Enzalutamide Could Have Pivotal Role in Metastatic Hormone-Sensitive Prostate Cancer

Christopher J. Sweeney, MBBS

Results of the ENZAMET trial showed that enzalutamide (Xtandi) significantly improved overall survival (OS) when added to the standard of care for patients with metastatic hormone-sensitive prostate cancer, although the benefits were lower for those slated to receive early docetaxel, explained Christopher Sweeney, MBBS.

In the phase III study, investigators randomized 1125 patients to receive testosterone suppression plus either enzalutamide or a nonsteroidal antiandrogen, such as bicalutamide (Casodex), nilutamide (Nilandron), or flutamide (Eulexin).

Interim findings showed that the 3-year OS rate was 80% in patients with metastatic hormone-sensitive prostate cancer who received the enzalutamide regimen compared with 72% of those who received a standard nonsteroidal antiandrogen agent.

Additionally, a subgroup of patients received early doses of docetaxel or abiraterone acetate (Zytiga) with testosterone suppression. In this group, the OS rates were similar between the 2 arms (HR, 0.90; 0.62-1.31).

The addition of enzalutamide, however, did exacerbate docetaxel-related adverse events (AEs). Docetaxel-related AEs in the enzalutamide versus nonsteroidal antiandrogen arms included neutropenic fever (14% vs 13%, respectively), grade 2 sensory neuropathy (9% vs 3%), nail discoloration (10% vs 5%), grade 1 or 2 watery eyes (20% vs 6%), and grade 2 fatigue (20% vs 14%).

“We need longer follow-up, but it is possible we will see that adding enzalutamide to docetaxel will have a clinical benefit. We can't say that yet because we've got to do the quality-of-life analysis to see if delaying progression improves the patient's quality of life. There were some extra side effects with adding the enzalutamide to docetaxel,” said Sweeney, a medical oncologist at Dana-Farber Cancer Institute.

In an interview with OncLive, Sweeney discussed the results of the ENZAMET trial and the next steps for researching the efficacy of enzalutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.

OncLive: Could you provide an overview of the ENZAMET trial design?

Sweeney: This is a study in the metastatic hormone-sensitive setting of prostate cancer. It's asking whether enzalutamide, which we know improved the survival of men with castration-resistant disease, is more effective when given at the start of hormonal therapy—testosterone suppression. In this hormone-sensitive setting, patients with a high volume of disease also benefit from getting docetaxel. That result came out in the CHAARTED study, which was not too long after we wrote, designed, and activated the ENZAMET study. We quickly activated an amendment that allowed patients to receive docetaxel based on physician and patient choice. The patients could either get testosterone suppression with a standard nonsteroidal—either bicalutamide, nilutamide, or flutamide—as an active control or enzalutamide. Then, patients were stratified by whether they received docetaxel. What ultimately happened is 50% of the patients received docetaxel, many of them with high-volume disease. Half of the patients received enzalutamide and half were treated with the nonsteroidal antiandrogen.

We saw that enzalutamide prolonged OS in both patients with high-volume and low-volume disease. We also saw that patients had a longer time to progression; the study was very positive. We get the readout early from the interim analysis, [but] we need longer follow-up.

Although early enzalutamide prolonged the time to progression for those who got docetaxel, there is not a big treatment effect yet. We will hopefully see a bigger treatment effect soon with longer follow-up. It's possible to do sequential therapy as long as patients get docetaxel and 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 OS—a very clear treatment effect. However, we've got a lot of work to do. We often need the longer follow-up to see if it translates into longer survival. Hopefully patients who have a longer time to progression get other agents and compound the early cancer control, resulting in a longer survival, but we haven't seen it yet at the early analysis.

Could you expand upon the safety findings with enzalutamide?

It's very important when we counsel patients on the efficacy benefits and the AEs. There is the same degree of enzalutamide-associated AEs that we expected; there is fatigue, increased concentration impairment, and falls. About 5% of patients experienced falls as an AE, which is a low number but more than we saw with patients who got the standard nonsteroidal. That's something we need to be careful about. There was also a 1% incidence of seizures in patients who received enzalutamide, despite excluding patients who had a predisposition to seizures.

The other very interesting thing is enzalutamide increased some of the AEs of docetaxel. There was the same grade of neutropenic fever, but there was also grade 2 sensory neuropathy at about 9%; there was only 3% who experienced sensory neuropathy with the standard nonsteroidal. We also saw some increasing eye tearing and nail discoloration—AEs we have learned to see with docetaxel. Enzalutamide seemed to increase their frequency.

What can you share regarding the quality-of-life (QoL) analysis for enzalutamide?

Stay tuned for the QoL analysis. The ENZAMET 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, which is unheard of. We focused on the efficacy endpoints and the AE endpoints. The next part is to focus on the QoL analysis because it is important for us to describe the total patient experience.

What is your takeaway message for those who are treating patients with metastatic hormone-sensitive prostate cancer?

I look at their risk category: do they high-volume or low-volume [disease]? Are they fit? Are they fit enough for chemotherapy? Then, I'll lay out the options: hormone suppression and docetaxel; hormone suppression and enzalutamide, abiraterone, or apalutamide (Erleada). [The docetaxel/hormone suppression option is] based on the different side effect profiles and if the patient has some problems being on enzalutamide for 3 years or longer. [In that case], you can get the docetaxel out of the way and maybe you add the other agents at progression until we find out that there is a clear benefit for doing it all concurrently. That is to be determined.

Otherwise, if the patient is not fit for chemotherapy and has low-volume disease, they can choose from testosterone suppression with abiraterone, enzalutamide, or apalutamide.

Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl; abstr LBA2).