The treatment of late-stage prostate cancer is shifting. With the approval of two new oral agents, abiraterone acetate (Zytiga) in April 2011 and enzalutamide (Xtandi) in August 2012, there are now options for men with metastatic prostate cancer who have progressed after chemotherapy treatment with docetaxel where there were none just two years ago. Since its initial approval, abiraterone has also been approved by the FDA for the use of abiraterone in chemotherapy-naïve patients with metastatic prostate cancer. Enzalutamide is also being tested in this patient population; a phase III trial is ongoing.
The reason for the shift? Research over the past 10 years has shown that metastatic prostate cancer tumors that are resistant to hormonal (androgen)- deprivation therapies still rely on androgen receptor (AR) pathways for growth. “Until this decade, we had assumed that tumors from [surgically or medically castrated patients who stopped responding to hormonal treatments] were no longer reliant on hormones for their growth and progression,” said Joshi J. Alumkal, MD, assistant professor of Medicine at the Oregon Health & Science University in Portland.
Next-Generation Androgen Receptor Signaling Agents
There are several mechanisms by which prostate tumors hijack androgen signaling to fuel cancer growth. Some castration-resistant prostate cancer (CRPC) tumors are able to make testosterone and androgen precursors. These tumors also amplify ARs on prostate cancer cells or develop mutations in AR genes. The next-generation androgen-targeting therapies, abiraterone and enzalutamide, target these mechanisms.
Joshi J. Alumkal, MD
“Abiraterone and enzalutamide are proof that at least in some patients, male hormones still matter and they are promoting prostate cancer growth. Those are the 50% of patients who respond [to these new agents], at least temporarily, and who may derive an overall survival benefit,” said Alumkal.
The two drugs have different mechanisms of action. Abiraterone works by inhibiting CYP17, an enzyme necessary to make a precursor of testosterone in the testes, adrenal glands, and within the prostate tumor itself. Enzalutamide is a second-generation oral antiandrogen that binds to the androgen receptor, inhibiting the interaction of testosterone to its receptor.
“Enzalutamide is selective—it works particularly well in tumors in which the androgen receptor is overactive, such as through amplification,” said Andrew J. Armstrong, MD, MSc, co-leader of the Genitourinary Oncology Research program at Duke University School of Medicine in Durham, North Carolina.
Andrew J. Armstrong, MD
Other novel hormonal agents in development include orteronel (TAK700), another oral nonsteroidal selective inhibitor of androgen synthesis that targets the same enzyme as abiraterone. The oral drug is being tested in phase III trials in patients with metastatic CRPC both before and after treatment with chemotherapy.
Another novel oral agent, ODM-201, has the same mechanism of action as enzalutamide, and thus interacts with the AR. The drug has shown high response rates in a phase I/II first-in-human trial presented at this year’s European Society for Medical Oncology (ESMO) Congress.
Management of Prostate Cancer in Urology Practices
As abiraterone, enzalutamide, and other oral androgen-targeting therapies become the standard of care, it is likely that more urologists will be treating patients with advanced prostate cancer and that these patients will remain in the care of their urologists longer, through the progression of their cancer.
This trend of prostate cancer management within urology practices will likely continue as these newer agents move into the nonmetastatic setting. “As we see the data emerge in the nonmetastatic setting, you may see more urologists consider using these drugs because they appear quite safe,” said Armstrong.
Armstrong emphasized that there are serious side effects of these agents that urologists may not wish to manage, such as heart failure, liver toxicity, muscle fatigue, risk of seizure, and drug interactions with other medications. But with proper training, he believes urologists can manage the toxicities.