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GU Cancers 2019 | Update on ARCHES trial: implications for prostate cancer treatment

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Andrew Armstrong

Andrew Armstrong, MD, of the Duke Cancer Institute, Durham, NC, presents an update on the ARCHES trial (NCT02677896), a trial of enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in patients with metastatic hormone sensitive prostate cancers. This interview was recorded at the 2019 Genitourinary Cancers Symposium, held in San Francisco, CA.

Transcript (edited for clarity):

… sure. The ARCHES trial addressed the major medical problem facing men who present with metastatic prostate cancer. These are men who tend to progress on hormone therapy alone within a few years and have a need for further systemic therapy to improve their outcomes. The ARCHES trial was a randomized phase III global study that tested the efficacy of Enzalutamide, first as ADT in this patient population. So, all men receive ADT, but half the patients, 1,150 of these men received Enzalutamide.

The types of patients in this study tended to have high-volume disease, 70%, Gleason 8 to 10, nearly 70%. De novo metastatic disease, about two-thirds. About one-third had relapse disease after surgery or irradiation. So, it’s fairly representative of a group of men who present with metastatic disease.

This study was positive, so good news for patients. Another option, which is Enzalutamide, demonstrated efficacy, its primary outcome, as well as key secondary outcomes. The primary objective of the study was called “radiographic progression-free survival.” That’s the time that a man has before his cancer worsens on bone scan or CT, or death. Whatever happens first is counted as an event. This trial met its primary endpoint, there is a substantial 60% improvement in the risk of that event over time. The result was so impressive that patients are being offered crossover, so that placebo patients can be offered a therapy that’s already known to improve survival in the castration-resistant settings. So, Enzalutamide is already established in the castration-resistant setting.

Our question is, “Does early use of Enzalutamide provide a clinical benefit?” The clear answer is there is clinical benefit. There’s a delay in the radiographic progression, there’s a substantial delay in PSA progression, castration resistance is delayed. The need for further therapies is substantially delayed, and quality of life is very high for these patients. Most of these men had minimal symptoms, and they maintained minimal symptoms through the lifetime of the followup that we have.

One caveat to ARCHES is that overall survival is still immature. There’s another study called ENZAMET, where overall survival is the primary endpoint, this is an Australian study, and that’s expected to report out in 2019. So, between these two studies, I think very shortly we’ll have very clear evidence from two randomized phase III studies demonstrating better outcomes for these patients.

Enzalutamide has a known side effect profile, it’s very well tolerated. There are concerns about fatigue, fall risk, fractures. We did not see any increased risk of seizures. We do see a higher risk of fatigue, but it’s mostly mild, and most of the time we can overcome this fatigue and risk of falls by encouraging men to exercise, stay fit, stay active. There is a risk of high blood pressure. We can minimize that risk by monitoring. Home blood pressure monitoring is something that I do in my practice to help men identify and then treat it, and that can largely prevent cardiovascular events that are known to occur from hormonal therapy.

While overall survival is immature, we did see a trend favoring Enzalutamide. We still only have 84 patients who have died in this study, and with crossover it’s going to be increasingly difficult to see on overall survival difference. Enzalutamide, as you know, is FDA-approved for all men when they progress, and it’s available fairly well globally as a treatment option. The challenge is showing overall survival when you have all these sequential therapies available to men.

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