PREVAIL Trial Investigator Discusses Pre-Chemo Enzalutamide Indication

Last week, the FDA expanded the approval for enzalutamide (Xtandi) to include the treatment of men with chemotherapy-naive metastatic castration-resistant prostate cancer.

Tomasz M. Beer, MD

The treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) continues to evolve, with the recent FDA approval of pre-chemotherapy enzalutamide (Xtandi).This expanded indication was based on extensions in overall survival and radiographic progression-free survival experienced by patients in the phase III PREVAIL trial.

To gain further insight into the expanded approval of this agent, OncLive interviewed the co-principal investigator on this pivotal trial, Tomasz M. Beer, MD, the deputy director of the Knight Cancer Institute and professor of medicine at Oregon Health & Science University.

Could you discuss the results of the PREVAIL study?

Looking at what happens from enrollment to progression–I think this is the most interesting and most direct comparison–we saw an 81% improvement with enzalutamide. The progression in placebo-treated patients was less than 4 months and enzalutamide patients had not progressed at the time of this analysis, though subsequent looks suggest that it was 16-19 months. Chemotherapy-free survival was extended by a median of 17 months with enzalutamide.

The overall survival is a little harder to explain because we focus very much on medians. At the time of the analysis, more than two-thirds of the patients were still alive–we are not anywhere close to an actual median survival. The median follow up was 22 months and the median survival in the enzalutamide group was around 30 months, so there is another 8 months beyond the median follow up.

We therefore estimated the survival medians. The more robust calculation was the hazard ratio, which was 0.71, indicating a 29% improvement in the risk of death. If you look at the medians on the first analysis, it was 32 versus 30 months, which doesn’t sound like as much as one would expect. On a subsequent analysis, with an additional 4 months, the median actually could not be estimated because additional patients that were still alive contributed to the data. So, I think that the hazard ratio is the more accurate description of the overall survival advantage than the median.

How does enzalutamide stack up with abiraterone? How will enzalutamide be used in practice?

We don’t really know how these drugs stack up. There has been no direct comparison of these two drugs, so it is not entirely fair to draw conclusions across studies. I wouldn’t feel comfortable looking at things like the hazard ratio in studies of abiraterone and enzalutamide and say one is better than the other. No one can validly say that.

I do think there are some differences that are worth pointing out in how patients were selected for the two studies because that impacts on how a clinician might treat a patient.

In the PREVAIL study, we allowed patients with visceral metastases to enroll. We saw a good level of drug activity in those patients. In the comparable abiraterone study, those patients were excluded. At that time, it was the thought that perhaps these patients should go directly to chemotherapy. When considering the treatment of patients with visceral metastases, enzalutamide is the only drug that has actually been studied pre-chemo in that population.

Similarly, the PREVAIL trial had somewhat less stringent restrictions on cardiac conditions. There are certain patients whereby virtue of who was allowed in the studies, you would select enzalutamide instead of abiraterone–not necessarily because one is better than the other, but because, for that subset of patients, it is the only appropriate drug.

Conversely, people with a seizure disorder were excluded from the PREVAIL trial and so anybody who has that history should receive abiraterone rather than enzalutamide.

If you get past these subtle differences between the studies, I think physicians are going to be making decisions with their patients, one patient at a time. I cannot imagine that the practice guidelines would recommend one drug over the other; I think they will both be recommended–they both have positive phase III trials and they are both good drugs.

Is there an opportunity to combine enzalutamide with chemotherapy?

Yes, there are many clinical trials now looking at combination. Trials are looking at enzalutamide in combination with any number of things: from abiraterone to immunotherapeutic agents to chemotherapeutic agents. The results of AFFIRM and PREVAIL studies suggest a high level of activity and a good tolerability profile–with few toxicities that would overlap with chemotherapy toxicities. Enzalutamide is both active and friendly for combination therapy.

What are the next steps for enzalutamide?

To me, the first question that should be answered is: What is the best place to use this drug so that we can provide patients the most benefit? We know it is useful in metastatic patients or castration-resistant: first post-chemo, now pre-chemo. But we have not yet determined if using it earlier will have an even bigger impact. Research needs to be done looking at patients with castration-resistant disease, a rising PSA, but no metastases. We also need to look in the context of frontline hormonal therapy: either for metastatic disease or as an adjuvant treatment with radiation. It would be very interesting to see if this drug makes things better.

Research also needs to be conducted looking at enzalutamide in combination with other agents, which I’ve already alluded to.

The third area, which we are very interested in, is trying to understand the biologic mechanisms of excellent responses at the cancer level and also of resistance and progression. With this information, we could co-target those mechanisms in a rational way–combinations of agents based on understanding the individual patient’s cancer biology and drug selection.

Right now, we are just making a global judgment about the data and doing a little bit of patient selection based on study design. Wouldn’t it be wonderful to have an easy test that identifies the mechanism of androgen signaling and activation in a particular patient’s cancer and whether or not they would benefit more from one agent or a combination? This would allow clinicians to personalize the approach to this new generation of hormonal therapies.