Androgen deprivation therapy (ADT) has long been a mainstay in the management of prostate cancer. Indeed, the vast majority of prostate cancers depend on androgens (hormones like testosterone) for their growth. Lowering testosterone levels with ADT is a reasonable approach. But it comes with two sets of problems.
The first has to do with the side effects of ADT. These are many, and some are very serious: hot flashes, fatigue, erectile dysfunction, decreased bone density, increased body fat, hyperglycemia, and insulin resistance. The last three are the signs of metabolic syndrome, which itself is a potentially life-threatening condition leading to diabetes and cardiovascular disease.
The second problem with ADT is that, sooner or later, it just stops working. In healthy cells, interactions between testosterone and its receptor (a protein called androgen receptor or AR) push cells to multiply. In advanced cancers, this promotes invasion and metastatic spread, which can be slowed with ADT. But during ADT, prostate cancer cells eventually develop alterations in the AR that make it work in overdrive mode, even without testosterone. The cancer may continue to grow in the absence of testosterone—a lethal condition known as castration-resistant prostate cancer (CRPC).
“If you can’t beat them, join them,” a proverb suggests. Researchers at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center decided to do just that. The idea was to flood cancer cells with the hormone they need so badly, and then deprive them of it again.
This paradoxical approach had already been explored long ago in breast cancer, another ‘hormonal’ cancer. Many breast cancers depend on estrogen, and treatment involves depleting estrogen supplies in the body. Similar to prostate cancers, breast cancers often stop responding to estrogen deprivation therapy. High doses of estrogen were given to breast cancer patients in the hope of restoring their sensitivity to subsequent estrogen withdrawal, but this did not play out well. It actually hastened death in some patients.
Now, at Johns Hopkins, a similar but more evolved approach to metastatic prostate cancer has been explored in a small clinical study reported in the journal Science Translational Medicine. Patients with low to medium metastatic disease who had received ADT for an average of 4 years were literally flooded with testosterone, receiving a high-dose injection once every 4 weeks. This was followed by the chemotherapy drug etoposide, given daily for 2 weeks. The cycle was repeated a total of three times.
The premise of the study was that prostate cancer cells that had adapted to thrive in low-testosterone environments would be ‘shocked’ by a high dose of the hormone. In response, they would reduce the amount of AR and become more sensitive to death by etoposide. The researchers also hypothesized that ADT therapy might be more effective after the testosterone shock. Previous studies conducted on cells in a laboratory setting supported this treatment schedule, dubbed bipolar androgen therapy (BAT).
Of 16 patients who received the testosterone shock treatment, 14 remained in the trial. Seven of these had a drop in PSA levels (PSA, or prostate-specific antigen, is used to monitor the progression of prostate cancer). Of these seven, four men stayed on testosterone therapy for 12 to 24 months. Ten patients had tumors that could be monitored by imaging scans. Five of them showed tumors shrinking and even disappearing entirely in one case. All ten patients received ADT after finishing testosterone treatments. In these patients, ADT triggered a decrease in PSA levels that had not been observed before the testosterone treatment. This could mean that the testosterone therapy indeed restored the cancers’ sensitivity to ADT.
Some limitations of the study are obvious; the small number of patients is one of them. But this is inevitable for pilot trials, especially for those, like this BAT study, that are based on somewhat unorthodox hypotheses. The second limitation is that it is too early to make conclusions about the long-term consequences of BAT and its effect on overall survival. Third, testosterone shock treatment is not suitable for all patients with prostate cancer. No one will be giving testosterone to patients who have not been on ADT—this will only fuel the growth of their cancers. Meanwhile, larger clinical studies of BAT are planned, hopefully with a long-term follow up of the patients.