William Oh, MD: Differences Between Side Effects of AR-Targeted Therapies

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

One of the leading types of treatments that I would use in this patient would be an AR-targeted therapy. And there are two available—abiraterone acetate, which is given with prednisone, and enzalutamide, which is not given with prednisone. These drugs work slightly differently from each other. One blocks the production of testosterone, that’s abiraterone, whereas the other, enzalutamide, blocks the action of androgen on the androgen receptor. So they’re slightly different from each other in how they work, and their side effect profiles are thus slightly different from each other.

Both treatments cause fatigue because we know that testosterone is actually an important driver of energy. So if we decrease testosterone or block testosterone, it can cause fatigue. These men may also have hot flashes. They may have increased weight gain and other known side effects of blocking testosterone function. But the side effects can differ a little bit between the two. The most important differences really relate to the metabolism of the drugs, and perhaps their effects on end organs, like muscle and the liver.

For example, abiraterone is known to cause liver function abnormalities at a slightly higher rate. So it’s very important to monitor liver function tests when a patient initiates abiraterone plus prednisone. Typically, the label would say that you should check the liver function tests every 2 weeks for the first 3 months, and that’s my practice. While it’s uncommon for patients to have significant liver toxicity, if you see that then you would stop or adjust the dose of the medicine.

Enzalutamide has a different side effect profile. It doesn’t cause as much liver toxicity. But in particular it may cause a little bit more fatigue and maybe some muscle weakness. We’ve been hearing that some patients will have more profound muscle weakness, or sometimes they’ll actually fall from being on enzalutamide, so you have to monitor those side effects closely.

An additional side effect that’s important to remember about enzalutamide is that it may cause seizures. Now the truth is that seizures are not very common with enzalutamide in the original studies. In the post-chemotherapy setting there was about a 1% rate of seizures. In the pre-chemotherapy setting they excluded anyone with a known seizure disorder, and in general, in my practice, if somebody has a risk for seizures or has a history of seizures, I would not use a drug like enzalutamide. But for the most part it has not been a major issue, but it’s something to look out for.

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