ADT use may have an immunological benefit during the pandemic

The CDC recommends Covid-19 testing for cancer patients who may be immune-compromised by their cancer or chemo treatment.The extra caution is justified only in men with late-stage PC. Those who have already had prostate radiation, may have some immune enhancement, perhaps especially with SBRT (pre-clinical). The exception may be those who have had whole-pelvic radiation. Assuming that Covid-19 (unlike Spanish Flu) is milder in those with better immune systems, it is possible that ADT may improve their immune response to the disease.

Data are showing that men are dying of Covid-19 at greater rates than women. This may be because of genetic effects and hormonal effects. Testosterone was found to be immunosuppressive for influenza.  ADT has been found to be immunoprotective (here and here).

(UPDATE MAY 26, 2022) Lee et al. reported in an observational study of 3,057 US Veterans using ADT:

ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

Early Covid-19 data are confirming this (here and here)

While normal levels of estrogen seem to be immunoprotective, high levels, as in pregnant women or men on Bipolar Androgen Therapy (because testosterone is metabolized to estradiol), reverses the protection. The implications for ADT use are:

• If you are on continuous ADT, stay on it. This is true even if ADT has been augmented with Zytiga and prednisone, or anti-androgens.Those taking Zytiga with prednisone needn't worry because the prednisone is only a replacement dose, and is not large enough to be immunosupressant. Because of negative feedback, it is more dangerous to take too little prednisone. 
• If you are on intermittent ADT, this might be a good time to end your ADT vacation. 
• Men using Bipolar Androgen Therapy on a clinical trial should discuss the timing with the trial investigator. Anyone taking supraphysiologic doses of testosterone should consider this as well. 
• If you are taking adjuvant ADT after radiation, or neoadjuvant ADT before radiation consider sticking with it a little longer.

(Update 9/23/21) A very small sample size retrospective study found there was no statistically significant difference in Covid-19 death or severity between men who used ADT for PCa  (11 men) and men with PCa and Covid-19 who did not use ADT (80 men).

Also see the recommendations for those getting radiation therapy.

Androgen deprivation followed by androgen supplementation may increase the efficacy of radiotherapy

We have seen the ability of androgen deprivation to increase the efficacy of high dose IMRT in controlling prostate cancer (see this commentary). A new study from Johns Hopkins turns conventional logic on its head by demonstrating that sequential androgen deprivation and androgen repletion may be optimal for enhancing the therapeutic efficacy of radiation in prostate cancer… at least in mice.

I don’t often comment on lab studies because what works in the mouse world often does not work when tested in humans. Johns Hopkins has been a leader in exploring the possibility of androgen sequencing, and is currently conducting a trial of “bipolar androgen therapy (BAT)” in men undergoing lifelong ADT for advanced cancer (see this commentary).

Haffner et al. discovered that androgens, like testosterone or DHT, can activate an enzyme (TOP2B) that induces double-strand breaks (breaks on both sides of the double helix) in the DNA of prostate cancer cells that express the TMPRSS2:ERG fusion gene.  This gene has been implicated in prostate cancer development and has been detected in about half the cases of prostate cancer. Coincidentally, double-strand breaking is exactly how radiation kills cancer cells. They hypothesized that after androgen deprivation is used to kill off those cancer cells susceptible to it, that restoring androgens combined with ionizing radiation might increase the therapeutic potential over radiation alone. Hedayati et al. report that this is exactly what happened in mice.

This may or may not eventually translate into protocol changes in radiation therapy, but at the very least it gives us a healthy appreciation for the very complex biochemical machinery involved in cancer genesis and therapeutics.

Written February 4. 2016