Sequencing Testosterone and Enzalutamide to Prevent Unfavorable Progression (The STEP-UP Trial)
Abstract
Recently, new hormone therapies have been shown to produce a few months improvement in survival. However, despite these advancements, prostate cancer remains incurable. Additionally, hormone therapy produces immediate and delayed side effects such as increased fatigue, decreased activity, weight gain, and loss of sexual function in men suffering from prostate cancer. Ideally, what is needed is a new treatment approach that increases the quantity of life, but also improves the quality of life in men with prostate cancer. All of the current types of hormone therapy work by depriving prostate cancer cells of the male hormone testosterone. Testosterone belongs to a class of chemical called androgens. Prostate cancer cells depend on androgens like testosterone to survive and grow. Androgens work by entering the prostate cancer cell and binding to the androgen receptor. If one thinks of the androgen as the “ball,” the androgen receptor can be thought of as the “glove.” When the androgen receptor catches the androgen, the ball and glove together stimulate the prostate cancer cell to grow and make things like PSA. When testosterone in the blood circulation is lowered by surgical castration or by drugs such as Lupron or Zoladex, many of the prostate cancer cells within a patient die off. Some of the cells survive because they adapt to the new environment of low testosterone. In some cases, additional blockade of the remaining low amounts of testosterone binding to the androgen receptor “glove” by other hormone therapies can also produce a benefit. Eventually, even with both testosterone lowering and testosterone blocking therapies, the prostate cancer cells continue to grow. Autopsy studies performed on men who had died from castration-resistant prostate cancer (CRPC) showed that, instead of throwing away the androgen receptor “glove,” surprisingly, the prostate cancer cells in these men adapted to the low testosterone environment through production of even more of the androgen receptor than they had before castrating therapies. Other studies showed that this increase in the androgen receptor may be the reason why testosterone-depriving therapies stop working. Experiments in our laboratory and others have further shown that human prostate cancer cells that are resistant to castrating therapies due to marked increase in the amount of androgen receptor can paradoxically be killed if rapidly exposed to high levels of testosterone. Based on this, we performed clinical trials in which we learned that men with metastatic CRPC could tolerate Food and Drug Administration-approved doses of testosterone that produced high blood levels of testosterone without worsening of side effects or disease. Recently, we completed a study in which we compared results between men treated with standard enzalutamide (Xtandi) hormone therapy to men treated with rapid alteration between high and low levels of testosterone. We call this rapid cycling “Bipolar Androgen Therapy” (BAT). We believe that rapid cycling between high and low testosterone levels does not allow time for the prostate cancer cells to adapt to the ever-changing environment. This treatment is designed for men who have been on chronic castrating therapy for = 1 year. The men must have no pain symptoms and a low to moderate amount of metastatic disease. The men receive either an injection of testosterone every 28 days or continuous treatment with Xtandi. We found that men responded equally well to testosterone vs. enzalutamide. Remarkably, only 25% of the men who received Xtandi without testosterone had a 50% decrease in PSA, and the median time on Xtandi before PSA increased was only 3 months. In contrast, 73% of the men who received Xtandi after first receiving testosterone had a 50% decrease in PSA, and the media response time was 11 months. The combined results from our clinical studies suggest that the best way to give hormone therapy would be to rapidly sequ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010177
Entities
People
- Samuel Denmeade
Organizations
- Johns Hopkins University
- United States Army