Based on the assumption that Enzalutamide (Xtandi) is approved for use in men with castrate resistant metastatic prostate cancer (advanced prostate cancer or mCRPC) who have not had prior chemotherapy, pretty much a foregone conclusion based on the extraordinary phase III Prevail Trial results, including a statistically significant survival advantage of 2.2 months with a 30% reduction in the risk of death, hazard ratio = 0.70 (p=0.0001); 81% reduction in the risk of radiographic progression or death, hazard ratio = 0.19 (p=<0.0001). Since the trial was stopped early because it achieved statistical significance it never achieved a valid survival advantage median which will now remain in question forever.
Zytiga, the main competitor and already FDA approved in this space, also had excellent phase III results (AA-302). In the trial Zytiga showed a 5.2-month survival advantage, however it failed to be statistically significant, just showing a trend towards survival.
The question now is how do you compare the efficacy of these two drugs against the other, especially when they are in the exact same treatment space? Xtandi showed statistically significant median survival advantage of 2.2 months at the time the trial was halted. This survival advantage reached statistical significance along with a mind-blowing hazard ratio. On the other hand, Zytiga had a much larger median survival advantage of 5.2 months but it never reach statistical signifance!
My statistical gurus tell me that the real difference could be in the trial design, however at 30 months the placebo arms of both trials were similar. These gurus tend to agree with each other; the most important point is that the Xtandi trial achieved statistical significance while the Zytiga trial only trended toward significance, this gives Xtandi an efficacy edge.
To really understand the difference in efficacy we need a head to head study that will probably never happen. Without such a study we will be simply comparing apples to oranges, so we need to do the best we are able.
So, which is a better drug? It is not really clear, but Zytiga does require the addition of steroids, which Xtandi does not need. Also, the dosing schedule for Xtandi is much easier than the schedule for Zytiga. On the flip side, Zytiga is much cheaper than Xtandi; in today’s climate this offers an advantage for Zytiga.
My prediction is that doctors will love Xtandi over Zytiga. There is no need to take steroids, it is easier to take and the survival numbers were significant. However, Zytiga is less expensive than Xtandi, so the insurance companies will probably favor Zytiga.
The question that remains unclear is the actual survival advantage as they compare to each other. Next week at ASCO GU we should be seeing the PREVAIL survival curves where this question might be clarified. The question we are left with is in understanding the difference in median survival when the medians are not reached, an impossible task.
Joel T Nowak, M.A., M.S.W.