Testosterone suppression with docetaxel, the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC), was combined with chemotherapy or enzalutamide (Xtandi) to assess the potential improvement in overall survival compared with non-steroidal anti-androgens like bicalutamide, nilutamide, and flutamide in the phase III ENZAMET trial. <br />
Christopher Sweeney, MBBS
Testosterone suppression with docetaxel, the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC), was combined with chemotherapy or enzalutamide (Xtandi) to assess the potential improvement in overall survival compared with non-steroidal anti-androgens like bicalutamide, nilutamide, and flutamide in thephase III ENZAMET trial.1,2
In the trial, patients were randomized to receive testosterone suppression plus either enzalutamide or a non-steroidal anti-androgen, based on the volume of disease, the planned administering of early docetaxel, planned anti-resorptive therapy, and the existence of comorbidities.
In the testosterone suppression plus enzalutamide arm, 297 of the 562 patients had high-volume metastatic disease, and 265 had low volume. About 143 patients presented with severe comorbidities. More than half of the arm (59%) had planned other prostate cancer-related therapies, such as androgen deprivation therapy or treatment for skeletal-related events.3
The 563 subjects who received testosterone suppression plus a non-steroidal anti-androgen showed 291 cases of high-volume disease (272 low volume), and 141 patients had severe comorbidities. Also, 62% of subjects in this arm were receiving other planned prostate cancer-related therapies.
With enzalutamide, the risk of death was reduced by 33% (HR, 0.67; 95% CI, 0.52-0.86;P= .002), as of the interim analysis. The 3-year overall survival rate was 72% in the non-steroidal anti-androgen group and 80% in the enzalutamide group. The time to clinical progression or prostate-specific antigen increase was also improved with the use of enzalutamide. These data show that when enzalutamide is added to the standard of care, overall survival can improve in patients with mHSPC.
Christopher Sweeney, MBBS, medical oncologist, Dana-Farber Cancer Institute, and Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) member, reviewed the background and findings of the ENZAMET trial, and discussed the ongoing quality-of-life analysis for patients in the trial, in an interview withTargeted Oncology.
TARGETED ONCOLOGY:Can you explain the design of the EZAMET trial and the purpose for it?
SWEENEY:This is a study in the mHSPC setting. And it's asking the question of whether enzalutamide, which we know improved the survival of men with castration-resistant disease, to see if it is more effective if we give it when starting hormonal therapytestosterone suppression. We also know that in the hormone-sensitive setting, patients with high-volume disease also benefit from getting docetaxel. That result came out from the CHAARTED study not too long after we actually wrote, designed, and activated the ENZAMET study.
So, we quickly activated an amendment that allowed patients to get docetaxel based on physician and patient choice. The patient could either get testosterone suppression with a standard non-steroidal as an active controlbicalutamide, nilutamide, flutamide—or enzalutamide, and then they were stratified by whether [or not] they got docetaxel. What ultimately happened is about 50% of the patients got docetaxel, and that was mostly in patients who have a high volume of disease, and 50% of the patients didn't.
TARGETED ONCOLOGY: What were the findings from the ENZAMET study?
We also noted that about 50% of the patients had low-volume disease, and less of them got docetaxel. Half of them got enzalutamide and half got the non-steroidal, standard antiandrogen. What we saw is that enzalutamide improved the overall survival in both patients with a high volume and low volume of disease. We also saw that patients had a longer time to progression. Then when we drilled into the data, we found something that was a little intriguing and requires us to do more work.
The study was very positive such that we got the readout early from the interim analysis, and we need longer follow-up. But, what we see is that although early enzalutamide prolonged the time to progression of those who got docetaxel, we don't see a big treatment effect yet in those who had prior docetaxel. Hopefully, we'll see that soon with longer follow-up.
So, it's possible that you can do sequential therapy as long as they get docetaxel and a drug like enzalutamide at some stage. On the other hand, patients who did not get docetaxel had a clear improvement in time to progression and a significant improvement in overall survivala very clear treatment effect. What's notable is, unlike with docetaxel in CHAARTED where we didn't see a benefit in the low-volume subgroup, we see a very clear improvement from about 82% at 3 years to 90% survival in patients with low volume who got enzalutamide. We also know that about 60% of patients are still on [the] study drug at the 3-year mark.
We've got a lot of work to do. We need longer follow-up. But, it is possible [that] we will see that adding enzalutamide to docetaxel will have a clinical benefit. We can't say that yet because we have to do the quality-of-life analysis to see if delaying progression improves the patient's quality of life. There were some extra [adverse] effects with adding the enzalutamide to docetaxel. We also need the longer follow-up to see if [these findings] translate into longer survival. By that, hopefully, patients who have a longer time to progression, then get other agents, which compounds the early cancer control and results in longer survival. We haven't seen this yet [in the] early analysis.
TARGETED ONCOLOGY: Based on the study data, how safe is it to prescribe standard-of-care therapy with or without enzalutamide in patients with mHSPC?
It's very important when we counsel patients on the efficacy benefits that we see [that we also explain] the [adverse] effects we have to be aware of. We noticed that there was the same degree of enzalutamide associated [adverse] effects that we expect. There is some fatigue. There is also some increased concentration impairment and some falls and syncope. There's about a 5% incidence of that. It's low, but it's more than we saw with those that just got the standard non-steroidal. So, that's something we need to be careful about.
The other thing that we noted was a 1% incidence of seizures despite excluding patients who had a predisposition to seizures. [Another] interesting thing is we saw enzalutamide increased some of the [adverse] effects of docetaxel. There was the same rate of neutropenic fever, but the other quality of life impairing adverse effects that we noted was that there was more grade 2 sensory neuropathy at about the 9% range, whereas there was only 3% with the standard non-steroidal. We also saw increases in eye tearing and nail discoloration[adverse] effects that we have learned to [expect] with docetaxel, and enzalutamide did seem to increase their frequency. [We need to counsel patients about this.
TARGETED ONCOLOGY: Can you provide the details on the quality-of-life analysis?
[We are staying tuned for the quality-of-life analysis]. The ANZUP team who worked with the clinical trial center based in Sydney, [Australia], has done an amazing job of getting these data out and getting the publication within 3 months of the interim analysis.2[This is] unheard of. We focused on the efficacy endpoints and adverse events.
Our next thrust of work is to focus on the quality of life analysis because it is important for us to describe the total patient experience.
TARGETED ONCOLOGY: What can community oncologist take away from these data?
I would like to share my approach. [When] patients come and see me to talk about therapy for mHSPC. I will look at their risk category. Are they high volume or are they low volume? Are they fit enough for chemotherapy? Then I'll lay out the opportunities; the options are hormones and docetaxel, hormones and enzalutamide, or abiraterone acetate (Zytiga) or apalutamide (Erleada). Then [I'll] have them make a choice if they’re high volume and chemotherapy fit based on the different adverse effect profiles.
There are some issues with being on enzalutamide for 3 years or longer. In some cases, you can get the docetaxel out of the way, and maybe we add the other agents on at progressionuntil we find out there's a clear benefit for doing it all concurrently. It's to be determined. [My recommendation is passing it out that way]. Otherwise, if they're not chemotherapy fit and high volume, or not chemotherapy fit and low volume—the testosterone suppression plus or minus abiraterone, enzalutamide, or apalutamide are all very good choices for those low volume and not chemotherapy-fit patients.