Identifying and Combating the Dangers of ADT in Prostate Cancer Patients

Micrograph of metastatic prostate carcinomaThe modification of the androgen axis plays a central role in men’s health, from maintaining vitality to controlling prostate cancer. Trying to balance the side effects and benefits of altering this axis is a fertile area of research.

Brigham and Women’s Hospital investigators not only have outlined some of the more serious complications of androgen deprivation therapy (ADT), but also are exploring ways to improve the health and quality of life of prostate cancer patients undergoing ADT.

In a review of current literature, Shehzad S. Basaria, MD, associate director of the Brigham’s Men’s Health: Aging and Metabolism Unit in the Division of Endocrinology, Diabetes and Hypertension, and colleagues documented side effects of androgen deprivation such as “bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events.”

More recent work by the Brigham published in the Journal of Urology in September 2018 found ADT to be associated with nonalcoholic fatty liver disease—an association that had never been examined previously. To conduct their study, investigators analyzed data from more than 82,000 men with localized prostate cancer in the Surveillance, Epidemiology and End Results (SEER)-Medicare database. They found that those who had received ADT therapy were more likely to be diagnosed with fatty liver disease and, importantly, noted a dose-response relationship between ADT doses and liver disease.

Another study, published in the Journal of the Endocrine Society in May 2018, showed that ADT produces electrophysiological changes in the heart that may have negative consequences. “We found that men with prostate cancer who underwent ADT experienced a significant prolongation of the QTc interval duration compared to men with a prior history of prostate cancer who have never received ADT,” explained Dr. Basaria, a study co-author. “This prolongation of QTc might explain the increased risk of sudden death that has been seen in some patients treated with ADT.”

Lastly, there have been concerns that while too little androgen is bad, too much may also cause serious medical problems. This was addressed by Alexander P. Cole, MD, of the Brigham’s Division of Urology in a paper published in the January 2018 BJU International. He and his coauthors demonstrated that too much androgen may not be as bad as we have thought.

This study cohort comprised 3,422 male U.S. military service members, retirees and their dependents who had been prescribed testosterone replacement therapy (TRT) for low testosterone. Each was matched for age and comorbidities with a man who had not taken TRT. The authors found that while there is a notably elevated risk of obstructive sleep apnea in men using TRT, “the cardiovascular risk associated with testosterone replacement therapy may be lower than once feared.”

“Our work has been important in understanding the effect of altering androgen levels pharmacologically, but we don’t want to simply document the side effects,” said Adam S. Kibel, MD, chief of the Division of Urology. “We want to do a better job of managing the hormonal health of men without adversely affecting treatment of the cancer and other diseases.”

An example of the latter goal is the work of Shalender Bhasin, MD, director of research programs in men’s health, aging and metabolism at the Brigham. He and his lab have focused on determining whether it is possible to maintain the positive impact of testosterone on prostate cancer while preserving testosterone-dependent functions such as sexual function and muscle and bone health.

“We’ve found that the mechanistic pathway by which testosterone increases muscle mass differs from those by which testosterone promotes prostate growth,” Dr. Bhasin said. “So there are strategies by which we can selectively block testosterone’s action on the prostate while sparing the muscle and other testosterone-dependent organs.”

One translation of this research has been the development of selective androgen receptor modulators (SARMs), which are compounds that bind to the androgen receptor but have very tissue-selective actions. Most first-generation SARMs, Dr. Bhasin noted, are relatively selective, but these compounds have been weak agonists on the muscle and weaker agonists on the prostate.

Dr. Bhasin’s team is working on a third-generation SARM that is an antagonist on the prostate and an agonist on the muscle and other androgen-dependent actions. The investigational drug, called LY SARM, is the subject of an early Phase II clinical trial in men who have undergone radical prostatectomy for prostate cancer and have low risk of recurrence.

The blinded study of 136 randomized participants began in February 2016 and is scheduled to be completed in 2019. Encouragingly, there have been no safety signals thus far, according to Dr. Bhasin.

“If LY SARM establishes prostate selectively and shows safety and efficacy, we’ll extend the use of this third-generation SARM to the ADT population, which is our real target,” he said. “Being able to use this SARM to prevent many of the undesired and unintended complications of ADT would be a very significant advance in the treatment of men receiving ADT.”

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