There has been some surprising and unexpected news recently reported by John’s Hopkins Kimmel Cancer Center. Testosterone, which is believed to be a feeder of prostate cancer has been found to also suppress some advanced prostate cancers and also may reverse resistance the to the testosterone-blocking drugs (ADT) used to treat advanced prostate cancer.

The small study led by Samuel Denmeade, M.D. looked at just16 men with metastatic prostate cancer and so it is still very early for us to make any judgments about the efficacy of these findings for clinical use.

In the normal course of treatment when men are believed to have developed metastatic prostate cancer they are put on hormone suppressive treatment (ADT). Eventually these ADT drugs stop working, the cancer becomes resistant and despite a man being castrate the cancer again begins to progress. At this time men are usually switched to some of the newer ADT type drugs (Xtandi or Zytiga)

According to Denmeade the ADT drugs may make prostate cancer more aggressive over time by enabling prostate cancer cells to subvert attempts to block testosterone receptors. Many men on these drugs experience harsh side effects, including impotence, weight gain, muscle loss and intense fatigue.

“This really is the most lethal form of prostate cancer,” says Michael Schweizer, M.D., researcher at Fred Hutchinson Cancer Research Center and contributor to the study during his fellowship at Johns Hopkins. “It’s the one that’s the most resistant, and typically once people progress to this stage it’s when we start to worry that they’re at a much higher risk for dying from prostate cancer.”

This new study tested a novel approach, which was based on the idea that if prostate cancer cells were flooded with testosterone, the cells might be killed by the hormone shock. The cells also might react by making fewer receptors, which may make the prostate tumor cells again vulnerable to androgen deprivation therapy.

For the study, Denmeade and his colleagues enrolled the 16 men who had been receiving ADT for metastatic prostate cancer at Johns Hopkins. All had been treated with at least one type of ADT and then had rising levels of prostate specific antigen (PSA) and radiographic evidence their cancers were becoming resistant.

In the trial the men were given three 28-day cycles of an intramuscular injection of testosterone and two weeks of a chemotherapy drug called etoposide. Men who showed decreases in PSA levels after three cycles were continued on testosterone injections alone.

Of the 16, two did not complete the study: One died of pneumonia and sepsis due to the chemotherapy drug, etoposide and the other experienced prolonged erection, a disqualifying side effect of the testosterone.

Of the 14 men who remained in the trial, seven experienced a dip in their PSA levels of between 30 and 99 percent, an indication their cancers were stable or lessening in severity while 7 of the men showed no decrease in their PSA scores.

In addition, four of the seven men stayed on testosterone therapy for 12 to 24 months with continued low PSA levels. Of 10 men whose metastatic cancers could be measured with imaging scans, five experienced tumor shrinkage by more than half, including one man whose cancer completely disappeared.
“Surprisingly, we saw PSA reductions in all of 10 men, including four whose PSA didn’t change during the trial, who were given testosterone-blocking drugs after the testosterone treatment,” says Denmeade.

The study authors have suggested that these results strongly suggest that testosterone therapy has the potential to reverse the resistance that eventually develops to testosterone-blocking drugs like enzalutamide.

Three of the study participants have died since the study began in 2010; the rest are still alive.

During the cycles of etoposide, many of the men experienced the usual side effects of chemotherapy, including nausea, fatigue, hair loss, swelling and low blood counts. In men receiving only the testosterone injection, however, side effects were rare among the men and usually low grade.

Denmeade says that more studies are being planned at Johns Hopkins and other hospitals. “There has been a groundswell of interest in the idea of reversing resistance to androgen deprivation therapy. We have plenty of anecdotes and some evidence in this small study, but it’s important to test it in larger groups of patients,” he adds.

An important note:

Dr, Denmeade, warned that the timing of testosterone treatment used in his research is critical and difficult to determine, and says men should not try to self-medicate their cancers with testosterone supplements available over the counter. He pointed out that prior studies have shown that taking testosterone at the wrong time — particularly by men with symptoms of active cancer progression who have not yet received testosterone-blocking therapy — can make the cancer worse.

Reported in the Jan. 7 issue of Science Translational Medicine.

Joe T. Nowak, M.A., M.S.W.