David Quinn, MD, Genitourinary Medical Oncologist, USC Norris Comprehensive Cancer Center, Los Angeles, California, discusses the significant outcome of the phase 3 ENZAMET clinical trial evaluating enzalutamide as first-line treatment for men with metastatic prostate cancer.

Transcript

Hi, I'm David Quinn. I'm a genitourinary medical oncologist at the University of Southern California Norris Comprehensive Cancer Center, where I'm also the Medical Director for the USC Norris Hospital and Clinics.

We wanted to talk today about the ENZAMET study, which was a trial conducted and led by the ANZUP group based in Australia and New Zealand but with contributors from various parts of the rest of the world, which looked at early metastatic prostate cancer which had not been treated with hormonal therapy.

The patients in this study there were 1125 of them randomized received standard of care therapy, which was either testosterone suppression, typically with LHRH injections, and in addition docetaxel where appropriate, and were randomized to either get enzalutamide, a newer pill which inhibits the androgen receptor, or some older pills which are less active against the androgen receptor but were a standard of care.

This study was conducted and accrued in less than 3 years, actually ahead of time, and tested the new paradigm of the pill enzalutamide to improve overall survival. The arms were compared and followed, and the data presented at ASCO 2019 and published in the New England Journal of Medicine.

Concurrently, were mature at the time of the first interim analysis, which was undertaken about 3 months before the ASCO meeting in March of 2019. What the results show is that there is a significant overall survival advantage to the addition of enzalutamide to the standard of care therapy, whether that be androgen deprivation or with the addition of docetaxel.

That was significant. The hazard ratio was 0.67, meaning a 33% reduction in the hazard of death in the patient population. There were some things that were significant about these results.

That was that patients appeared to benefit whether they had a high-risk metastatic pattern with more metastases or with a pattern of metastases that we know is associated with a poor risk, but also in a low risk pattern.

Previous studies with docetaxel and abiraterone had shown distinct improvement in the high-risk group, with lesser effect or no effect in the low risk group, meaning that there was only a select group of patients that might receive docetaxel and abiraterone in that context. In that case, it would be docetaxel or abiraterone.

What we've seen here is that enzalutamide has an effect across those groups of patients. It was broadly applicable and, from that perspective, can be given to a large range of patients.

This is a significant advance and follows up on the early presentation of the ARCHES trial, which looked at enzalutamide versus no treatment in a slightly different group of patients and reported a progression free survival end point but was not mature for overall survival when presented at GU ASCO in 2019. This is interesting.

In this context, does enzalutamide have any side effects? We're used to the side effects of enzalutamide in our patients because we've given it now for more than 5 years in the later castration resistant group, where it's a standard therapy and demonstrates a survival advantage both after docetaxel and before docetaxel. That led to its approval by the FDA and in other parts of the world.

The side effects that we were looking at relate to fatigue, high blood pressure, rate of falls, and also seizure activity, which have been reported in a small number of patients in some of these prior trials.

What we saw was that these side effects were an issue when you added enzalutamide. For example, some 1% of patients given enzalutamide did experience a seizure even though patients at risk of seizures were excluded. We didn't see that in the control arm. Whilst there's an overall benefit, there are some side effects that need to be managed.

Did everyone benefit from having docetaxel when they were given it, which was about just over half of patients in this trial? That had become a new standard for patients in this setting just before the trial launched.

Most patients were given that potentially as a standard of care if they and their treating oncologist thought it was appropriate. Interestingly, when we looked at the patients that were given docetaxel therapy, they did not appear to benefit from the addition of enzalutamide.

There's an interaction effect here.

In this study, if they got docetaxel, they completed their 6 cycles of therapy before they went on to study treatment, before they were randomized in fact. They were stratified for docetaxel. At this stage, it suggests that giving both therapies, chemotherapy and a hormonal pill, may not be the best thing to do. This will be looked at in several more studies to come.

Are there other drugs in this area that we've seen approved? I mentioned docetaxel and abiraterone. We'd seen data from apalutamide from the TITAN study that showed an advantage with a similar hazard ratio.

Interestingly, if we look at all of these agents in this setting, they all appear to have a similar level of reduction of hazard of death, about 33% or so, give or take a few percentage points. The issue of choice will be based on the particular patient and how they fit with the side effect profile of the prospective drug and also the financial factors in delivering those drugs.