Editing Hormonal Therapy (section)

==== Androgen-receptor antagonists i.e. anti-androgens ====
* '''<span style="color:#ff0000">Classified: steroidal vs. non-steroidal</span>'''

===== Steroidal anti-androgens (cyproterone acetate) =====
* '''Block androgen action at the cellular level'''
** '''Stimulates the AR in the hypothalamic-pituitary axis thereby activating negative feedback inhibition of the hypothalamus, resulting in decreased LH and testosterone'''§
* '''The classic steroidal antiandrogen''' '''cyproterone acetate''' rapidly lowers testosterone levels to 70-80%
* '''Adverse events (3):'''
*# '''Fluid retention'''
*# '''Thromboembolism'''
*# '''Hypogonadism'''

===== Non-steroidal anti-androgens (<span style="color:#0000ff">-lutamide</span>) =====
* '''Mechanism of Action: Block ARs, both at target tissues and in the hypothalamic-pituitary axis'''
** '''Inhibits the AR in the hypothalamic-pituitary axis thereby blocking negative feedback inhibition of the hypothalamus, resulting in increased LH and testosterone'''§
* '''<span style="color:#ff0000">Advantages over steroidal:</span>'''
*# '''<span style="color:#ff0000">Reduced risk of hypogonadism and sexual dysfunction</span> (no anti-gonadotropic effects)'''
*#* '''With non-steroidal anti-androgens, testosterone levels reach about 1.5x the normal levels of hormonally intact men (recall steroidal anti-androgens reduce LH and testosterone)'''
*#* '''Potency may be preserved'''
*#** However, in clinical trials examining erectile functioning and sexual activity in men on flutamide monotherapy, long-term preservation of those domains was only 20%, not very different than men undergoing surgical castration.
*# '''<span style="color:#ff0000">Reduced risk of osteoporosis</span>'''
* '''<span style="color:#ff0000">Disadvantage over steroidal:</span>'''
*# '''<span style="color:#ff0000">Increased risk for adverse cardiovascular effects</span>'''
* '''Adverse events:'''
*# '''Liver toxicity'''
*#* Ranges from reversible hepatitis to fulminant hepatic failure
*#* '''Requires periodic monitoring of liver function tests'''
*#* '''Associated with all non-steroidal anti-androgens'''
*# '''Gastrointestinal toxicity'''
*#* '''Most notably diarrhea'''
*#* More common with flutamide than the other non-steroidal anti-androgens
*# '''Gynecomastia and breast pain'''
*#* Due to the peripheral aromatization of increased testosterone to estradiol

====== First-generation (flutamide, bicalutamide, nilutamide) ======
* '''MOA: acts by binding to the AR in a competitive fashion'''
* '''Flutamide'''
** '''Short half-life,''' '''three times per day dosing'''
* '''Bicalutamide'''
** '''Long half-life''', once per day dosing
** '''Pharmacokinetics are not affected by age, renal insufficiency, or moderate hepatic impairment'''
** '''Associated with maintenance of serum testosterone levels in the majority of patients'''
** '''150 mg/day bicalutamide monotherapy appears to have equivalent efficacy to medical or surgical castration in men with metastatic or locally advanced disease.'''
*** Bicalutamide monotherapy (150 mg/day) is also associated with significantly better quality of life in the domains of sexual interest and physical capacity compared to surgical castration. There are, however''', higher rates of gynecomastia (66.2%) and breast pain (72.8%)'''
* '''Nilutamide'''
** About 1/4 men on nilutamide therapy will note a '''delayed adaptation to darkness after exposure to bright illumination'''

====== Second-generation: enzalutamide, apalutamide, darolutamide ======
* '''<span style="color:#ff0000">Enzalutamide</span>'''
** '''<span style="color:#ff0000">MOA: irreversibly binds directly to the androgen receptor and inhibits the binding of androgens, AR nuclear translocation, and AR–mediated DNA binding</span>'''
** '''<span style="color:#ff0000">Contraindications</span>'''
***'''<span style="color:#ff0000">History of seizures</span>'''
**'''<span style="color:#ff0000">Adverse events (note that first 6 also apply to apalutamide:</span>'''
**# '''<span style="color:#ff0000">HTN</span>'''
**# '''<span style="color:#ff0000">Diarrhea</span>'''
**# '''<span style="color:#ff0000">Fatigue</span>'''
**# '''<span style="color:#ff0000">Seizures</span>'''
**#* '''<1% of patients in clinical trials'''
**# '''<span style="color:#ff0000">Falls</span>'''
**# '''<span style="color:#ff0000">Fracture</span>'''
**# '''<span style="color:#ff0000">Hot flashes</span>'''
**# '''Neutropenia'''
**# '''Memory impairment'''
**# '''Arthralgia'''
** '''Recommended clinical monitoring (as per Cancer Care Ontario (accessed March 2020))'''
*** '''Blood pressure: baseline and each visit'''
*** '''ECG and electrolytes: Baseline and at each visit, in patients at risk of QT prolongation'''
*** '''INR monitoring for patients on warfarin: baseline and at each visit'''
*** '''Clinical assessment of adverse events: at each visit'''
** '''Trials with enzalutamide'''
*** '''AFFIRM: post-docetaxel mCRPC'''
*** '''PREVAIL: pre-docetaxel mCRPC'''
*** '''PROSPER: M0 CRPC'''
*** '''ENZAMET: M1 CSPC'''
*** '''ARCHES: M1 CSPC'''
* '''<span style="color:#ff0000">Apalutamide</span>'''
** '''<span style="color:#ff0000">MOA: binds directly to the</span>''' ligand-binding domain of '''the androgen receptor''' and prevents androgen-receptor translocation, DNA binding, and androgen-receptor–mediated transcription
** '''<span style="color:#ff0000">Contraindications</span>'''
***'''<span style="color:#ff0000">History of seizures</span>'''
**'''<span style="color:#ff0000">Adverse events (first 6 same as enzalutamide):</span>'''
**# '''<span style="color:#ff0000">HTN</span>'''
**# '''<span style="color:#ff0000">Diarrhea</span>'''
**# '''<span style="color:#ff0000">Fatigue</span>'''
**# '''<span style="color:#ff0000">Seizures</span>'''
**#* '''<1% of patients in clinical trials'''
**# '''<span style="color:#ff0000">Falls</span>'''
**# '''<span style="color:#ff0000">Fracture</span>'''
**# '''<span style="color:#ff0000">Hypothyroidism</span>'''
**# '''Rash'''
**# '''Increased cholesterol'''
**# '''Anemia'''
**# '''Hyperglycemia'''
**# '''Nausea'''
**# '''Weight loss'''
**# '''Arthralgia'''
** '''Recommended monitoring (as per Cancer Care Ontario)'''
*** '''TSH: baseline and as clinically indicated'''
*** '''ECG: baseline and as clinically indicated; more frequent in patients at risk of QTc prolongation'''
*** '''INR: if warfarin cannot be discontinued; baseline and during apalutamide treatment'''
*** '''Clinical assessment of adverse events: at each visit'''
** '''Trials with apalutamide'''
*** '''SPARTAN: MO CRPC'''
*** '''TITAN: M1 CSPC'''
* '''<span style="color:#ff0000">Darolutamide</span>'''
** '''<span style="color:#ff0000">Low penetration of the blood–brain barrier and low binding affinity for γ-aminobutyric acid type A receptors</span>'''
** '''Advantage:'''
**# '''Fewer and less severe toxic effects than apalutamide and enzalutamide'''
** '''Trials with darolutamide'''
*** '''ARAMIS: M0 CRPC'''