The basis of ARCHES was to provide better outcomes for men who have metastatic hormone sensitive prostate cancer. These are men who present after either prostatectomy or radiation with a relapse in metastatic disease or they present de novo with metastatic prostate cancer with no opportunity for local therapy. These men tend to progress within 1-3 years after hormones and there’s an unmet need to improve their outcomes with these novel hormonal therapies. ARCHES was a phase III global randomised study testing whether enzalutamide could delay progression or death in these patients, that was the primary endpoint. 1,150 men were enrolled to test this.
What did you find?
The primary endpoint was met after about 262 events; there was a major difference between the two groups. There was a hazard ratio of 0.39 with a p-value of less than 0.0001, so that’s a 61% improvement in the hazard of death or progression, that’s a major difference. There are also substantial delays in PSA progression, castration resistance, time to next therapy, maintenance of a very high quality of life consistent with being basically asymptomatic in both groups, which is great. The safety profile is very well known for enzalutamide, it’s been on the market and available globally for many years. We didn’t see any new safety findings; we saw very rare seizures, for example two in each group, no increased risk over placebo. The safety profile of enzalutamide requires attention to fatigue, high blood pressure, fall risk, particularly in men over the age of 75 risk of fracture because of that. So it’s important in these men to consider calcium, vitamin D, exercise, home blood pressure monitoring, cardiac risk reduction strategies to make sure these men don’t have other complications. But we did not see any increased risk of death from side effects; there was a very low discontinuation rate because of side effects, very similar to placebo.
In conclusion it was a very positive study. It met all of its primary and secondary endpoints. The one endpoint that we’re still waiting on is overall survival. As you know, these men are living longer and longer, there’s the availability of enzalutamide itself for men when they progress on placebo. We are now offering crossover therapy as part of an open label extension phase of the ARCHES trial so that all men who are treated with placebo can be offered effective therapy to further delay their risk of progression. So we expect overall survival to be improved but it may take several years to determine that. So that will be a key secondary event when about 342 deaths have been reported, we expect that in two or three years or so.
Some of the key subsets of ARCHES can inform your practice today. So if you have a patient with high volume prostate cancer you’re treating them with ADT and docetaxel right now. You may now look at our subset of 20% of patients who received prior docetaxel and in that subset there is a 50% further delay in the risk of metastatic progression or death, suggesting that maybe triple therapy for these high volume patients with both docetaxel and a potent AR inhibitor such as enzalutamide may be an optimal strategy for these high volume patients. For low volume patients where there are no clear benefits of docetaxel enzalutamide has a substantial delay in the risk of progression or death over time and is a reasonable treatment option and standard option for these patients.
