Editing Hormonal Therapy (section)

== Androgen Axis Blockade ==

* History
** In 1946, Charles Huggins demonstrated the influence of hormonal therapy in prostate cancer. He studied 8 men with metastatic prostate cancer and found that bilateral orchiectomy and estrogen reduced serum acid phosphatase (PSA wasn't discovered until 1979), while testosterone therapy increased serum acid phosphatase.§ He won the nobel prize in 1966 for his work.

=== Approaches for Androgen Axis Blockage ===

* '''<span style="color:#ff0000">Classified into (4): inhibit </span><span style="color:#0000ff">source, stimulation, synthesis, and receptor</span>'''
*# '''<span style="color:#ff0000">Ablation of </span><span style="color:#0000ff">sources<span style="color:#ff0000"> (bilateral orchiectomy)</span>'''
*# '''<span style="color:#ff0000">Inhibition of </span><span style="color:#0000ff">stimulation<span style="color:#ff0000"> i.e. luteinizing hormone–releasing hormone (LHRH/GnRH) and/or LH release (estrogen, LHRH agonists/antagonists)</span>'''
*# '''<span style="color:#ff0000">Inhibition of </span><span style="color:#0000ff">synthesis<span style="color:#ff0000"> (ketoconazole, abiraterone)</span>'''
*# '''<span style="color:#ff0000">Androgen-</span><span style="color:#0000ff">receptor<span style="color:#ff0000"> antagonists i.e anti-androgens''' '''(cyproterone acetate, flutamide, bicalutamide, enzalutamide, apalutamide, daralutamide)</span>'''

==== Ablation of Androgen Sources ====
* '''<span style="color:#ff0000">Bilateral orchiectomy</span>'''
** '''<span style="color:#ff0000">Quickly reduces circulating testosterone levels to < 50 ng/dL (considered castrate).</span>'''
*** '''Within 24 hours, testosterone levels are reduced by > 90%</span>'''
** '''Has largely been replaced by LHRH analogues'''
** '''Subcapsular orchiectomy (removal of glandular tissue only) has been advocated as a technique of ADT that avoids the psychological consequences of an empty scrotum'''

==== Inhibition of LHRH and/or LH release ====

===== Estrogen =====
* '''Historical'''
** First agent used at a central inhibitor
** Largely replaced by LHRH analogues
* '''MOA: potent negative feedback of estrogen on LH secretion'''
** Estradiol is 1000x more potent at suppressing LH and FSH secretion than testosterone
* '''Diethylstilbestrol (DES)'''
** '''As effective as surgical castration'''
** '''Association with cardiovascular toxicity has limited its use'''

===== LHRH agonists =====
* '''<span style="color:#ff0000">As effective as orchiectomy</span>'''
** Initially, the clinical utility of LHRH agonists were hampered by their short half-life, requiring daily injections. The generation of long-acting depot preparations, lasting several months, has established LHRH agonists as the dominant treatment in hormone therapy for prostate cancer.
* '''<span style="color:#ff0000">Initially co-administered with an androgen-receptor antagonist to block the LH and testosterone surge</span>'''
** Initial exposure to LHRH agonists results in a surge of LH (up to 10x) and testosterone levels. This '''surge''' '''can result in a severe, life-threatening exacerbation of symptoms'''
** Co-administration of an anti-androgen (bicalutamide 50mg daily) functionally blocks the increased levels of testosterone.
*** '''The testosterone flare may last for 10-20 days and therefore co-administration of anti-androgen is required for only 21-28 days'''
**** Although some have argued that the administration of the anti-androgen should precede the administration of the LHRH agonist by at least a week, others have found no differences in PSA levels with the simultaneous administration of both agents.
** '''Following the LH surge, the loss of phasic pituitary stimulation results in plummeting LH levels'''
** '''In the absence of LH, Leydig cell production of testosterone drops to castrate levels'''
* <span style="color:#ff0000">'''Drugs and Dosages'''</span>
** <span style="color:#0000ff">'''-relin/-rolide'''</span><span style="color:#ff0000">''', Goserelin (Zoladex), Triptorelin (Trelstar) and Leuprolide (Lupron)'''</span>
**Goserelin (Zoladex) 10.8mg SC q3 months
** Leuprolide (Lupron) 22.5mg SC q3months

===== LHRH antagonists =====
* '''<span style="color:#ff0000">Advantages of LHRH antagonists over agonists:'''
*# '''<span style="color:#ff0000">Does not require co-administration of an anti-androgen''' due to lack of LH surge from lack of agonist activity
*# '''<span style="color:#ff0000">Testosterone levels can drop very quickly (within 3 days)'''
*#* '''May be preferred in hormonally naive patients in whom urgent castration is needed (impending spinal cord compression or severe bone pain)''' or in whom surgical castration is not appropriate
*#* LHRH antagonists bind immediately and competitively to the LHRH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration and testosterone levels dropping quickly with 34.5%, 60.5%, and 98.1% of men chemically castrate at 2, 4, and 28 days, respectively. [With LHRH agonists, the LH surge can last up to 2 weeks so testosterone levels only decrease after that§]
* In a phase III study, degarelix was compared to leuprolide: at 1 year of treatment degarelix was not inferior to leuprolide (Klotz et al, 2008)
* <span style="color:#ff0000">'''Drugs and Dosages'''</span>
**<span style="color:#0000ff">'''-lix </span><span style="color:#ff0000">(Abarelix, Cetrorelix, Degarelix, Relogolix)'''</span>
*'''<span style="color:#ff00ff">HERO (NEJM 2020)'''
** Population: 930 patients with 1 of 3 clinical disease presentations:
**# Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent
**# Newly diagnosed hormone-sensitive metastatic disease
**# Advanced localized disease unlikely to be cured by local primary intervention with curative intent.
** Randomized to in a 2:1 ratio, to receive relugolix (120 mg orally once daily) vs. leuprolide (injections every 3 months) for 48 weeks.
** Primary outcome: sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks.
** Secondary outcomes: noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15.
** Results:
*** Testosterone suppression: regurolix superior and non-inferior to leuprolide (96.7% regurolix vs. 88.8% leuprolide at 48 weeks)
*** Secondary outcomes all improved with regurolix
*** Cardiovascular outcomes significantly improved with regurolix (HR 0.46)
** [https://pubmed.ncbi.nlm.nih.gov/32469183/ Shore, Neal D., et al."Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer." ''New England Journal of Medicine'' (2020).]
* '''Many of the first- and second-generation antagonists induced significant histamine-mediated side effects; these do not occur as often observed in third- and fourth-generation.'''
** '''Nevertheless, severe allergic reactions can occur with abarelix, even after previously uneventful treatment'''
** '''Unlike abarelix, the LHRH antagonist degarelix has no systemic allergic reaction'''

* '''<span style="color:#ff0000">LH/FSH levels by method of ADT</span>'''
** '''<span style="color:#ff0000">LHRH agonists: reduced LH and only partially suppressed FSH</span>'''
** '''<span style="color:#ff0000">LHRH antagonists: reduce both LH and FSH levels</span>'''
** '''<span style="color:#ff0000">Surgical castration: significantly elevated LH and FSH</span>'''

==== 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'''

==== 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'''