Editing Hormonal Therapy (section)

=== 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** '''Has largely been replaced by LHRH analogues'''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'''