Hormonal Therapy: Difference between revisions

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

* '''Estrogen~~'''~~

** '''Historical'''

===== Estrogen =====

*** First agent used at a central inhibitor

* '''Historical'''

*** Largely replaced by LHRH analogues

** First agent used at a central inhibitor

** '''MOA: potent negative feedback of estrogen on LH secretion'''

** Largely replaced by LHRH analogues

*** Estradiol is 1000x more potent at suppressing LH and FSH secretion than testosterone

* '''MOA: potent negative feedback of estrogen on LH secretion'''

** '''Diethylstilbestrol (DES)'''

** Estradiol is 1000x more potent at suppressing LH and FSH secretion than testosterone

*** '''As effective as surgical castration'''

* '''Diethylstilbestrol (DES)'''

*** '''Association with cardiovascular toxicity has limited its use'''

** '''As effective as surgical castration'''

* '''~~LHRH agonists ~~(-relin/-rolide, Goserelin (Zoladex), Triptorelin (Trelstar) and Leuprolide (Lupron))'''

** '''Association with cardiovascular toxicity has limited its use'''

** '''As effective as orchiectomy'''

*** 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.

===== LHRH agonists =====

** '''Initially co-administered with an androgen-receptor antagonist to block the LH and testosterone surge'''

* '''As effective as orchiectomy'''

*** 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'''

** 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.

*** Co-administration of an anti-androgen (bicalutamide 50mg daily) functionally blocks the increased levels of testosterone.

* '''Initially co-administered with an androgen-receptor antagonist to block the LH and testosterone surge'''

**** '''The testosterone flare may last for 10-20 days and therefore co-administration of anti-androgen is required for only 21-28 days'''

** 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'''

***** 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.

** Co-administration of an anti-androgen (bicalutamide 50mg daily) functionally blocks the increased levels of testosterone.

*** '''Following the LH surge, the loss of phasic pituitary stimulation results in plummeting LH levels'''

*** '''The testosterone flare may last for 10-20 days and therefore co-administration of anti-androgen is required for only 21-28 days'''

*** '''In the absence of LH, Leydig cell production of testosterone drops to castrate levels'''

**** 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.

** Dosing

** '''Following the LH surge, the loss of phasic pituitary stimulation results in plummeting LH levels'''

*** Goserelin (Zoladex) 10.8mg SC q3 months

** '''In the absence of LH, Leydig cell production of testosterone drops to castrate levels'''

*** Leuprolide (Lupron) 22.5mg SC q3months

* '''Drugs and Dosages'''

* '''~~LHRH antagonists (~~-~~lix~~ (~~Abarelix~~, ~~Cetrorelix, Degarelix, Relogolix~~))'''

** '''-relin/-rolide'''''', Goserelin (Zoladex), Triptorelin (Trelstar) and Leuprolide (Lupron)'''

** '''Advantages of LHRH antagonists over agonists:'''

**Goserelin (Zoladex) 10.8mg SC q3 months

**# '''Does not require co-administration of an anti-androgen''' due to lack of LH surge from lack of agonist activity

** Leuprolide (Lupron) 22.5mg SC q3months

**# '''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 =====

**#* 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§]

* '''Advantages of LHRH antagonists over agonists:'''

** 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)

*# '''Does not require co-administration of an anti-androgen''' due to lack of LH surge from lack of agonist activity

** '''HERO'''

*# '''Testosterone levels can drop very quickly (within 3 days)'''

*** Population: 930 patients with 1 of 3 clinical disease presentations:

*#* '''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

***# Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent

*#* 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§]

***# Newly diagnosed hormone-sensitive metastatic disease

* 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)

***# Advanced localized disease unlikely to be cured by local primary intervention with curative intent.

* '''Drugs and Dosages'''

*** Randomized to in a 2:1 ratio, to receive relugolix (120 mg orally once daily) vs. leuprolide (injections every 3 months) for 48 weeks.

**'''-lix (Abarelix, Cetrorelix, Degarelix, Relogolix)'''

*** Primary outcome: sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks.

*'''HERO (NEJM 2020)'''

*** 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.

** Population: 930 patients with 1 of 3 clinical disease presentations:

*** Results:

**# Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent

**** Testosterone suppression: regurolix superior and non-inferior to leuprolide (96.7% regurolix vs. 88.8% leuprolide at 48 weeks)

**# Newly diagnosed hormone-sensitive metastatic disease

**** Secondary outcomes all improved with regurolix

**# Advanced localized disease unlikely to be cured by local primary intervention with curative intent.

**** Cardiovascular outcomes significantly improved with regurolix (HR 0.46)

** Randomized to in a 2:1 ratio, to receive relugolix (120 mg orally once daily) vs. leuprolide (injections every 3 months) for 48 weeks.

*** Shore, Neal D., et al."Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer." ''New England Journal of Medicine'' (2020).

** Primary outcome: sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks.

** '''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.'''

** 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.

*** '''Nevertheless, severe allergic reactions can occur with abarelix, even after previously uneventful treatment'''

** Results:

*** '''Unlike abarelix, the LHRH antagonist degarelix has no systemic allergic reaction'''

*** 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'''

* '''LH/FSH levels by method of ADT'''

** '''LHRH agonists: reduced LH and only partially suppressed FSH'''

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**More potent than ketoconazole

====== ~~'''~~Adverse events (7)~~'''~~ ======

====== Adverse events (7) ======

# '''HTN'''

# '''Hypokalemia'''

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* '''Recommended clinical monitoring (as per Cancer Care Ontario)'''

** '''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'''

** '''Clinical assessment of adverse events: at each visit'''

** '''Blood pressure and serum potassium: baseline and monthly'''

** '''Blood pressure and serum potassium: baseline and monthly'''

** '''Liver function tests, bilirubin: baseline, every 2 weeks for the first 3 months and monthly thereafter, or as clinically indicated'''

** '''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'''~~ ======

====== Trials with Abiraterone ======

* '''COU-AA-301: post-docetaxel CRPC'''

* '''COU-AA-302: pre-docetaxel CRPC'''

@@ Line 58: / Line 58: @@
 ==== Inhibition of LHRH and/or LH release ====
-* '''Estrogen'''
-** '''Historical'''
+===== Estrogen =====
-*** First agent used at a central inhibitor
+* '''Historical'''
-*** Largely replaced by LHRH analogues
+** First agent used at a central inhibitor
-** '''MOA: potent negative feedback of estrogen on LH secretion'''
+** Largely replaced by LHRH analogues
-*** Estradiol is 1000x more potent at suppressing LH and FSH secretion than testosterone
+* '''MOA: potent negative feedback of estrogen on LH secretion'''
-** '''Diethylstilbestrol (DES)'''
+** Estradiol is 1000x more potent at suppressing LH and FSH secretion than testosterone
-*** '''As effective as surgical castration'''
+* '''Diethylstilbestrol (DES)'''
-*** '''Association with cardiovascular toxicity has limited its use'''
+** '''As effective as surgical castration'''
-* '''<span style="color:#ff0000">LHRH agonists (</span><span style="color:#0000ff">-relin/-rolide</span><span style="color:#ff0000">, Goserelin (Zoladex), Triptorelin (Trelstar) and Leuprolide (Lupron))</span>'''
+** '''Association with cardiovascular toxicity has limited its use'''
-** '''<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.
+===== LHRH agonists =====
-** '''<span style="color:#ff0000">Initially co-administered with an androgen-receptor antagonist to block the LH and testosterone surge</span>'''
+* '''<span style="color:#ff0000">As effective as orchiectomy</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'''
+** 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.
-*** Co-administration of an anti-androgen (bicalutamide 50mg daily) functionally blocks the increased levels of testosterone.
+* '''<span style="color:#ff0000">Initially co-administered with an androgen-receptor antagonist to block the LH and testosterone surge</span>'''
-**** '''The testosterone flare may last for 10-20 days and therefore co-administration of anti-androgen is required for only 21-28 days'''
+** 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'''
-***** 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.
+** Co-administration of an anti-androgen (bicalutamide 50mg daily) functionally blocks the increased levels of testosterone.
-*** '''Following the LH surge, the loss of phasic pituitary stimulation results in plummeting LH levels'''
+*** '''The testosterone flare may last for 10-20 days and therefore co-administration of anti-androgen is required for only 21-28 days'''
-*** '''In the absence of LH, Leydig cell production of testosterone drops to castrate levels'''
+**** 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.
-** Dosing
+** '''Following the LH surge, the loss of phasic pituitary stimulation results in plummeting LH levels'''
-*** Goserelin (Zoladex) 10.8mg SC q3 months
+** '''In the absence of LH, Leydig cell production of testosterone drops to castrate levels'''
-*** Leuprolide (Lupron) 22.5mg SC q3months
+* <span style="color:#ff0000">'''Drugs and Dosages'''</span>
-* '''<span style="color:#ff0000">LHRH antagonists (</span><span style="color:#0000ff">-lix</span><span style="color:#ff0000> (Abarelix, Cetrorelix, Degarelix, Relogolix))'''
+** <span style="color:#0000ff">'''-relin/-rolide'''</span><span style="color:#ff0000">''', Goserelin (Zoladex), Triptorelin (Trelstar) and Leuprolide (Lupron)'''</span>
-** '''<span style="color:#ff0000">Advantages of LHRH antagonists over agonists:'''
+**Goserelin (Zoladex) 10.8mg SC q3 months
-**# '''<span style="color:#ff0000">Does not require co-administration of an anti-androgen''' due to lack of LH surge from lack of agonist activity
+** Leuprolide (Lupron) 22.5mg SC q3months
-**# '''<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 =====
-**#* 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§]
+* '''<span style="color:#ff0000">Advantages of LHRH antagonists over agonists:'''
-** 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">Does not require co-administration of an anti-androgen''' due to lack of LH surge from lack of agonist activity
-** '''<span style="color:#ff00ff">HERO'''
+*# '''<span style="color:#ff0000">Testosterone levels can drop very quickly (within 3 days)'''
-*** Population: 930 patients with 1 of 3 clinical disease presentations:
+*#* '''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
-***# Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent
+*#* 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§]
-***# Newly diagnosed hormone-sensitive metastatic disease
+* 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)
-***# Advanced localized disease unlikely to be cured by local primary intervention with curative intent.
+* <span style="color:#ff0000">'''Drugs and Dosages'''</span>
-*** Randomized to in a 2:1 ratio, to receive relugolix (120 mg orally once daily) vs. leuprolide (injections every 3 months) for 48 weeks.
+**<span style="color:#0000ff">'''-lix </span><span style="color:#ff0000">(Abarelix, Cetrorelix, Degarelix, Relogolix)'''</span>
-*** Primary outcome: sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks.
+*'''<span style="color:#ff00ff">HERO (NEJM 2020)'''
-*** 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.
+** Population: 930 patients with 1 of 3 clinical disease presentations:
-*** Results:
+**# Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent
-**** Testosterone suppression: regurolix superior and non-inferior to leuprolide (96.7% regurolix vs. 88.8% leuprolide at 48 weeks)
+**# Newly diagnosed hormone-sensitive metastatic disease
-**** Secondary outcomes all improved with regurolix
+**# Advanced localized disease unlikely to be cured by local primary intervention with curative intent.
-**** Cardiovascular outcomes significantly improved with regurolix (HR 0.46)
+** Randomized to in a 2:1 ratio, to receive relugolix (120 mg orally once daily) vs. leuprolide (injections every 3 months) for 48 weeks.
-*** Shore, Neal D., et al."Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer." ''New England Journal of Medicine'' (2020).
+** Primary outcome: sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks.
-** '''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.'''
+** 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.
-*** '''Nevertheless, severe allergic reactions can occur with abarelix, even after previously uneventful treatment'''
+** Results:
-*** '''Unlike abarelix, the LHRH antagonist degarelix has no systemic allergic reaction'''
+*** 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>'''
@@ Line 134: / Line 141: @@
 **More potent than ketoconazole
-====== '''<span style="color:#ff0000">Adverse events (7)</span>''' ======
+====== <span style="color:#ff0000">Adverse events (7)</span> ======
 # '''<span style="color:#ff0000">HTN</span>'''
 # '''<span style="color:#ff0000">Hypokalemia</span>'''
@@ Line 154: / Line 161: @@
 * '''Recommended clinical monitoring (as per Cancer Care Ontario)'''
-** '''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'''
 ** '''Clinical assessment of adverse events: at each visit'''
-** '''Blood pressure and serum potassium: baseline and monthly'''
+** '''<span style="color:#ff0000">Blood pressure and serum potassium: baseline and monthly'''
-** '''Liver function tests, bilirubin: baseline, every 2 weeks for the first 3 months and monthly thereafter, or as clinically indicated'''
+** '''<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''' ======
+====== Trials with Abiraterone ======
 * '''COU-AA-301: post-docetaxel CRPC'''
 * '''COU-AA-302: pre-docetaxel CRPC'''