Prostate cancer is a hormonally driven illness that, for 70 years, has been treated in kind—by blocking androgen production or wasting its supplies. But once metastatic prostate cancer resisted the depleting effect of castration or the castrating chemotherapy agents, it was commonly believed the disease had escaped androgen regulation and hormonal agents would no longer have an impact.
Now there’s a theory gaining in supporting evidence that androgen produced outside the gonads and perhaps within the tumor itself may contribute to castration-resistant disease. With this idea in mind, researchers have started to investigate the use of abiraterone acetate—a powerful inhibitor of CYP17, a key enzyme in testosterone biosynthesis—for men with advanced illness. The orally administered drug has shown promise in fighting tumors in phase I and II trials.
Now, the report of a phase III trial published in this week’s NEJM finds that the drug actually prolongs survival and supports this enormous shift in thinking about disease mechanisms.
De Bono et al recruited nearly 1200 men whose disease had progressed after treatment with the chemotherapy agent docetaxel and randomly assigned them to receive either abiraterone acetate and prednisone (given to mitigate adverse events and frequently used in men with advanced prostate cancer) or placebo and prednisone. They found that the intervention group had a 35% reduction in risk of death with median survival of 14.8 months compared to 10.9 months among the placebo group; similar effects were seen in secondary endpoints. These results were promising enough for the Data and Safety Monitoring Board to recommend that the trial be terminated early.
The treatment group were more prone to adverse events including fluid retention (31%. vs. 22%), hypertension (10% vs. 8%), and hypokalemia (17% vs. 8%). These effects are probably related to excess production of mineralocorticoids (aldosterone) as a consequence of the androgen synthesis blockade.
Last month, the Food and Drug Administration approved abiraterone for patients with metastatic castration-resistant prostate cancer who failed docetaxel. In an accompanying editorial, Emmanuel S. Antonarakis, M.D., and Mario A. Eisenberger, M.D. of Johns Hopkins University suggest that the drug’s safety and efficacy supports its use even in patients without prior chemotherapy—further trials to demonstrate activity in this setting are ongoing. “It is clear, however, that our knowledge of the biological mechanisms involved in the progression of metastatic castration-resistant prostate cancer has reached a level at which the discovery of more effective targeted approaches will probably further improve outcomes,” they wrote.
These findings also support the hypothesis that in some men, even castration-resistant prostate cancer remains driven by androgen and can therefore be treated with an androgen-blocking agent.
“I think this is an extremely important paper for several reasons. One is that the demonstration of improved survival in this setting is a very hard endpoint,” says Dr. Dan Longo, NEJM deputy editor. He also calls it “a mechanistic breakthrough to realize that the [previous] failure to respond to hormone interventions doesn’t mean the tumor is hormone independent.”
How will these study results affect your clinical decisions? What other therapies might be considered in light of these mechanistic findings?