Bipolar androgen therapy, where the body is alternately flooded with and starved of testosterone, is safe and effective for the treatment of metastatic prostate cancer, according to a study presented at the 28th Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany.
The researchers, led by Samuel Denmeade, MD, professor of oncology at Johns Hopkins University School of Medicine in Baltimore, presented results from 47 men with metastatic prostate cancer resistant to chemical or surgical treatment who have completed at least three cycles of bipolar androgen therapy.
For the study, RESTORE (NCT02090114), the researchers injected a high dose of testosterone (400 mg) into the muscle of the men every 28 days. The men continued to receive luteinizing hormone-releasing hormone (LHRH) agonist therapy to inhibit their natural testosterone production, but stopped treatment with the anti-cancer drugs Zytiga (abiraterone) and Xtandi (enzalutamide) that inhibit androgen receptor signaling, against which they had developed resistance.
“Our goal is to shock the cancer cells by exposing them rapidly to very high, followed by very low, levels of testosterone in the blood,” Denmeade said in a press release.
The first arm of the study looked at 30 men who were treated with testosterone after their disease became resistant to Xtandi and started to progress. The results showed the levels of prostate specific antigen (PSA) declined in about 40% of the patients. This decline was more than 50% in 30% of the patients.
In addition, the disease progression was halted in several patients for more than a year. In some patients, the size of the tumor decreased. In one case, PSA levels dropped to zero after three months and have remained at that level for 22 cycles of treatment.
In the second arm of the study 17 of the 30 patients whose disease had started to progress again after treatment with Zytiga, received testosterone. PSA levels also dropped in this group. In six patients, the levels of a protein associated with resistance to treatment with Xtandi dropped to zero, and two patients had 50% or more decline in PSA levels.
“We think the results are unexpected and exciting,” Denmeade said. “We are still in the early stages of figuring out how this works and how to incorporate it into the treatment paradigm for prostate cancer.”
“The benefits of the treatment are particularly evident in men who have had no sexual function for many years due to impotence caused by hormone deprivation. These men are quite happy with the new treatment,” he added. “Other positives include increase in muscle strength, increased energy and decreased fatigue. This does not occur in every man and we are not sure exactly why.”
The treatment was well-tolerated by all men. One patient reported an increase in pain and one had urine retention problems.
According to the researchers, more research is needed to fully understand the effect of bipolar androgen therapy. Denmeade warned that testosterone treatment definitely can worsen pain in men with prostate cancer who have pain from their disease.
“This therapy should only be given to men who are asymptomatic,” he said.
A second trial called TRANSFORMER (NCT02286921) is testing bipolar androgen therapy in men with metastatic castrate-resistant prostate cancer whose disease had progressed after being treated with Zytiga.
Traditionally, prostate cancer has been treated by lowering the levels of testosterone because it was thought that testosterone induced tumor growth. But according to Denmeade, there is no evidence that testosterone promotes cancer.
“Indeed, earlier research in prostate cancer cell lines has shown that treatment with high doses of testosterone could inhibit growth and kill cancer cells,” he said. “The exact mechanism is not known and there may be many things happening since the androgen receptor is the key signaling pathway in prostate cancer.”
Denmeade added that previous research in his laboratory has shown that “testosterone interferes with part of the cell division process in cancer cells called DNA licensing and also makes breaks in the DNA of tumor cells, causing them to die.”
Jean-Charles Soria, PhD, of the Institut Gustave Roussy in France and the chair of the scientific committee for the symposium, said the use of testosterone in men with castration-resistant prostate cancer “is an intriguing concept that was previously advocated some years ago, but this is the first time we have clinical data in patients whose disease has progressed after treatment with [Zytiga] or [Xtandi].”