Dr. Sartor: It's a pleasure for me to be able to cover the Presidential Session that presented PSMAfore, which is a new trial for taxane-naïve metastatic CRPC. So, basically what PSMAfore looked at were patients who had previously received both ADT and an ARPI, and the ARPI was typically going to be either abiraterone or enzalutamide, but no prior taxane. The randomization in this phase III trial was between PSMA-617–lutetium-177 — and I'm going to call that lutetium —and an alternative hormonal therapy, ARPI, which was abiraterone or enzalutamide. I'm just going to call that the hormonal therapy arm.
Now, the primary endpoint was radiographic progression–free survival, and this was determined by blinded independent central review. Very importantly, if you were on the hormonal arm and hit the endpoint of RPFS by blinded review, you could cross over. And I'm going to tell you right offhand that 84% of the patients who were eligible for crossover, actually did cross over. So, there was a huge number of crossover patients in this randomized trial.
Now, lutetium was given in the usual manner, every 6 weeks using 7.4 GBq, the same dose that was used in the VISION trial. I might also add that all the patients were PSMA PET–selected, in order to ensure that they had PSMA PET–positive metastatic disease.
Efficacy endpoints overall were solidly positive
Okay, enough on the background. What did they find? Number one: RPFS, the primary endpoint, was substantially improved. In a primary analysis presented prior to ESMO, the hazard ratio was 0.41. At the more mature analysis presented at ESMO, the hazard ratio was 0.43. Tight confidence intervals did not overlap 1.
The median in the hormonal arm was 5.59 months for time to radiographic progression, and it was 12.02 months in the lutetium arm. There were also a variety of secondary endpoints, things like objective response rate as measured by RECIST. In the lutetium arm, that was slightly over 50%. In addition, things like PSA decline. A 50% PSA decline or better was found in 57% of lutetium-treated patients. There were health-related quality-of-life and pain-related endpoints that were also better with lutetium, and these were unequivocally positive in time to deterioration.
In addition, skeletal-related events were better again in the lutetium arm. In a prespecified analysis of overall survival, using a crossover adjustment, the hazard ratio was 0.8. Not statistically significant because the confidence intervals overlapped 1, but nevertheless trending in the right direction.
The intent-to-treat overall survival was 1.16. Confidence intervals were large, and that's because not all of the patients have met the endpoint of death. What I'll simply say is that the efficacy endpoints were solidly positive when taken in their totality.
Adverse events lower in the lutetium arm
But what about adverse events? What about other parameters that we look at in trials? I'll simply say that the grade 3/4 adverse events were less in the lutetium arm. The serious adverse events were less in the lutetium arm. The discontinuation from treatment was the same in the lutetium arm and the hormonal arm, both at about 5%.
Yes, there were some grade 1 adverse events in the lutetium arm that were notable: dry mouth, some GI side effects, and some anemia. But, remember, the grade 3/4 AEs and the SAEs were both less in the lutetium as compared to the hormonal arm.
All in all, encouraging results
In totality, the RPFS, the primary endpoint for PSMAfore, was strongly positive for patients with metastatic CRPC who were taxane-naïve. The secondary endpoints were positive, but the overall survival is still going to have confidence intervals overlapping 1, and, remember, the crossover of 84%. Adverse events favor lutetium.
All in all, I think this is a very nice data set to support the use of lutetium earlier than what the VISION trial currently supports. But, of course, the FDA and other regulators will be making the decision appropriately for when this type of therapy actually moves into standard of care.