone, enzalutamide, docetaxel, or cabazitaxel, so I do think this was a very heavily pretreated patient population.
Right now, the patients I would consider for lutetium-177 PSMA-617 targeted therapy are the patients who fit the VISION trial eligibility criteria. The key things are they are patients that have received prior AR-targeted therapy like abiraterone and enzalutamide, and received at least 1 prior taxane. In the future, there will be many clinical trials done that are in the prechemotherapy setting, and I think those will have interesting results. I think they hold a lot of promise, but we have yet to see it. The reason is that there are data that, as you march a little bit later into the disease—for instance, metastatic castration-resistant prostate cancer—generally, there is a higher PSMA expression on the prostate cancer cells. With that being said and done, we still do need to do the studies for earlier-stage disease. Right now, if and when the FDA approval comes—I will be surprised if it does not come reasonably soon—I am going to use it for patients who fit that label, which we have yet to see exactly. There are some unanswered questions. Will PET be mandated because most patients met the PET eligibility criteria at screening? Do we need to do PET scans? That is a very good question. In regard to the disease state, at least 1 prior AR-targeted therapy, at least 1 prior taxane chemotherapy, that is when I would use it.
This transcript has been edited for clarity.