Editing Hormonal Therapy (section)

==== Inhibition of Androgen Synthesis ====

===== Aminoglutethimide (historical) =====
* Inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis.
** Given its inhibition of a very proximal step in adrenal function, aminoglutethimide blocks production of aldosterone and cortisol.
* As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone.

===== Ketoconazole (historical) =====
* Orally active, '''broad-spectrum antifungal agent'''
* '''Non-specific inhibitor of several cytochrome P450–dependent pathways, resulting in loss of adrenal steroid synthesis and testosterone synthesis by Leydig cells'''
* '''Effects are rapid''', '''with testosterone levels dropping to the castrate level with 4 hours of administration''' in some cases. The effects are also immediately reversible, indicating '''dosing must be continuous (every 8 hours) to maintain low testosterone levels.'''
* Previously used as the first or second agent in so-called secondary hormonal manipulation for CRPC
* Adverse events include gynecomastia (caused by alterations in testosterone/estradiol ratios), lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea.
* Because of the adrenal suppression, usually given with hydrocortisone (20 mg BID).

===== Abiraterone acetate =====
* Orally active

====== <span style="color:#ff0000">Mechanism of Action</span> ======

*'''<span style="color:#ff0000">Potent, selective, non-steroidal, irreversible inhibitor of cytochrome P450 isoform 17 (CYP17)</span>'''
** CYP17 has both 17,20-lyase and 17α-hydroxylase activity and is a key enzyme in androgen synthesis
*** '''Inhibition of 17α-hydroxylase results in excess synthesis of aldosterone''' and its precursors, causing a suppression of cortisol with a '''<span style="color:#ff0000">compensatory rise in ACTH</span>'''.
**'''Blocks androgen synthesis by testis, adrenals, and prostate cancer cells that generate their own testosterone as part of a back door pathway'''
**More potent than ketoconazole

====== <span style="color:#ff0000">Adverse events (7)</span> ======
# '''<span style="color:#ff0000">HTN</span>'''
# '''<span style="color:#ff0000">Hypokalemia</span>'''
# '''<span style="color:#ff0000">Fluid overload</span>'''
# '''<span style="color:#ff0000">Fatigue</span>'''
# '''<span style="color:#ff0000">Hepatotoxicity</span>'''
# '''<span style="color:#ff0000">Myopathy and rhabdomyolysis</span>'''
# '''<span style="color:#ff0000">Increased triglycerides and cholesterol</span>'''
* '''Generally well tolerated'''
* '''<span style="color:#ff0000">Hypertension, hypokalemia, and fluid overload</span>'''
** '''<span style="color:#ff0000">Related to an increase in the mineralocorticoids</span>, due to the effects of blocking the conversion of pregnenolone to 17-hydroxypregnenolone,''' resulting in an increase of the mineralocorticoids deoxycorticosterone and corticosterone.
** '''<span style="color:#ff0000">Management</span>'''
***'''<span style="color:#ff0000">Abiraterone is co-administered with prednisone to suppress the increases in ACTH resulting from increased mineralocorticoids and decreased cortisol</span>'''
**** '''<span style="color:#ff0000">Concomitant steroid may exacerbate hyperglycemia in diabetics</span>'''
* '''Hepatotoxicity'''
** '''Most serious potential adverse event and can be severe and potentially life threatening.'''
*** '''Adverse event most likely to cause dose reduction or discontinuation.'''
** '''Liver enzymes as well as electrolytes must be checked frequently when initiating the medication.'''

* '''Recommended clinical monitoring (as per Cancer Care Ontario)'''
** '''Clinical assessment of adverse events: at each visit'''
** '''<span style="color:#ff0000">Blood pressure and serum potassium: baseline and monthly'''
** '''<span style="color:#ff0000">Liver function tests, bilirubin: baseline, every 2 weeks for the first 3 months and monthly thereafter, or as clinically indicated'''
** '''Cholesterol and triglycerides: baseline, every 2 to 3 months and as clinically indicated'''
**'''Monitor for adrenal insufficiency: as clinically indicated when prednisone is withdrawn, or during periods of infection/stress'''
** '''Monitor for mineralocorticoid excess: as clinically indicated if patient continues on abiraterone after stopping prednisone'''

====== Trials with Abiraterone ======
* '''COU-AA-301: post-docetaxel CRPC'''
* '''COU-AA-302: pre-docetaxel CRPC'''
* '''LATITUDE'''
** '''See below section on hSPC'''
* '''STAMPEDE'''