Leading Enzalutamide Investigator Offers Insights Into Pivotal Data

Neal D. Shore, MD

Since the phase III AFFIRM trial of enzalutamide (formerly MDV3100) was halted early in November 2011 after meeting its endpoint of improved overall survival, physicians have remained hopeful about its potential as a treatment for prostate cancer.

Among them is Neal D. Shore, MD, of Atlantic Urology Clinics in Myrtle Beach, South Carolina, and its independent clinical research arm, the Carolina Urologic Research Center. As medical director of the research center, Shore has participated in more than 200 clinical trials, including studies of sipuleucel-T (Provenge) and abiraterone (Zytiga).

His center was a high-enrolling site in the AFFIRM trial, which tested the androgen receptor signaling inhibitor enzalutamide in patients with metastatic castrate-resistant prostate cancer (mCRPC) who had failed docetaxel. Now, Shore is serving as global primary investigator for the phase II TERRAIN trial investigating the drug in the prechemotherapy setting in patients with mCRPC.

Medivation, Inc, which is developing enzalutamide in partnership with Astellas Pharma, Inc, said a new drug application and request for priority review were submitted to the FDA in May.

Shore presented the results of the AFFIRM study on May 22 during the American Urological Association Annual Meeting in Atlanta, Georgia. In an interview with OncologyLive, Shore said the drug is noteworthy because it is orally administered once a day, drove a significant improvement in overall survival in trial participants, has an excellent safety profile, and works through three distinct mechanisms of action.

“Its overall favorability profile,” he said, “makes it rather unique.”

OncologyLive: What are enzalutamide’s mechanisms of action? Shore: First, it impacts at the level of the androgen receptor by inhibiting binding of androgens to the androgen receptor on the prostate cancer cell. Second, it inhibits nuclear translocation of the androgen receptor from the cellular membrane as it then is transported through the cell cytoplasm to the nucleus. And third, it inhibits the association of the androgen receptor with DNA within the nucleus.

To understand the drug’s multiple mechanisms of action is to fully appreciate that it should be complementary to all currently approved therapies, and potentially could be given in combination. But we have to do combinatorial studies to prove that efficacy and safety.

What were the parameters of the AFFIRM trial?

The trial was specifically designed for patients with mCRPC who had received at least one course of docetaxel and progressed. There were 1199 patients in this multinational trial that took place at 156 sites in 15 countries. Patients were randomized in a double-blind, prospective fashion; two out of three got enzalutamide 160 mg once a day, and the rest got placebo. The primary endpoint was overall survival.¹

“

This study boasts the largest overall survival benefit ever recorded in a postchemotherapy setting for mCRPC. ”

—Neal D. Shore, MD

What were the trial’s main findings?

This study boasts the largest overall survival benefit ever recorded in a postchemotherapy setting for mCRPC.

At the end of the day, it showed that there was a 4.8-month improvement in overall survival at the median. There was a hazard ratio of 0.631, which translates to a 37% reduction in risk of death for patients taking enzalutamide compared with those getting placebo. The P value was highly statistically significant, less than 0.0001, compared with getting the placebo.

Once patients progressed, they were allowed to go on to additional approved treatments such as cabazitaxel [Jevtana], abiraterone, or docetaxel, and what’s interesting is that the patients on the enzalutamide arm stayed on their drug therapy more than five months longer. The median was 8.3 months on enzalutamide versus three months on placebo.

Also really interesting was the fact that, in the enzalutamide arm, 54% of patients had greater than a 50% decrease in their baseline PSA [prostate-specific antigen], and approximately 25% had a greater than 90% decrease in their PSA from baseline.

What were the findings regarding the drug’s side-effect profile?

If you look at all adverse events, there were essentially the same percentage recorded for enzalutamide and placebo. The number of discontinuations due to adverse events was slightly higher in the placebo arm than in the enzalutamide arm, at 9.8% versus 7.6%. Looking at adverse events of special interest, there was a slight increase in all grades of fatigue for patients on enzalutamide versus placebo of 33.6% versus 29.1%. But for very severe grades of fatigue, more was noted with placebo, at a rate of 7.3% versus 6.3%.

In terms of any cardiac or liver function abnormalities, there was no significant difference in percentages in either arm. There were five reported cases of patients having had seizures in the enzalutamide arm, which gave that side effect an incidence of 0.6%. And that was really it. The drug appears to have been very well tolerated.

How does enzalutamide compare with abiraterone, a hormonal treatment for prostate cancer that the FDA approved in 2011 for the same population of men who were tested in the AFFIRM trial?

Abiraterone is also an oral, daily drug, but it has to be given on label with 5 mg of prednisone two times a day in order to reduce the side-effect profile of the drug, which can lead to, in a small number of patients, a lowering of potassium, fluid retention, and possible elevation of blood pressure. While enzalutamide can be taken with or without food, abiraterone has to be taken two hours before eating or an hour afterward, because it can result in an increase in absorption of the drug and its bioavailability.

Abiraterone has a distinct mechanism of action from enzalutamide, so it’s possible that these two drugs, if given together, might have a rather profound and significant effect on progression and ultimate survival for patients.

What other studies of enzalutamide are being conducted?

We are participating in a multinational, phase II trial, the TERRAIN trial, randomizing 370 patients with asymptomatic M1CRPC disease, who have progressed after hormonal treatment or surgery, to receive enzalutamide versus bicalutamide. There’s also the phase III PREVAIL trial, in which 1700 patients with asymptomatic M1CRPC who have not received chemotherapy are getting randomized to enzalutamide versus placebo. Medivation is also overseeing a phase II study of enzalutamide monotherapy in hormone-naïve men with prostate cancer.²

Patients in the M0 stage of castrate-resistant prostate cancer, who have failed localized and then androgen- suppressive therapies and have rising PSAs but no radiologic evidence of disease, need to be studied, and there are trials addressing that population.

In the same population, there are patients who are still androgen-sensitive who are on androgen-deprivation therapies, traditional LHRH [luteinizing hormonereleasing hormone] agonists or antagonists, and many have thought: “Can we do a better job of suppressing the androgen receptor axis by considering these newer hormonal agents such as abiraterone or enzalutamide, or both?” I think that will be studied, too.

References

1. Scher HI, Fizazi K, Saad F, et al. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study. J Clin Oncol. 2012; 30 (suppl 5; abstr LBA1).
2. Medivation, Inc. Product Pipeline. Medivation website. www.medivation.com/product-pipeline. Accessed May 17, 2012.