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Bipolar androgen therapy benefited men with prostate cancer and no symptoms
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Testosterone has been found to suppress some advanced prostate cancers, countering previous beliefs that the hormone feeds the disease, according to research published in Science Translational Medicine.
“Cyclic high-dose testosterone, or bipolar androgen therapy, shows early signs of promise as a treatment in men with asymptomatic, castration-resistant prostate cancer,” Michael T. Schweizer, MD, of the University of Washington/Fred Hutchinson Cancer Research Center, Seattle, told Endocrine Today. “It may also potentially serve to resensitize prostate cancer to treatments to which resistance has developed.”
Michael T. Schweizer
Schweizer, with Samuel Denmeade, MD, of Johns Hopkins University School of Medicine, and colleagues recruited 16 men with metastatic prostate cancer for an open-label, single-site, single-arm pilot study to assess the safety and efficacy of bipolar androgen therapy (BAT).
The men were all receiving testosterone-lowering treatment, had been previously treated with at least one androgen deprivation therapy, and showed rising levels of prostate-specific antigen (PSA) and radiographic evidence that their cancers were growing resistant.
Patients received three 28-day cycles of intramuscular testosterone injection and 2 weeks of the chemotherapy drug etoposide; those demonstrating reduced PSA levels after the cycles continued on the injections alone.
Samuel Denmeade
Two men did not complete the study; one died of pneumonia and sepsis, and another experienced prolonged erection, respectively attributed to etoposide and testosterone.
Half of the remaining 14 patients showed improved PSA levels, with reductions between 30% and 99%, whereas the other half showed no decreases; four of the seven men continued on testosterone therapy for 12 to 24 months and had low PSA levels.
Further, half of the 10 patients with cancers evaluable through imaging experienced greater than 50% tumor shrinkage; in one patient, the cancer disappeared completely.
The timing of testosterone therapy is critical and difficult to determine, and the researchers cautioned men against attempts to self-medicate with over-the-counter supplements.
“The prostate cancer cells have the ability to adapt to the level of testosterone in the environment,” Denmeade told Endocrine Today. “At the beginning of treatment they are living in normal testosterone. When we suddenly lower testosterone, the cells will die because they need testosterone for survival. If we gave additional testosterone as therapy at this point, we know the disease would get worse, not better.”
Previous studies have revealed a worsening of the disease in men who take testosterone at certain times, he said, particularly those who have not yet received testosterone-blocking therapy and those who are experiencing symptoms of active cancer progression.
After long exposure to low testosterone, the prostate cancer cells adapt so they can continue to survive and grow, Denmeade said; the major adaptation is to produce more androgen receptor protein.
“What we finds is that this high production of the androgen receptor makes the cell vulnerable to high testosterone,” Denmeade said. “We think that this is because the high testosterone stabilizes the androgen receptor to degradation.”
Androgen receptor degradation is required for the cell to go through the cell cycle and create daughter cells, he said.
“Cells that survive the high testosterone by lowering the androgen receptor become vulnerable to death when the testosterone level suddenly drops over the course of a cycle of BAT, during which testosterone goes from super high to super low over 28 days,” Denmeade said.
Further clarification is needed on which patients are most likely to benefit, Schweizer said, noting that it seems less likely that BAT would help those with untreated disease.
“BAT is clearly not ready for the clinic yet,” Schweizer said. “It shows promise in this small study, but these results need to be confirmed in larger randomized trials.”
One large randomized trial has been designed and will open sometime in the first half of 2015, Schweizer said. In the study, men who have progressed on the prostate cancer treatment abiraterone (Zytiga, Janssen Biotech) would randomize between BAT and enzalutamide (Xtandi, Astellas). “This should give us a better idea of how well this works,” Schweizer said. – by Allegra Tiver
For more information:
Michael T. Schweizer, MD, can be reached at Division of Oncology, Department of Medicine, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA 98109; email: schweize@uw.edu.
Samuel R. Denmeade, MD, can be reached at the Cancer Research Building I, 1650 Orleans Street, Baltimore, MD 21231; email: DENMESA@jhmi.edu.
Disclosure: Funding for this work was provided by the One-in-Six Foundation, Akron, Ohio. Denmeade reports serving as consultant for GenSpera, Medicenna and Sophiris.
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