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© The Canadian Journal of Urology™; 23(Supplement 1); February 2016
33
The primary care physician’s role in the monitoring and management of the potential sequelae of the medical
treatment of prostate cancer: early and late
The most common side effects of abiraterone
include elevations in triglycerides and cholesterol,
liver function tests (LFTs), fatigue, musculoskeletal
pain, abnormal electrolyte(s), edema, constipation, and
hot flashes. Severe hepatotoxicity has been reported
in approximately 7% of patients and is more common
in patients with abnormal LFTs at baseline. Most
cases of hepatotoxicity appear to be reversible after
discontinuation of abiraterone.
Case reports of myopathy and rhabdomyolysis
occurred generally within the first month of treatment
and resolved following drug discontinuation.
Mineralocorticoid effects, which include hypertension,
fluid retention and hypokalemia, are commonly
reported. Patients on prednisone may require an
increased dose of a corticosteroid before, during and
after stressful conditions, such as surgery, trauma or
severe infections. There were slightly more cardiac
events (mainly grade 1/2) reported in the abiraterone
group (11%-16%) than in the placebo group (7%-14%).
Enzalutamide (Xtandi)
Enzalutamide (160 mg PO daily) is a very potent
androgen receptor inhibitor which competitively
inhibits the binding of androgen to the receptor.
15
The most common side effects for enzalutamide
include fatigue, musculoskeletal pain, rise in LFTs,
diarrhea, androgen deprivation symptoms, edema,
headache, hypertension, dizziness and insomnia.
Enzalutamide is associatedwith an increased risk of
seizure, especially at doses above 160mg. The lowering
of the seizure threshold may be due to enzalutamide
and its active metabolite crossing the blood brain
barrier and inhibiting GABA gated chloride channel
activity.Treatment-emergent hypertension should
be managed appropriately. Posterior reversible
encephalopathy syndrome (PRES) has been reported
rarely, with and without associated hypertension.
Enzalutamide should be discontinued in patients who
develop PRES. Increases in non-pathological fractures
and falls were observed as compared to placebo.
Concomitant neurological symptoms or presyncope
were rarely reported with the falls.
Caution should be exercised in the following patient
populations: history of significant cardiovascular
disease, QT prolongation, risk factors for Torsades
de Pointes, and/or medications known for QT
prolongation. Caution should also be exercised in
those with either a history of seizures or those who
have known risk factors for seizures (e.g., brain injury
with loss of consciousness, recent TIA, CVA, brain
metastases, and/or medications that lower the seizure
threshold).
Enzalutamide may cause neuropsychiatric events
such as cognitive or memory impairment, seizures,
hallucinations, etc. Patients should take caution
and avoid tasks in which mental impairment or loss
of consciousness may harm themselves or others.
Monitor INR levels closely for patients on warfarin.
Potential drug-drug interactions
Abiraterone is mainly metabolized by CYP3A4 and
SULT2A1. The drug moderately inhibits CYP2C9,
2C19 and P-glycoprotein in vitro (may not be clinically
significant), and is a potent CYP1A2 inhibitor (no
observed increase in systemic theophylline exposure),
potent CYP2D6 and CYP2C8 inhibitor in vitro;
therefore, exercise caution with concomitant use of
CYP2C8/1A2 substrates and monitor closely.
16
Enzalutamide is an inducer and inhibitor of several
CYP isoenzymes and susceptible to many drug
interactions. Since the half-life of enzalutamide is 5.8
days, the effects on enzymes may persist for onemonth
or greater after stopping the drug.
17
Table 2 summarizes the potential drug-drug
interactions of these two new hormonal agents with
other commonly prescribed drugs.
18
Other novel compounds used in mCRPC
Radium 223 dichloride (Xofigo)
Radium 223 dichloride is a therapeutic alpha particle-
emitting pharmaceutical and targets bone metastases
by acting as a calcium mimetic. It naturally targets
new bone growth in and around bone metastases,
and has been shown to reduce skeletal complications.
Radium 223 is indicated for the treatment of patients
with CRPCwith symptomatic bone metastases and no
known visceral metastatic disease.
19
This radiopharmaceutical is excreted by the small
intestine. The most common side effects include
nausea, diarrhea, vomiting, edema, and bone marrow
suppression (notably thrombocytopenia, neutropenia,
leukopenia and pancytopenia).
Denosumab (Xgeva)
Denosumab (120 mg SC q monthly) is indicated
for reducing the risk of developing skeletal-related
events in patients with bone metastases from
prostate cancer. This agent is a fully human IgG2
monoclonal antibody which inhibits osteoclast
formation, function and survival, thus decreasing
bone resorption and interrupting cancer-induced
bone destruction. Patients being treated with
denosumab should not be treated concomitantly
with bisphosphonates.
20