Posted: Jul 05, 2016
In July, Prostatepedia discusses recent advances in hormonal therapy. For years, cancer control was confined to a small set of drugs with limited utility and too short-term effect. Everything changed with Zytiga (abiraterone) and Xtandi (enzalutimide), both of which opened the door to further advances.
In our first conversation, Dr. Thomas E. Keane reviews current agents that shut off testosterone production. Luteinizing hormone (LH) is released from the pituitary gland as a part of an elaborate system that controls serum testosterone in men. If testosterone levels fall, the amount of LH increases to stimulate the testes to produce more testosterone. If testosterone levels are too high, LH levels drop until testosterone concentration returns to normal ranges. LH release is controlled by luteinizing hormone–releasing hormone (LHRH).
Older LHRH agonists commonly used, such as Lupron (leuprolide) and Eligard (leuprolide), over-stimulate the pituitary gland and exhaust its ability to release LH. An LH surge leads to a dramatic jump in testosterone. After a few days, though, the pituitary response begins failing and LH release falls. By the end of the first week, testosterone levels generally start to gradually decline, and, after 3 to 4 weeks, reach concentrations similar to those seen after surgery.
Newer drugs bind directly to LHRH receptors in the pituitary gland to immediately stop LH release. There is a rapid drop in serum testosterone to castrate levels within days, not weeks. Because these drugs block LHRH action, we call them antagonists.
Keane also reviews the evidence that antagonist Firmagon (degarelix) may offer superior cancer control when compared to agonist Lupron (leuprolide), especially in terms of cardiovascular events in patients with preexisting heart disease.
Next, Dr. Emmanuel Antonarakis discusses AR-V7, an altered form of the androgen receptor. Antiandrogens compete with testosterone for binding to the androgen receptors. AR-V7 is missing the part of the protein that binds testosterone or the antiandrogens, yet is still able to trigger cancer cell growth. The cancer cell becomes truly independent of testosterone and resistant to drugs such as Xtandi (enzalutamide) and Zytiga (abiraterone). In contrast, the cancer remains sensitive to taxane chemotherapy drugs.
A circulating tumor cell (CTC) test developed at Johns Hopkins University can detect and quantify the AR-V7 splice variant and holds promise for physicians wishing to use it to make treatment decisions. The test is not yet FDA approved, which Antonarakis acknowledges limits the clinical utility of the test. I’m excited to share with you first-class translational research by one of today’s best young investigators.
In our third conversation, Dr. Mary-Ellen Taplin of the Dana-Farber Institute discusses galeterone, a new oral hormonal therapy agent. Galeterone combines Xtandi’s (enzalutamide) ability to block the testosterone receptor with Zytiga’s (abiraterone) ability to block testosterone production. It also degrades both testosterone and AR-V7 mutant receptors.
The ARMOR3-SV clinical trial tests the therapeutic benefit of galeterone in men with the AR-V7 mutant androgen receptor. ARMOR3-SV is an important trial: determining if a drug has clinically significant benefit for patients with aggressive prostate cancer, whose current treatment options are few. As Dr. Taplin points out, ARMOR3-SV may tell us something important about AR-V7’s clinical significance.
Finally, Dr. Brian Gonzalez discusses a genetic variation associated with an increased risk of cognitive impairment during ADT. His genetic studies use terms many might find confusing, so please read the side bar alongside his comments. His findings have profound implications for those of you on hormonal therapy.
– Dr. Charles E. Myers