Enzalutamide improves survival for men with metastatic hormone-sensitive prostate cancer

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Published: 2 Jun 2019
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Dr Christopher Sweeney - Dana-Farber Cancer Institute, Boston, USA

Dr Christopher Sweeney presents results at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting from the ENZAMET trial.

This was a phase III internationally randomised trial in which patients with mHSPC who received testosterone suppression were also given enzalutamide or standard nonsteroidal androgen receptor inhibitors, with those receiving enzalutamide surviving longer after 3 years (80% to 72%).

Watch the interview here.

Watch a comment from Dr Neeraj Agarwal here.


First of all I’d like to just emphasise that this trial called ENZAMET is an academic global collaborative trial and there are some differences from the study that was presented on Friday with a similar drug, apalutamide. One is that this is academic and there are some differences in the designs that come from it being an academic study where we had some more flexibility to respond to the changes in treatment that were occurring. I’d also like to say that this is a wonderful collaboration between the Clinical Trials Centre based in Australia, the Canadian Cancer Trails Group, CCTG, Cancer Trials Ireland and the Dana-Farber Cancer Institute and it was led by a new co-operative group out of Australia called ANZUP. I’m an ANZUP member as well but based in Boston and I have the huge honour of presenting the results on behalf of Ian Davis, the study co-chair who is with us, and the co-authors.

By way of background, until 2014 testosterone suppression plus or minus the standard antiandrogens was the only therapy. We knew patients with a higher burden of disease had a shorter overall survival and that was the state of affairs for about 70 years. Improvements in outcome for hormone sensitive prostate cancer emerged with the use of agents that were active in castration resistant disease, when cancers were growing with a low testosterone, with agents like docetaxel. In 2014 we presented the results of the CHAARTED study then and in 2017 we learned about the results of the hormone abiraterone that also improved the survival of men when used in the hormone sensitive setting.

Enzalutamide is a potent direct androgen receptor inhibitor, so another type of hormonal therapy. Again it has been shown to work in men with castration resistant disease, namely disease growing despite low testosterone. At GU ASCO we learned that enzalutamide delayed the time to progression as measured by changes on scans and this study allowed patients to have had prior docetaxel based on the CHAARTED data, the study was called ARCHES.

Janssen Pharmaceutical company had the results presented at ASCO on Friday of apalutamide showing that it prolonged progression free survival and overall survival and, again, it allowed prior docetaxel.

ENZAMET is the first trial to present the overall survival results of enzalutamide plus testosterone suppression and the outcomes if patients also received concurrent docetaxel. There’s the key difference that I want to highlight. The design was quite simple, it was testosterone suppression alone with the non-steroidal. So the other differentiating factor is that we actually put in the weaker antiandrogens which were the standard, not a placebo but the actual standard of care which has some activity, and compared that to testosterone suppression plus full dose more potent androgen receptor inhibition. We stratified patients by their volume of disease, good prognosis versus poorer prognosis, planned use of the daily docetaxel concurrent with the enzalutamide, performance status and use of agents like denosumab and zoledronic acid and how fit a patient was, their comorbidity scores.

Notably, the patient population was representative of prostate cancer in terms of age – 69 years. Notably this was a global study with most of the accrual coming out of Australia and New Zealand with 60% of patients, Canada with about 20%, the UK and Ireland with about 17% and the United States as represented by just one institution, Dana-Farber, at about 4%.

Notably we had about 45% of patients received concurrent docetaxel which differentiates itself greatly in terms of not only being concurrent but the frequency of use of docetaxel, recognising that some patients’ standard of care is testosterone suppression alone. In about half the patients testosterone suppression with the docetaxel is the standard of care, depending on a patient’s chemo-fitness and how much cancer they have in their prognosis. We also note that half the patients had a poor prognosis with a greater burden of metastases, namely four or more bony metastases. Visceral metastases is what high volume is defined as.

The highlight is that we actually saw at the first interim analysis, so this the first look, and we were told to report these results early because there was a survival benefit already seen after half the information was received. The first thing to note is that there was a 33% decrease in the rate of death, the hazard ratio of 0.67, it was statistically significant at the level to say that we should report the results at the interim analysis so it was a very stable result. But in absolute terms for the overall group it meant that there was an increase of percentage of patients alive at three years, is an easier way to reference this, going from 72% to 80%.

What we did note also is that the therapy significantly delayed the time to PSA rise on therapy or clinical progression or death. Then when we took out the variable of PSA rise we noted that there was also a longer time to clinical progression, independent of the blood test, namely worsening changes on images, symptoms or signs that the patients experience from their progressive cancer. Both of them had a hazard ratio of about 0.394, meaning there was a 60% decreased rate of progression at any one time.

When we brought this study out, and this is where the long conversation is going to be, we saw that when docetaxel was added to the testosterone suppression there was again a significant improvement or delay in the time to progression, as seen in the top left curve, but the top right curve we actually do not see a significant treatment effect on overall survival at this early analysis with a hazard ratio of 0.9. So that’s the first information that we, as the investigators, will have to think through as to what treatment to give our patients if they’ve had docetaxel. However, two things, most of those patients who got docetaxel had the high volume, were the poor prognosis patients who do benefit from the early docetaxel. On the other hand, men who did not have the docetaxel there was a significant delay in the time to progression, again with a hazard ratio of about 0.66, 66% decreased rate of progression, but the overall survival benefit was quite marked with a 47% decreased rate of death in those patients. Mostly these patients were the low volume, good prognosis patients where we have not seen benefit from the early docetaxel.

Side effects is a very real factor when we compare not only the treatment benefit but what is the cost in terms of adverse events. Enzalutamide has got some associated fatigue, hypertension and some men have some frailty in the 5% range which may make them have some falls and be a little bit frail. We as physicians have to say are the patients fit enough, even for the hormone enzalutamide and there are some side effects and concentration impairment that we need to be counselling our patients about the risks.

So the overall conclusion is early enzalutamide substantially improved the time to progression and overall survival when added to metastatic hormone sensitive therapy, be it testosterone suppression alone or with docetaxel. The clinical interpretation is enzalutamide added to testosterone suppression represents an appropriate option for men with metastatic prostate cancer commencing testosterone suppression. The benefit is clear in both low and high volume patients which distinguishes what we know with docetaxel. There is a delay in progression with improvement in overall survival but there is toxicity. What I didn’t show here but will show in the presentation is that the enzalutamide actually increased the docetaxel related toxicity that needs to be reconciled.

We do plan to do quality of life analyses and we may actually see that there’s a benefit from adding enzalutamide to the docetaxel if there’s a meaningful quality of life improvement or longer follow-up actually shows that there’s an improved survival over three years. I thank everyone for their attention and highlight again this wonderful academic global collaboration that I had the honour to be a part of.