Metastatic Prostate Cancer with Charles Ryan, MD and William K. Oh, MD: Case 1 - Episode 4

Charles Ryan, MD: The Differences in Side Effects Between the Two AR-Targeted Therapies

How do the two androgen receptor (AR)—targeted therapies differ in terms of side effects?

Abiraterone and enzalutamide, we call them both AR-targeted therapies, but, in reality, enzalutamide directly targets and binds to the AR, whereas abiraterone is a drug that reduces the amount of ligand that is available to the AR. So they have different mechanisms of action. And, in fact, I think of them as actually being two different points along the same sort of pathway—abiraterone a little bit higher up in the production of hormones and enzalutamide blocks the binding of hormones to the androgen receptor directly.

Now, one of the major considerations is that as abiraterone reduces androgen production in the adrenal glands and in the tumor, it can also cause a slight dysregulation of the adrenal gland. What happens is the adrenal gland is actually stimulated because of an apparent deficit to make more adrenal hormones. And it doesn’t make androgens because that pathway is blocked by CYP17 but it does make mineralocorticoid and that’s what causes the fluid retention, the salt retention, and the potassium loss. So those are the main things that we need to be aware of with abiraterone, and those are pretty much mediated by the use of prednisone in this situation.

Enzalutamide is different. It crosses into the tumor, it blocks the androgen receptor directly and has very important positive effects in that setting. However, this particular drug is able to cross into the central nervous system, and much of the effects that we think we see with regards to fatigue and falls may be centrally mediated, meaning it’s blocking the androgen receptor’s effect in the brain. And we know and we’re discovering, it seems every year now, more and more activities of the androgen receptor and testosterone in the brain and those are being affected by this drug. So those are the main considerations to keep in mind. We also think that enzalutamide may enter into the muscles and target some muscle androgen receptor activity, and that may be the reason for some of the fatigue that is seen as well.

CASE: Metastatic Prostate Cancer (Part 1)

Stanley S is an 83-year-old Caucasian male whose past medical history includes diagnosis of adenocarcinoma of the prostate in 2012 with no evidence of metastasis. At the time, he was started on bicalutamide and his serum PSA levels subsequently decreased to 1.2 ng/ml.

During his most recent follow-up exam, the patient complained of intermittent back pain and increasing fatigue.

  • His serum PSA level is 56.9 ng/ml and his alkaline phosphatase is 258 U/L
  • CT scan shows enlarged lumbar bone metastasis with associated soft tissue component, as well as symptomatic nodes with lumbar bone metastases
  • Biopsies of the prostate and transrectal ultrasound reveal the prostate is 42 grams
  • Ten of 14 cores are positive for prostate cancer for a Gleason score of 8 (4 + 4)
  • His ECOG performance status score is a 2