Enzalutamide–ADT Combo significantly Improves PFS in Metastatic Hormone-Sensitive Prostate Cancer

In a recent interview with Oncology Learning Network, Andrew J. Armstrong, MD, Professor of Medicine, Duke Cancer Institute, Durham, North Carolina, discussed the findings and clinical significance of a recent study that he and his team of co-investigators conducted comparing the use of androgen-deprivation therapy (ADT) plus enzalutamide with ADT alone in patients with metastatic hormone-sensitive prostate cancer (HSPC).

Transcript:

I'm Dr Andrew Armstrong, I'm a professor of medicine at the Duke Cancer Institute in our Center for Prostate and Urologic Cancers. I'm a medical oncologist. At the ASCO GU Symposium this past week, I presented data from the phase 3 ARCHES trial, which is a randomized global study of men who had metastatic HSPC.

The ARCHES trial comes in at a time when many clinical studies are demonstrating improvements in outcome in the setting, include docetaxel, abiraterone, and even radiation to the primary, even in the face of metastatic disease.

Men are living longer, they're living better, and they're having opportunities for more effective therapy than standard ADT alone. It's in this context that we designed and conducted the ARCHES trial.

The ARCHES trial enrolled men who had metastatic disease, most of whom of these 1150 men, most of whom had what we call high volume disease, but about a third had low volume disease as defined the ECOG chartered criteria.

Low-volume generally means no visceral metastases, and a small number of bone metastases, or lymph node–only disease. We also permitted men to have received prior docetaxel since this was a life-prolonging therapy that was known at the time that ARCHES was designed and conducted. At the time we conducted the study the data around abiraterone was not available, so this was really a randomized study of ADT alone, plus or minus enzalutamide, a potent AR-inhibitor. About 20% of men had prior docetaxel, up to 6 cycles in the hormone-sensitive disease state.

This is really the first study to ask the question, “Can potent AR inhibition provide a further benefit to these men who have already had the best standard of care, which is ADT and docetaxel, as one of these life-prolonging options?”

So, the overview of the study—this was, again, a global study, this was conducted in North America, Asia, Europe, and had good representation by race, ethnicity, and global representation. Again, 20% of men had prior docetaxel, >60% were high-volume, a significant fraction were also low-volume.

These are all prespecified subgroups, to look at the efficacy of enzalutamide, the primary end point of ARCHES is called radiographic progression-free survival (PFS). This is the time that a man has before he develops progressive disease on imaging, either soft tissue or bone scan, or death.

Secondary end points that were critical to determine the efficacy were overall survival (OS), time to PSA progression, time to castration resistance, quality of life (QoL) end points, safety, and the time to next therapy. All of these end points were measured, and at the GU Symposium I particularly presented the primary end point that was positive.

The DSMB reviewed this data, recommended that the study be unblinded, and that men be offered the active therapy with enzalutamide based on the strong efficacy signals that were observed for this primary end point.

The radiographic PFS was improved by 61% with a very significant P <.0001. The hazard ratio of .39 was a substantial benefit, very similar to latitude with abiraterone, even though you can't really do a cross-trial comparison.

We know that reducing the chance of progression or death over time generally has translated into a survival advantage, and we would anticipate that ARCHES would show a survival advantage over time. At this point only 84 men have died, and because men on the placebo group are being offered crossover (we felt it was our ethical obligation to do so) they are receiving the benefits now of open-label extension of the enzalutamide itself to improve their outcomes.

Important takeaway messages from ARCHES are, number 1, there is a substantial benefit overall, both irrespective of the subgroup of patients, so regardless of disease volume, prior docetaxel, age, functional status, pattern of spread. There was pretty universal benefit with enzalutamide. In fact, there was a 70% delay in progression in the low-volume subset, and a 50% delay in PFS in the prior docetaxel subset, which was mostly high-volume patients.

The toxicities were as expected, enzalutamide has been on the market and used by many men globally now, and we understand that there are some notable increases in fatigue, high blood pressure, that's quite manageable, usually grade 1 and 2. We see a slightly higher risk of falls. We see a very high level of quality of life overall, despite some of these hormonal side effects.

We see that most men in the ARCHES study started off asymptomatic, despite a large number of metastatic sites, and maintained that asymptomatic state through about 14.5 months of follow up. These men are doing very well, they're remaining progression-free.

Another key end point of this study was response rate. These men have metastatic disease on imaging when they're entering the study, and their PSAs largely are still detectable. We see that a significantly higher number of men achieve a complete remission on imaging, and a complete response by PSA, that's an undetectable PSA.

If you're interested in seeing some of the details, the slides and data are on the GU Symposium virtual meeting, and you can see the Kaplan-Meier plots and some of the secondary outcomes as well as initial quality of life data.

We will anticipate future meetings to have more time to present the quality of life data, data on skeletal events, subgroups of important groups of men including prior docetaxel. Then, of course, OS which we would anticipate to come in the coming years.

The implications of this study are immediate, so you may consider enzalutamide as an option pending, of course, FDA approval and insurance authorization. Particularly for men who have had docetaxel, for men who want to consider an alternative to abiraterone, where we anticipate this delay in progression may lead to an OS advantage. Certainly, we have other studies that are coming that in 2019 we'll likely hear about.

This includes the TITAN study of apalutamide which is very similar. We have the ENZUMET study which another Australian but large phase 3 study powered around OS as a primary end point, testing enzalutamide with docetaxel much more integrated into the treatment algorithm. These results are good news for patients. We anticipate more good news for patients as the year progresses as more data is revealed.

Very soon we'll be faced with many treatment choices, and largely we'll be looking at these studies to help inform on those treatment choices and individualizing the care of these men to pick the right therapy or sequence of therapies for these men, usually based on their volume and risk of disease.