It was over 2 decades ago that my colleagues and I reported in The New England Journal of Medicine that a first-generation oral antiandrogen, flutamide, when added to a luteinizing hormone–releasing hormone (LHRH) agonist, improved survival by nearly 6 months compared to an LHRH agonist alone in men with newly diagnosed metastatic disease.1 The rationale for combining the antiandrogen with the agonist was to additionally block androgens produced by the adrenal gland. These findings were met with much controversy, primarily because it was felt that the daily subcutaneous LHRH agonist administered in the clinical trial was not as good as estrogens or bilateral orchiectomy in reducing testosterone production—and, therefore, that flutamide acted as a crutch to support the failure of the LHRH agonist.
Evolving Strategy
Over the ensuing decade, a number of comparative trials were performed to test the concept of what became known as combined androgen blockade. Of concern was our second Southwest Oncology Group Intergroup trial, which showed that the addition of flutamide to a regimen of bilateral orchiectomy did not result in the same 6-month improvement in survival.2 This seemed to suggest that the antiandrogen did little except to prevent the testosterone flare from the agonist.
E. David Crawford, MD
Shortly after the approval of flutamide, a three-times-daily–dosed oral agent—a more potent second-generation antiandrogen—was studied. Clinical trials found it to be beneficial in advanced disease, it was administered once daily, and the newer therapy was devoid of some of the side effects of flutamide, including diarrhea and liver toxicity. The drug, bicalutamide, replaced flutamide in clinical trials and practice. It was subsequently studied at three times the approved dose (ie, 150 mg/d) as a monotherapy. Unfortunately, a large international trial of the drug at this dosage revealed increased toxicity, primarily in the domain of cardiac events.3
Third-Generation Antiandrogens
Many of us who treat prostate cancer felt that one of the best drugs to treat the disease in advanced stages would be an antiandrogen that was effective in completely blocking the androgen receptor, preventing mutation and ligand-binding of the androgen receptor and translocation of the androgen receptor into the nucleus. A number of companies tried to develop these third-generation compounds. Active drugs were abundant, but they did not proceed to approval because of an unfavorable risk-benefit ratio. One of the early promising and effective drugs was withdrawn from clinical trials because of an increased rate of seizures.
The quest for an effective and safe third-generation antiandrogen continued. Fortunately, one emerged—enzalutamide (Xtandi)—and that is the subject of the two clinical trials just reported by Shore and colleagues4 and Penson and colleagues5 and reviewed in this issue of The ASCO Post. (In addition to enzalutamide, a number of other new agents have been approved in the past 5 years, including the androgen biosynthesis inhibitor abiraterone [Zytiga].)
These two trials of enzalutamide are examples of how antiandrogens have moved from the postchemotherapy stage to the prechemotherapy stage and now even to the nonmetastatic castration-resistant stage. Similarly, abiraterone has been moved up to the newly diagnosed metastatic disease setting. A further step forward has been the evaluation of enzalutamide in men who are on active surveillance.
Impressive Data
The trials of enzalutamide were well executed, and the authors are to be congratulated for the important contributions to the urologic oncology literature. The TERRAIN trial, reported by Shore and colleagues, compared enzalutamide vs bicalutamide in men who were asymptomatic or minimally symptomatic with metastatic disease progressing on hormone therapy. The results are impressive, showing a significant difference in median progression-free survival of 15.7 vs 5.8 months.
The effectiveness of this drug was also reflected in the fact that among men who had predominately soft-tissue disease at baseline, 37% in the enzalutamide group had an objective response vs only 5% in the bicalutamide group. TERRAIN clearly identifies enzalutamide as a third-generation antiandrogen. Adverse events were common in both groups; one that stands out with enzalutamide is fatigue (28% vs 20%).
The STRIVE trial, reported by Penson and colleagues, compared enzalutamide and bicalutamide in men with castration-resistant nonmetastatic or metastatic disease from sites in the United States. Of interest is the fact that 50% of men in both arms had very high-grade cancers (Gleason score 8–10). Adverse events again were relatively similar, with a 10% increase in fatigue in the enzalutamide group.
Median progression-free survival in STRIVE was 19 months vs 5.7 months. An improvement in prostate-specific antigen progression was also observed. Entry criteria included testosterone levels < 50 ng/dL; it would be instructive to see if there were any response differences based on testosterone levels < 20 ng/dL vs > 20 ng/dL.
The Way Forward
So the march continues from postchemotherapy to prechemotherapy to castration-resistant metastatic and nonmetastatic settings and onward. These are important landmark studies that pave the way. The way forward is now to look at combinations, not monotherapy. In every advanced cancer that we cure, it’s not monotherapy but combinations that work.
Just recently, the CHAARTED trial showed a greater than 1-year survival advantage by adding docetaxel to androgen-deprivation therapy.6 What if we built on that and added sipuleucel-T (Provenge) and radium-223 dichloride (Xofigo), as well as androgen-deprivation therapy with degarelix (Firmagon), abiraterone, and enzalutamide? Perhaps patients would not need to be treated for a lifetime, but rather, for a set interval during which a more powerful blow is delivered by such treatment. Treatment could be reinstituted at progression—or hopefully never—in those who demonstrate prolonged disease stabilization. ■
Disclosure: Dr. Crawford is a consultant for Bayer, Medivation, Janssen, and Ferring.
Dr. Crawford is Professor of Surgery/Urology/Radiation Oncology and Head of Urologic Oncology at the University of Colorado, Denver.
