The Role of Apalutamide in Patients with Metastatic Castration-Sensitive Prostate Cancer - Episode 2
Drs Agarwal and Chowdhury analyze the survival data from the phase 3 TITAN study of apalutamide in men with mCSPC.
Simon Chowdhury, MD: This is the analysis we’re talking about, and this is looking at overall survival. I’ll be very interested in Neeraj’s opinion here. One of the things that always strikes me here is what the placebo arm is doing. We try to keep studies as broad as possible, but studies do have selection bias and the youngest, fittest patients. But we can see here that in men who are treated with ADT [androgen deprivation therapy] alone, and as Neeraj eloquently said, go on to have active therapies, the overall survival is 52 months. That isn’t lung cancer, but that’s less than 5 years. These are young, fit men whose normal life expectancy would’ve been significantly longer than that. With apalutamide, we can see the curves come apart early and stay apart. We can see a hazard ratio of 0.65.
Neeraj, myself, the statisticians, were very involved in this inverse probability sensory weighting analysis, which you can see in figure B. That basically estimates overall survival, allowing for those 40% who crossed over. You have 3 patient [groups] here. You have the intention-to-treat population, the apalutamide—that’s relatively straightforward—plus ADT, and the placebo group. In that placebo group, some of the patients will have progressed, but a lot of the patients will have then crossed over, as Neeraj said. That weighting is very important. You can see that the hazard ratio comes down to 0.52. This shows they’re very active therapies.
For me, these slides say ADT alone isn’t enough. This is a lethal illness, and apalutamide is a very active drug, and we need to think about implementing this to benefit as many men as possible with this lethal disease. I don’t know if I’ve missed anything there, Neeraj. You often have to explain this to me. Is there anything about the weighting?
Neeraj Agarwal, MD: You’re very kind. I’ll just summarize. This was also the main point of a paper we published in the Journal of Clinical Oncology in 2021—how to account for patients who were on placebo and then crossed over to the apalutamide arm, and how to take that into account when we’re looking for overall survival benefit with apalutamide. Simon, you said it so nicely. The bottom line is that if you take into account those 40% of patients who were in the placebo arm and crossed over to apalutamide, the hazard ratio improves from 0.65 to 0.52. With a 33% reduction in risk of death with apalutamide, the risk of death further decreases to 50% with apalutamide when we adjust for this crossover of patients in the placebo arm to the apalutamide arm. These are very powerful and clinically meaningful data.
Simon Chowdhury, MD: That’s it, clinically meaningful. In some studies in other diseases, we see small benefits. And we know that when we go into the clinic, even with clinicians as skilled as Neeraj and his team at the Huntsman Cancer Institute, there’s a decrease in efficacy and increase in toxicity. But even if there’s a decrease in efficacy in the real world, this is still a very large benefit.
We’ll move on to the next slide because some of these points are here. This is looking at the forest plot. I’ll bring out a couple of things and then I’ll get Neeraj’s thoughts on it. One of the big things that comes out to me here is the volume. There’s a lot of talk about volume being prognostic. This is volume looking at number of metastases, typically 4 with 1 outside the axial skeleton, as per the CHAARTED criteria. The definition was slightly different in the TITAN trial. I’ve never understood how the number of metastases on a conventional imaging with bone scan and CT scan is going to predict the biological response to a treatment, particularly active treatment like apalutamide. For me, disease volume is prognostic; it’s certainly not predictive. We can see here that the hazard ratio is better with patients with low-volume disease. It takes longer to get there, but we see that difference there. That’s one of the ones I wanted to pick out. I don’t know if Neeraj had any thoughts on that or any other bits that strike him from these data.
Neeraj Agarwal, MD: As you said, the message I’m getting from this slide is that almost all subgroups seem to be benefiting. I don’t want to take too much out of this slide, because these are subsets of this large patient population of 1052 patients who were randomized on the TITAN trial. If we start dissecting into various subgroups, the patient numbers are smaller, and the trials weren’t powered for age groups of younger than 65, or 65 to 74, or older than 74. The general message here is that all patients seem to be benefiting, whether they had high-volume disease or low-volume disease, whether they had de novo metastasis or non–de novo metastasis, and whether they were younger patients or older patients. That’s the overall message I take from this slide.
Simon Chowdhury, MD: I completely agree. You very eloquently brought that out. And you’re right: I’ve been cherry-picking some of the statistics there, but you, a more pure academic, rightly called me on that.
Transcript edited for clarity.