Affirming the Promise of Enzalutamide: A New Opportunity for Integrative Care in Prostate Cancer

Neal D. Shore, MD

In separate talks at the annual meeting of the American Urological Association (AUA) in Atlanta, Georgia, Neal D. Shore, MD, updated his peers about a promising new treatment for prostate cancer and encouraged them to incorporate novel therapies into their practices.

Shore, of Atlantic Urology Clinics in Myrtle Beach, South Carolina, discussed the novel therapy enzalutamide (MDV3100), the first androgen receptor signaling inhibitor, and the results of the phase III AFFIRM trial.¹

As medical director of his practice’s independent clinical research arm, the Carolina Urologic Research Center, Shore has participated in more than 200 trials, including studies of enzalutamide. His center was a high-enrolling site in the AFFIRM trial, which was stopped in November 2011, after the drug improved overall survival in patients with metastatic castrate-resistant prostate cancer (mCRPC) who had failed docetaxel. Shore now serves as global primary investigator for the phase II TERRAIN trial evaluating the drug in the pre-chemotherapy setting in patients with mCRPC.

In addition to speaking about enzalutamide, Shore took time to advise his colleagues about the growing role urologists can play in seeing patients through their experience with a disease that is quickly becoming more treatable, particularly in advanced stages. It makes sense for urologists to understand and administer the newest treatments for prostate cancer, he said, since they are the doctors most likely to diagnose the disease and to follow patients long-term, even during their treatment by medical or radiation oncologists.

“These are all really very brand-new therapies, so there’s a learning curve that anyone interested in working with these patients can achieve,” said Shore, who has also participated in studies of abiraterone (Zytiga, Janssen Biotech, Inc) and sipuleucel-T (Provenge, Dendreon). “Read the literature, and partake in educational courses offered by the AUA, the American Society of Clinical Oncology, the Society of Urologic Oncology (SUO), and the Large Urology Group Practice Association as well as symposia offered at sectional, regional, and national meetings. If you have an interest, there’s no reason you should not be able to become familiar, knowledgeable, and comfortable in offering these therapeutics to your patients.”

Enzalutamide seems poised to become an exciting addition to the growing list of novel therapies approved for the treatment of prostate cancer, Shore told the audience. He explained that the drug is notable because it is orally administered once a day with or without food, drives a significant improvement in overall survival in trial participants, has an excellent safety profile, and works through distinct mechanisms of action.

The AFFIRM trial of enzalutamide, Shore said, demonstrated the largest overall survival benefit ever recorded in a post-chemotherapy setting for mCRPC.

The multinational trial included 1199 patients at 156 sites in 15 countries. Patients were randomized in a double-blind, prospective fashion; two out of three received enzalutamide 160 mg once a day, and the rest received placebo. The primary endpoint was overall survival.

The study was stopped early in November 2011 because it had demonstrated a significant 4.8-month improvement in overall survival. The hazard ratio was 0.631, which translates to a 37% reduction in risk of death for patients taking enzalutamide compared with those getting placebo (18.4 months vs 13.6 months; P <.0001).

“Once patients progressed, they were allowed to go onto additional approved treatments such as cabazitaxel, 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,” Shore said. “Also really interesting was the fact that, in the enzalutamide arm, 54% of patients had more than a 50% decrease in their baseline PSA, and approximately 25% had more than a 90% decrease in their PSA from baseline.”

The drug was also extremely well tolerated among patients in the trial, Shore noted.

Overall, he said, 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%. 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 (0.6%) reported cases of patients having had seizures in the enzalutamide arm.

Enzalutamide has three distinct mechanisms of action, Shore explained. “It impacts at the level of the androgen receptor by inhibiting binding of androgens to the androgen receptor on the prostate cancer cell,” he said. “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.”

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Prostate cancer is a very heterogeneous disease. By the same analogy, the practice and the clinical evaluation and treatment strategies can be heterogeneous, depending upon whether you’re a medical oncologist, a urologist, or a radiation oncologist. The most important thing is collaboration among the specialties, a multidisciplinary approach with integrative care.”

—Neal D. Shore, MD

Because it works so differently from other prostate cancer drugs, Shore said, enzalutamide is a good candidate for combinatorial studies evaluating its use with any approved therapy for the disease, including another recently approved hormonal treatment, abiraterone.

According to a company press release, the developer of enzalutamide, Medivation, Inc, filed a few drug application with the FDA at the end of May and is seeking fast-track approval of the drug.²

In the meantime, Medivation, which will copromote the drug with Astellas Pharma US, Inc, is testing enzalutamide in other patient populations.³ The phase III PREVAIL trial is looking at the use of enzalutamide versus placebo in patients with asymptomatic M1 CRPC who have not received chemotherapy, and the phase II TERRAIN trial is evaluating enzalutamide versus bicalutamide in patients with the same stage of disease. The company is also overseeing a phase II study of enzalutamide monotherapy in hormone-naïve men with prostate cancer.

For urologists, Shore said, it’s important to understand how pipeline drugs like enzalutamide may work to treat late-stage prostate cancer, as well as to know the ins and outs of recently approved therapies, including which populations they are likely to help and how they should be administered. That knowledge is at the core, he said, of a new approach to urologic practice made possible—and, perhaps, even necessary—by enormous progress in the treatment of laterstage prostate-cancer that has occurred over the last couple of years.

Prior to the introduction of docetaxel in 2004, Shore pointed out, “we had no agents that extended survival in men with mCRPC.”

Dramatic changes in that landscape began in April 2010 with the approval of sipuleucel-T, the first therapeutic vaccine immunotherapy for solid tumors in asymptomatic or minimally symptomatic mCRPC. Since then, several other gamechanging drugs have been approved in mCRPC: chemotherapy drug cabazitaxel; denosumab, a monoclonal antibody that delays the onset of skeletal-related events from bone metastases; and abiraterone.

In addition, last fall, radium-223 chloride (Alpharadin, Algeta) became the first radioisotope to show, in a phase III trial, an improvement in overall survival for patients who had progressed after chemotherapy, Shore said. And now, of course, enzalutamide is on the table as a potential treatment.

Shore addressed those new options and their place in urology in a session focused around mCRPC and held by the SUO in conjunction with the AUA meeting.

He noted a growing trend toward community urology practices offering new treatments for advanced prostate cancer—rather than sending patients to large cancer centers—and credited that development to the ease of use of the newest medicines. It’s easy for doctors to understand the therapies, as well as to identify, select, and monitor eligible patients, Shore said.

“This is just an exceptional time in advanced prostate cancer therapy,” he said. “I think it’s absolutely critical that anyone who wants to offer the best therapy to these patients with advanced disease—whether they’re a urologist, a medical oncologist, or a radiation oncologist—learn about these novel agents, which are, for the most part, easy to administer, have very favorable patient safety profiles, and, most importantly, have contributed, with different mechanisms of action, to extend life.”

Shore added that a multidisciplinary approach is crucial when it comes to treating mCRPC.

“Prostate cancer is a very heterogeneous disease, with some very aggressive variants and some slower-progressing variants,” he said. “By the same analogy, the practice and the clinical evaluation and treatment strategies can be heterogeneous, depending upon whether you’re a medical oncologist, a urologist, or a radiation oncologist. Sometimes, there are still differences of opinion in the same specialty. The most important thing is collaboration among the specialties, a multidisciplinary approach with integrative care.”

While that kind of approach can be a built-in advantage of working in a larger cancer center, it can be achieved in community practice too, Shore said.

References

1. Scher HI, Fizazi K, Saad F, et al. Effect of MDV3100, an androgen receptor signaling inhibitor, 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. Medivation and Astellas announce submission of new drug application for enzalutamide for the treatment of castration-resistant prostate cancer in patients previously treated with chemotherapy [press release]. Available at: http://investors.medivation.com/releasedetail.cfm?ReleaseID=675497. Accessed June 14, 2012.
3. Medivation, Inc. Product Pipeline. www.medivation.com/product-pipeline. Accessed May 17, 2012.