Editing Hormonal Therapy (section)

===== 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>'''