Some men are exceptional responders to Bipolar Androgen Therapy (BAT). Its pioneer, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, has a few patients who have remained on BAT alone for several years. But for many men, the response is temporary; just a few months. Why? Could it have something to do with mutated genes? What about the immune system?
“One of the things observed in the lab by our colleague Dr. Sushant Kachhap is that when we give testosterone, the prostate cancer cells get stressed and turn on all these immune factors,” says Denmeade. “Testosterone activates immune pathways.” When three men who had participated in BAT trials later had “dramatic” responses to immunotherapy – 100-percent decreases in PSA, and one man remains in long-term remission – “we thought that might be the secret: androgen plus immunotherapy.”
COMBAT, a small, phase 2 study supported by PCF, co-led by Hopkins investigators Mark Markowski, M.D., Ph.D., and Emmanuel Antonarakis, M.D., (now Director of Genitourinary Oncology at the University of Minnesota) tested the combination of BAT and immunotherapy in 45 men with metastatic castration-resistant prostate cancer (mCRPC). The men were treated with BAT in combination with nivolumab (an immunotherapy agent). “We saw an impressive clinical response rate of 40 percent,” says Markowski. “We also observed a durable benefit, lasting over a year, in a few patients who had received extensive prior therapies.” The results suggested that BAT alone has significant efficacy, while nivolumab improves responses in some patients. The combination of BAT with nivolumab was safe and well tolerated by the participants. Markowski and Antonarakis are designing a randomized Phase 3 study to compare combined BAT plus nivolumab versus standard treatments for patients with mCRPC.
In the COMBAT trial, “we treated a group of incredible men who agreed to have tumor biopsies before and after three cycles of BAT,” says Denmeade. “We are studying the heck out of these biopsies,” looking for specific biomarkers or gene mutations that might help predict who will have the deepest and longest-lasting responses. The team is also performing additional studies of the interactions between BAT and the immune system to discover how this treatment can be improved.
Could More Testosterone Be the Hidden Key to Curing Prostate Cancer? Read more in this series.