“BATty” Prostate Cancer Drive
Part Two: How BAT Works
Several years ago, medical oncologist Samuel Denmeade, MD, Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable idea for attacking prostate cancer: alternating ADT with high-dose testosterone. He recently took the time to explain to me how and why this works in an interview for the Prostate Cancer Foundation website. Watch the first part of this interview here.
Patients asked Denmeade if this treatment, called Bipolar Androgen Therapy (BAT), could be used as initial treatment for metastatic cancer instead of androgen deprivation therapy (ADT), or even as primary treatment instead of prostatectomy or radiation. “No and no,” He says. “BAT was designed to act against castration-resistant prostate cancer (CRPC).”
In CRPCthe environment of the cancer is significantly different than in the early stage Cancer. As CRPC cells learn to adapt to the lack of testosterone with ADT, they “turn the androgen receptor (AR) high” and become comfortable in the new environment. But with high AR levels, cancer cells are sitting ducks, vulnerable to the shotgun blast of a large dose of testosterone. “Flooding the prostate cancer cell with testosterone gum works: suddenly, the cancer cells have to deal with too much androgen (male hormone) bound to the receptor. This disrupts their ability to divide. They either stop growing or die.”
It’s about creating chaos in the environment, making cancer cells unable to thriveand time is of the essence. “ADT initially works because prostate cancer cells are suddenly deprived of testosterone, and most of them cannot survive this shock.” Cancer cells die by the thousands, PSA plummets, imaging scans show the cancer is shrinking and symptoms are improving. But prostate cancer, like the Road Runner, is elusive. Over time, the resistant zone of surviving cells rebuilds, adapts to life in a low-testosterone environment, and begins to grow again. “BAT is a similar type of hormonal shock – just in the opposite direction,” says Denmeade. “A key feature of BAT is the rapid change from a very high to a low level of testosterone.” Men remain on ADT and receive monthly doses of high-dose testosterone, which gradually tapers off and then comes back on again with the next monthly shot. This is the bipolar part of Bipolar Androgen Therapy (Denmead uses the image below to explain to his patients). “The repeated shocks of BAT cycling do not give cancer cells time to adapt, “because the underlying environment is always changing.”
So far, in four clinical trials at Hopkins, Denmeade and his colleagues have given BAT to about 350 men with CRPC, most of whom have also received enzalutamide (Xtandi), abiraterone (Zytiga), or both. For men with CRPC whose disease worsens on ADT or AR-inhibiting drugs such as enzalutamide or abiraterone, BAT holds promise. In the recent TRANSFORMER study, we “compared BAT head to head with enzalutamide” in patients with CRPC who had progressed on ADT and abiraterone. “It was a somewhat strange study, comparing a drug with its exact opposite: an androgen versus an anti-androgen.. I don’t know if anyone has ever done such a study. To our surprise, BAT and enzalutamide were almost identical in their effect.” PSA levels fell in about 25 percent of men on either treatment, and for both treatments, the response lasted about six months.
However, the real difference between the treatment arms was seen after the crossover – when men with BAT were switched to enzalutamide or vice versa. “If we gave BAT first and afterward enzalutamide, nearly 80 percent responded, and the response lasted nearly a year. This is quite an improvement in response rate and duration.” Among patients who received enzalutamide first, followed by BAT, the response rate to enzalutamide was only 23 percent.
This begs the question: Why stop after one round of BAT and then enzalutamide? Why not continue? “We should be able to cycle back and forth over and over again,” says Denmeade. The STEP-UP test, of 150 patients at Johns Hopkins and eight other centers nationwide, is looking at just that, “androgen and anti-androgen sequencing. There are two arms of BAT treatment: in one, patients are simply switched every two months – two months of testosterone, two months of enzalutamide. In the other, men stay on testosterone until their PSA rises, then switch to enzalutamide and stay on it until their PSA rises,” then repeat. Cancer response is also monitored with regular CT scans and bone scans. Patients stop treatment if scans show cancer progression.
BAT studies so far have been small, says Denmeade. “We need a big phase 3 study. We’re just nibbling on the edges.” At this time, BAT remains under investigation. positive results from larger randomized trials are needed to be considered standard of care. Although not a cure for advanced prostate cancer, BAT can become an option to prolong life and, most importantly, improve quality of life.
Note: BAT is not recommended for men with symptomatic bone pain from metastatic prostate cancer because it may worsen this pain. “This increase in pain occurs within a few hours of testosterone injectionand subsides as blood testosterone levels decline during the first cycle of BAT,” says Denmeade. “The worsening pain is not due to the rapid growth of the prostate cancer, but is more likely to the release of inflammatory factors stimulated by testosterone.”
BAT and the immune system
Some men respond exceptionally well to BAT. Denmeade has some 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 become stressed and activate 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% decrease in PSA and one man remains in long-term remission – “We thought this might be the secret: androgens plus immunotherapy.”
COMBAT, a small PCF-supported phase 2 study led by Hopkins investigators Mark Markowski, MD, Ph.D., and Emmanuel Antonarakis, MD, (now Director of Urogenital 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 40 percent clinical response rate,” Markowski says. “We also observed a sustained benefit, lasting more than a year, in a few patients who had received extensive prior treatments.” The results showed 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 participants. Markowski and Antonarakis are designing a randomized Phase 3 study to compare combined BAT plus nivolumab versus standard therapies 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 study the good from these biopsies,” looking for specific biomarkers or gene mutations that could help predict who will have the deepest and longest-lasting responses. The team is also performing additional studies on the interactions between BAT and the immune system to discover how this treatment can be improved.
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Additionally with Book, I have written much more about prostate cancer on the Prostate Cancer Foundation website, pcf.org. The stories I have written are in the “Understanding Prostate Cancer” and “For Patients” categories. As Patrick Walsh and I have said for years in ours books, Knowledge is power: Saving your life can start with going to the doctor and knowing the right questions to ask. I hope all men put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s and if you are of African descent or have a family history of cancer and/or prostate cancer, you should be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask.
©Janet Farrar Worthington
