Hormonal Therapy Flashcards
(116 cards)
1
Q
SERM drugs
A
selective estrogen receptor modulators
- tamoxifen (Soltamox)
- toremifene (Fareston)
- raloxifene (Evista)
2
Q
SERD drugs
A
selective estrogen receptor downregulators
- elacestrant (Orserdu)
- fulvestrant (Faslodex)
3
Q
aromatase inhibitor drugs
A
- anastrozole (Arimidex)
- exemestane (Aromasin)
- letrozole (Femara)
4
Q
LHRH agonist drugs
A
luteinizing hormone releasing hormone agonists
- goserelin (Zoladex)
- leuprolide (Lupron, Eligard, Camcevi)
- triptorelin (Trelstar)
5
Q
LHRH antagonist drugs
A
luteinizing hormone releasing hormone antagonists
- degarelix (Firmagon)
- relugolix (Orgovyx)
6
Q
antiandrogen drugs
A
- bicalutamide (Casodex)
- flutamide (Eulexin)
- nilutamide (Nilandron)
- abiraterone (Zytiga, Yonsa)
- apalutamide (Erleada)
- darolutamide (Nubeqa)
- enzalutamide (Xtandi)
7
Q
proportion of HR+ breast cancer
A
~70% of breast cancers express estrogen (ER) and/or progesterone (PR) receptors
these cancers grow in response to estrogen
8
Q
main endogenous estrogens
A
3!
- estradiol
- estrone
- estriol
9
Q
main source of estrogen in premenopausal women
A
ovaries
10
Q
main source of estrogen in postmenopausal women
A
androgens (from adrenal glands and ovaries) are converted to estrogen by aromatase
this conversion occurs primarily in adipose tissue and muscle
11
Q
SERM MOA
A
inhibit estrogen binding to the estrogen receptor
block estrogen stimulation of hormone-sensitive cancers
12
Q
tamoxifen MOA
A
SERM
- inhibit estrogen binding to the estrogen receptor
- block estrogen stimulation of hormone-sensitive cancers
antagonist in breast tissue and vaginal mucosa
agonist in endometrium, bone, liver, and coagulation system
13
Q
toremifene MOA
A
SERM
- inhibit estrogen binding to the estrogen receptor
- block estrogen stimulation of hormone-sensitive cancers
antagonist in breast tissue and vaginal mucosa
agonist in endometrium, bone, liver, and coagulation system
14
Q
raloxifene MOA
A
SERM
- inhibit estrogen binding to the estrogen receptor
- block estrogen stimulation of hormone-sensitive cancers
antagonist in breast and endometrium
agonist in bone, liver, and coagulation system
15
Q
differences in tissue effects between SERMs
A
ALL
- antagonist in breast
- agonist in bone, liver, and coagulation system
TAMOXIFEN/TOREMIFENE
- antagonist in vaginal mucosa
- agonist in endometrium
RALOXIFENE
- antagonist in endometrium
16
Q
mechanisms of resistance to SERMs
A
loss or mutation of ER
altered coactivator/corepressor balance
activation of EGFR, HER2, IGF1 pathways
upregulation of MAPK or PI3K/AKT/mTOR
changes in cell cycle regulators
17
Q
coactivators and corepressors that confer tamoxifen resistance
A
increased coactivator
- NCoA3 or NCoA1
decreased corepressor
- NCoR1
can cause tamoxifen to act as an agonist
18
Q
tamoxifen BBW
A
↑ risk of uterine malignancies
↑ risk of stroke and pulmonary embolism
C/I
- concomitant warfarin
- history of DVT or PE and on risk reduction therapy for DCIS
19
Q
toremifene BBW
A
QT prolongation (dose- and concentration-dependent), risk of TdP
C/I
- long QT syndrome
- uncorrected hypoK or hypoMg
20
Q
raloxifene BBW
A
↑ risk of DVT, PE, and stroke
C/I
- active or past VTE
21
Q
early onset class toxicities of SERMs
A
hot flashes, nausea, night sweats
mood changes, fatigue, cognitive changes
vaginal discharge
irregular menses or amenorrhea
decreased cholesterol, increased TGs
22
Q
late onset class toxicities of SERMs
A
endometrial hyperplasia or cancer (tamoxifen/toremifene)
thromboembolic events
osteopenia in premenopausal women
cataracts and retinal toxicity
23
Q
SERM with lowest endometrial cancer risk
A
raloxifene (per STAR trial vs tamoxifen)
24
Q
SERM with lowest VTE risk
A
raloxifene (per STAR trial vs tamoxifen)
25
how does CYP2D6 metabolism affect tamoxifen?
tamoxifen is a prodrug converted to endoxifen by CYP2D6
- endoxifen 100x more potent
strong/moderate CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, bupropion) may reduce efficacy
ASCO/NCCN:
- avoid inhibitors if possible
- routine genotyping not recommended
26
SERM DDIs
warfarin: tamoxifen inhibits CYP2C9 → ↑ bleeding risk
CYP3A4 inhibitors (incl gfj): ↑ tamoxifen/toremifene levels
QT-prolonging drugs: avoid with toremifene
cholestyramine: ↓ raloxifene absorption
thiazide diuretics: ↑ hyperCa risk with toremifene
27
tamoxifen DDIs
warfarin: tamoxifen inhibits CYP2C9 → ↑ bleeding risk
CYP3A4 inhibitors (incl gfj): ↑ tamoxifen levels
strong/moderate CYP2D6 inhibitors: less conversion to endoxifen (active metabolite)
- strong: fluoxetine, paroxetine, bupropion
- moderate: duloxetine, terbinafine
28
toremifene DDIs
warfarin: use caution
CYP3A4 inhibitors (incl gfj): ↑ toremifene levels
QT-prolonging drugs: avoid
thiazide diuretics: ↑ hyperCa risk
29
raloxifene DDIs
warfarin: use caution
cholestyramine: ↓ raloxifene absorption
30
tamoxifen toxicity and monitoring
monitor CBC
- thromboembolism
monitor LFTs
- hepatotox
monitor TGs
- can ↑ TG despite lowering cholesterol
annual gyn exam
- endometrial hyperplasia or cancer
ophthalmology exam annually
- cataracts or retinal toxicity
other AEs
- hot flashes,
- sleep disturbance, mood changes
- vaginal discharge
- ↑ risk of stroke, PE, DVT (BBW)
- ↓ bone density in premenopausal women
- teratogenic: use contraception
31
toremifene toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation (BBW)
- C/I in long QT syndrome or uncorrected hypoK/Mg
monitor LFTs
- hepatotox
annual gyn exam
- endometrial cancer risk
annual ophthalmology exam
- cataracts
monitor CBC, TGs prn
- thrombosis
- hyperlipidemia
other AEs
- hot flashes, nausea, mood changes
- C/I in VTE or heart failure
- use contraception
32
raloxifene toxicity and monitoring
annual gyn exam
- less endometrial risk than tamoxifen
annual ophthalmology exam
- cataract risk (lower than tamoxifen)
monitor CBC, LFTs, TGs as needed
- VTE risk, lipid changes
other AEs
- hot flashes
- mood changes
- vaginal dryness
- ↑ DVT, PE, stroke (BBW)
- C/I in active or past VTE
- teratogenic: use contraception
33
tamoxifen dosing and administration
20 mg PO daily
- low-dose options: 5 mg daily or 10 mg every other day (in DCIS, LCIS, ADH) x 3 years
oral tablet or oral solution (Soltamox)
notes
- avoid grapefruit products (CYP3A4 interaction)
- prodrug converted to endoxifen by CYP2D6
t1/2 = 5-7 days
34
toremifene dosing and administration
60 mg PO daily
oral tablet (Fareston)
notes
- avoid grapefruit products
- monitor QT in high-risk patients
t1/2 = 5 days
35
raloxifene dosing and administration
60 mg PO daily
oral tSablet (Evista)
use caution in renal impairment (CrCl <50 mL/min)
t1/2 = 32.5 hrs
36
SERD MOA
binds ER and inhibits dimerization
accelerates proteasomal degradation of ER
37
fulvestrant MOA
SERD
- binds ER and inhibits dimerization
- accelerates proteasomal degradation of ER
100x greater affinity for ER than tamoxifen
- pure ER antagonist with NO agonist activity
- antagonist in breast tissue, vaginal mucosa, endometrium, bone, and coagulation system
38
elacestrant MOA
SERD
- binds ER and inhibits dimerization
- accelerates proteasomal degradation of ER
39
SERD resistance mechanisms
ESR1 mutations lead to estrogen-independent constitutive ER activation and resistance
FULVESTRANT
- ESR1 Y537S confers resistance to fulvestrant
ELACESTRANT
- retains activity in tumors with ESR1 mutations, including Y537S
40
fulvestrant resistance mechanisms
ESR1 mutations (e.g., Y537S) cause constitutive ER activation and resistance
41
elacestrant resistance mechanisms
retains activity in tumors with ESR1 mutations, including Y537S
42
SERD class toxicities
vasomotor sx: hot flashes, sweats, nausea, sleep disturbance
menopausal sx: fatigue, mood changes, depression, cognitive dysfunction, loss of libido, and dyspareunia
N/V/D or constipation
back pain, musculoskeletal pain, fatigue, headache
osteoporosis risk with long-term use
[ fulvestrant ]
caution with dorsal gluteal injection (sciatic nerve proximity)
[ elacestrant ]
- hypercholesterolemia
- hypertriglyceridemia
43
fulvestrant toxicity and monitoring
monitor LFTs
- hepatotox
monitor injection site
- pain
- bruising (especially with anticoagulants)
- caution with dorsal gluteal injection (sciatic nerve proximity)
other AEs
- hot flashes, mood changes, nausea, sleep disturbance
- N/V/D or constipation
- back pain, musculoskeletal pain, fatigue, headache
- osteoporosis risk with long-term use
- fetal harm: use contraception
44
elacestrant toxicity and monitoring
monitor LFTs
- hepatotox
monitor lipid panel
- hypercholesterolemia
- hypertriglyceridemia
other AEs
- hot flashes, mood changes, nausea, sleep disturbance
- N/V/D or constipation
- back pain, musculoskeletal pain, fatigue, headache
- osteoporosis risk with long-term use
- fetal harm: use contraception
45
fulvestrant dosing and administration
500 mg IM on days 1, 15, 29, then every 28 days
IM injection
reduce to 250 mg if child-pugh B; not studied in C
caution with dorsal gluteal injection (sciatic nerve proximity)
t1/2 = 40 days
46
elacestrant dosing and administration
345 mg PO daily
reduce to 258 mg if child–pugh B; avoid in C
take with food
- ↓ nausea
- ↑ AUC and Cmax
t1/2 = 30-50 hrs
47
fulvestrant DDIs
caution with anticoagulants
- ↑ risk of bruising or injection site bleeding
48
elacestrant DDIs
avoid strong/moderate CYP3A4 inducers/inhibitors
- ↓ or ↑ elacestrant levels
avoid P-gp or BCRP substrates
- elacestrant is a P-gp/BCRP inhibitor → ↓ dose of substrate drugs
take with food
- ↓ nausea
- ↑ AUC and Cmax
49
aromatase inhibitor MOA
aromatase inhibitor
- nonsteroidal, reversible = letrozole, anastrozole
- steroidal, irreversible = exemestane
blocks peripheral estrogen production
use only in postmenopausal women
50
anastrozole MOA
aromatase inhibitor
- nonsteroidal, reversible
blocks peripheral estrogen production
use monotx only in postmenopausal women
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
51
letrozole MOA
aromatase inhibitor
- nonsteroidal, reversible
blocks peripheral estrogen production
use monotx only in postmenopausal women
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
52
exemestane MOA
aromatase inhibitor
- steroidal, irreversible
blocks peripheral estrogen production
use monotx only in postmenopausal women
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
53
aromatase inhibitor resistance mechanisms
ESR1 mutations (e.g., D538G, Y537S) → estrogen-independent ER activation → complete resistance to aromatase inhibitors
strategy: switch to fulvestrant (except Y537S)
54
early onset class toxicities of aromatase inhibitors
vasomotor sx: hot flashes, sweats, nausea, sleep disturbance
menopausal sx: fatigue, mood changes, depression, cognitive dysfunction, loss of libido, and dyspareunia
arthralgias, myalgias
vaginal dryness, urogenital complaints
hypercholesterolemia
55
late onset class toxicities of aromatase
osteoporosis and fracture risk
cardiovascular disease
56
anastrozole toxicity and monitoring
monitor DEXA q2yrs & vitamin D level
- osteoporosis
- fracture risk
monitor lipid panel
- hypercholesterolemia
monitor LFTs prn
- hepatotox
pregnancy test before initiation
- use contraception (fetal harm risk)
other AEs
- hot flashes, nausea, arthralgia, vaginal dryness
- fatigue, mood changes, insomnia
57
letrozole toxicity and monitoring
monitor DEXA q2yrs & vitamin D level
- osteoporosis
- fracture risk
monitor lipid panel
- hypercholesterolemia
monitor LFTs prn
- hepatotox
pregnancy test before initiation
- use contraception (fetal harm risk)
other AEs
- hot flashes, nausea, arthralgia, vaginal dryness
- fatigue, mood changes, insomnia
58
exemestane toxicity and monitoring
monitor DEXA q2yrs & vitamin D level
- osteoporosis
- fracture risk
monitor lipid panel
- hypercholesterolemia
monitor LFTs prn
- hepatotox
pregnancy test before initiation
- use contraception (fetal harm risk)
other AEs
- hot flashes, nausea, arthralgia, vaginal dryness
- fatigue, mood changes, insomnia
59
anastrozole dosing and administration
1 mg PO daily
take with or without food
- food ↓ Cmax 16% and delays Tmax
no renal or hepatic adjustment needed
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
60
letrozole dosing and administration
2.5 mg PO daily
adjust to 2.5 mg every other day if child–pugh C
not studied in CrCl < 10 mL/min
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
61
exemestane dosing and administration
25 mg PO daily with food
take with food
- ↑ AUC 59%
- ↑ Cmax 39%
for men or postmenopausal women:
- combine with LHRH agonist to suppress ovarian estrogen production
- in premenopausal women, peripheral estrogen suppression triggers ↑ ovarian estrogen via negative feedback
62
aromatase inhibitor DDIs
avoid estrogen products
- ↓ efficacy of AIs
avoid concurrent tamoxifen
- ↓ AI concentrations (especially anastrozole and letrozole)
take exemestane with food
- increases absorption
avoid strong CYP3A4 inducers
- ↓ exemestane efficacy (e.g., rifampin, phenytoin) → may increase dose to 50 mg daily
63
role of androgen in prostate cancer
androgens (testosterone, DHT) promote prostate cancer growth
80–90% testosterone from testes, 10–20% from adrenal glands
testosterone binds androgen receptor (AR) → gene activation for cell survival, growth, PSA secretion
64
prostate cancer hormone cascade
GnRH (aka LHRH)
- secreted by hypothalamus in pulsatile manner
- stimulates pituitary to release LH and FSH
LH
- promotes testosterone synthesis in Leydig cells (testes)
ACTH
- stimulates adrenal glands to produce DHEA and androstenedione (androgen precursors)
testosterone & DHT
- bind androgen receptor (AR)
- AR dimerizes → enters nucleus → binds androgen response elements (AREs)
- regulates gene expression for prostate cell growth, survival, and PSA secretion
note
- DHT has greater AR affinity and activates gene expression more efficiently
65
LHRH agonist MOA
(leuprolide, goserelin, triptorelin)
binds LHRH receptors on anterior pituitary → initial LH/FSH surge → testosterone (men) or estrogen (women) production
sustained activation → receptor downregulation → ↓ LH/FSH → castrate/menopausal hormone levels
results in androgen deprivation (men) or ovarian suppression (women)
**synthetic LHRH agonists have greater LHRH affinity and are less susceptible to degradation → 100x more potent than natural gonadotropin-releasing hormone (GnRH)
66
leuprolide MOA
LHRH agonist
binds LHRH receptors on anterior pituitary → initial LH/FSH surge → testosterone (men) or estrogen (women) production
sustained activation → receptor downregulation → ↓ LH/FSH → castrate/menopausal hormone levels
results in androgen deprivation (men) or ovarian suppression (women)
**synthetic LHRH agonists have greater LHRH affinity and are less susceptible to degradation → 100x more potent than natural gonadotropin-releasing hormone (GnRH)
67
goserelin MOA
LHRH agonist
binds LHRH receptors on anterior pituitary → initial LH/FSH surge → testosterone (men) or estrogen (women) production
sustained activation → receptor downregulation → ↓ LH/FSH → castrate/menopausal hormone levels
results in androgen deprivation (men) or ovarian suppression (women)
**synthetic LHRH agonists have greater LHRH affinity and are less susceptible to degradation → 100x more potent than natural gonadotropin-releasing hormone (GnRH)
68
triptorelin MOA
LHRH agonist
binds LHRH receptors on anterior pituitary → initial LH/FSH surge → testosterone (men) or estrogen (women) production
sustained activation → receptor downregulation → ↓ LH/FSH → castrate/menopausal hormone levels
results in androgen deprivation (men) or ovarian suppression (women)
**synthetic LHRH agonists have greater LHRH affinity and are less susceptible to degradation → 100x more potent than natural gonadotropin-releasing hormone (GnRH)
69
early class toxicities of LHRH agonists
*tumor flare (bone pain, cord compression, urinary obstruction)* - symptoms may last 2-3 weeks
vasomotor symptoms (hot flashes, night sweats, insomnia)
mood changes, depression, fatigue, loss of libido, dyspareunia
arthralgias, myalgias
gynecomastia
anemia (normochromic, normocytic)
sexual dysfunction (ED, decreased libido)
injection site reaction
dry eyes, body hair loss
acute kidney injury
70
late onset class toxicities of LHRH agonists
osteoporosis and fracture risk (2–5x)
metabolic syndrome
CV disease (↑ LDL/HDL/TG; QTc prolongation)
- ADT may increase CVM&M notably in the first 6 months of therapy, and also in men with 2+ CV events
diabetes (↓ insulin sensitivity, hyperglycemia)
sarcopenia (↓ lean mass, ↑ fat mass)
VTE
cognitive dysfunction
71
leuprolide toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation
- use caution with other QT-prolonging drugs
- correct hypoK/Mg before treatment
monitor DEXA, vitamin D, calcium
- osteoporosis and fracture risk
- supplement calcium 1200 mg/day + vitamin D3 800–1000 IU/day
- consider bisphosphonates or denosumab
monitor CBC
- anemia
monitor metabolic parameters
- glucose, A1c, lipids, BP per USPSTF guidelines
other AEs
- tumor flare (consider antiandrogen pre-treatment, sx may last 2-3 wks)
- hot flashes, fatigue, gynecomastia, injection site reaction
- use contraception; fetal harm risk
(same for LHRH agonists + antagonists)
72
goserelin toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation
- use caution with other QT-prolonging drugs
- correct hypoK/Mg before treatment
monitor DEXA, vitamin D, calcium
- osteoporosis and fracture risk
- supplement calcium 1200 mg/day + vitamin D3 800–1000 IU/day
- consider bisphosphonates or denosumab
monitor CBC
- anemia
monitor metabolic parameters
- glucose, A1c, lipids, BP per USPSTF guidelines
other AEs
- tumor flare (consider antiandrogen pre-treatment, sx may last 2-3 wks)
- hot flashes, fatigue, gynecomastia, injection site reaction
- use contraception; fetal harm risk
(same for LHRH agonists + antagonists)
73
troptorelin toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation
- use caution with other QT-prolonging drugs
- correct hypoK/Mg before treatment
monitor DEXA, vitamin D, calcium
- osteoporosis and fracture risk
- supplement calcium 1200 mg/day + vitamin D3 800–1000 IU/day
- consider bisphosphonates or denosumab
monitor CBC
- anemia
monitor metabolic parameters
- glucose, A1c, lipids, BP per USPSTF guidelines
other AEs
- tumor flare (consider antiandrogen pre-treatment, sx may last 2-3 wks)
- hot flashes, fatigue, gynecomastia, injection site reaction
- use contraception; fetal harm risk
(same for LHRH agonists + antagonists)
74
leuprolide dosing and administration
IM
- Lupron
subQ
- Eligard
- Camcevi (prefilled syringe)
3.75 - 45 mg once every 1 - 6 months
75
goserelin dosing and administration
subQ implant:
- 3.6 mg q1mo
- 10.8 mg q3mo
76
triptorelin dosing and administration
IM:
- 3.75 mg q1mo
- 11.25 mg q3mo
- 22.5 mg q6mo
77
LHRH agonist DDIs
not metabolized by CYP enzymes
use caution with QTc-prolonging agents
78
mechanisms of resistance to LHRH agonists
prostate cancer cells can:
(1) adapt to low-testosterone environment
(2) may synthesize their own androgens
(3) increase androgen receptor (AR) sensitivity through:
- AR gene overexpression
- AR gene mutation
- AR splice variants
- upregulation of transcriptional coactivators
- overexpression of androgen-producing enzymes
79
LHRH agonists and tumor flare
at start of LHRH agonist tx, there is a
surge in LH and testosterone that can flare the symptoms of the metastatic deposits → ↑ bone pain, spinal cord compression, or obstructive bladder symptoms
symptoms may last for 2–3 weeks
for pts with overt metastases in weight-bearing bones at risk of developing symptoms:
- antiandrogen therapy should precede or
be coadministered with the LHRH agonist
- AND be continued in combination for at least 7 days.
80
monitoring bone health with LHRH agonists
obtain baseline DEXA if fracture risk is elevated (via FRAX)
- repeat q1–2yrs depending on risk and prior results
check vitamin D before starting; recheck prn
- supplement calcium (1,200 mg/day in divided doses)
- supplement vitamin D3 (600–1,000 IU/day)
initiate bisphosphonate or denosumab in high-risk patients per guidelines:
- denosumab 60 mg SQ every 6 months
- zoledronic acid 5 mg IV annually
- alendronate 70 mg PO weekly
81
LHRH antagonist MOA
(degarelix, relugolix)
irreversibly bind LHRH receptors in the pituitary
- rapidly suppress LH/FSH
- reduce testosterone to castrate levels without initial surge
avoids tumor flare
82
degarelix MOA
LHRH antagonist
blocks pituitary LHRH receptors → rapid testosterone suppression (castrate level in ~7 days)
avoids LH/FSH surge and tumor flare
83
relugolix MOA
oral LHRH antagonist
blocks pituitary LHRH receptors → testosterone suppression
- 56% achieve castrate levels by day 4
- 98.7% by day 15
avoids tumor flare
84
differences in class toxicities from LHRH antagonists compared to agonists
antagonists are similar to LHRH agonists except:
- no tumor flare
- ↓ risk of major adverse CV events in men with CVD (relugolix vs. leuprolide in HERO trial)
85
class toxicities of LHRH antagonists
no tumor flare (no initial LH/FSH surge)
- LHRH agonists DO cause this
↓ risk of major adverse CV events in men with preexisting CVD disease (e.g., HERO trial: relugolix 2.9% vs. leuprolide 6.2%)
injection site reactions with degarelix: pain, erythema, swelling, induration, nodule formation
hypersensitivity reactions with degarelix: urticaria, angioedema, anaphylaxis
other common androgen deprivation effects:
- hot flashes, sexual dysfunction, fatigue, mood changes
- anemia
- metabolic changes
- bone density loss
- cognitive effects
86
degrarelix toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation
- use caution with other QT-prolonging drugs
- correct hypoK/Mg before treatment
monitor DEXA, vitamin D, calcium
- osteoporosis and fracture risk
- supplement calcium 1200 mg/day + vitamin D3 800–1000 IU/day
- consider bisphosphonates or denosumab
monitor CBC
- anemia
monitor metabolic parameters
- glucose, A1c, lipids, BP per USPSTF guidelines
other AEs
- NO tumor flare (unlike LHRH agonists)
- hot flashes, fatigue, gynecomastia, injection site reaction
- *postmarketing reports of anaphylaxis, urticaria, and angioedema with degarelix*
- use contraception; fetal harm risk
(same for LHRH agonists + antagonists)
87
relugolix toxicity and monitoring
monitor EKG and electrolytes
- QT prolongation
- use caution with other QT-prolonging drugs
- correct hypoK/Mg before treatment
monitor DEXA, vitamin D, calcium
- osteoporosis and fracture risk
- supplement calcium 1200 mg/day + vitamin D3 800–1000 IU/day
- consider bisphosphonates or denosumab
monitor CBC
- anemia
monitor metabolic parameters
- glucose, A1c, lipids, BP per USPSTF guidelines
other AEs
- NO tumor flare (unlike LHRH agonists)
- hot flashes, fatigue, gynecomastia, injection site reaction
- use contraception; fetal harm risk
- ↓ risk of major adverse CV events in men with CVD compared to LHRH agonists (relugolix vs. leuprolide in HERO trial)
(same for LHRH agonists + antagonists)
88
degarelix dosing and administration
loading: 240 mg subQ once
maintenance: 80 mg subQ every 4 weeks
89
relugolix dosing and administration
loading: 360 mg PO on day 1
maintenance: 120 mg PO daily
90
degarelix DDIs
caution with QT/QTc-prolonging agents
91
relugolix DDIs
avoid P-gp inhibitors
- if needed: take relugolix first, separate by ≥ 6h, monitor closely
avoid P-gp inducers and strong CYP3A inducers
- if needed: increase relugolix to 240 mg PO daily
caution with QT/QTc-prolonging agents
92
which drugs are first-gen antiandrogens?
bicalutamide
flutamide
nilutamide
93
which drugs are second-gen antiandrogens?
apalutamide
enzalutamide
darolutamide
94
first-gen antiandrogen MOA
competitively inhibit AR binding, blocking AR translocation to the nucleus
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
95
bicalutamide MOA
first-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
96
flutamide MOA
first-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
97
nilutamide MOA
first-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
98
second-gen antiandrogen MOA
competitively inhibit AR binding, blocking AR translocation to the nucleus
- higher AR affinity than first-gen antiandrogens (darolutamide > apalutamide, enzalutamide)
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
99
apalutamide MOA
second-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
- higher AR affinity than first-gen antiandrogens (darolutamide > apalutamide, enzalutamide)
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
100
darolutamide MOA
second-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
- higher AR affinity than first-gen antiandrogens (darolutamide > apalutamide, enzalutamide)
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
101
enzalutamide MOA
second-gen antiandrogen
competitively inhibit AR binding, blocking AR translocation to the nucleus
- higher AR affinity than first-gen antiandrogens (darolutamide > apalutamide, enzalutamide)
do NOT decrease LH → testosterone remains normal or increased
often used in combination with LHRH agonists
102
CYP17 inhibitor MOA
IRREVERSIBLE CYP17 inhibitor
→ inhibits 17α-hydroxylase and 17,20-lyase activity
→ blocks conversion of pregnenolone and progesterone to DHEA and androstenedione
→ lowers testosterone to castrate levels
requires concurrent corticosteroids to mitigate mineralocorticoid excess
used with LHRH agonist or post-orchiectomy
103
abiraterone MOA
IRREVERSIBLE CYP17 inhibitor (antiandrogen)
→ inhibits 17α-hydroxylase and 17,20-lyase activity
→ blocks conversion of pregnenolone and progesterone to DHEA and androstenedione
→ lowers testosterone to castrate levels
requires concurrent corticosteroids to mitigate mineralocorticoid excess
used with LHRH agonist or post-orchiectomy
104
class toxicities of first-gen antiandrogens
gynecomastia, mastodynia, hepatotoxicity
GI upset: diarrhea, nausea, vomiting
vasomotor symptoms, sexual dysfunction
less bone loss and vasomotor flushing vs. ADT
105
class toxicities of second-gen antiandrogens
fatigue, hypertension, rash, arthralgia
diarrhea, anorexia, weight loss
falls and fractures (esp. older adults)
CV: ischemia, arrhythmia
seizure risk (enzalutamide, apalutamide)
limited CNS effects with darolutamide
106
AR mutation L701H
confers abiraterone resistance
activated by glucocorticoids and progesterone
107
AR mutation T878A
confers abiraterone + enzalutamide resistance
activated by glucocorticoids and progesterone
does not impact darolutamide efficacy
108
AR mutation F877L
confers abiraterone + enzalutamide resistance
does not impact bicalutamide or darolutamide efficacy
109
AR mutation W742L
confers bicalutamide resistance
does not impact darolutamide efficacy
110
AR mutation AR-V7
splice mutant
- leads to a truncated AR that lacks a ligand binding domain, resulting in ligand-independent androgen pathway signaling
biomarker predicting resistance to abiraterone and enzalutamide but NOT taxane chemotherapy
111
AR mutation AR-V567
splice mutant
- leads to a truncated AR that lacks a ligand binding domain, resulting in ligand-independent androgen pathway signaling
112
bicalutamide dosing and administration
50 mg PO daily (tablet)
- with or without food
use with caution in moderate to severe hepatic impairment
used in combination with LHRH agonists
long t1/2 (~6 days) allows once-daily dosing
113
flutamide dosing and administration
250 mg PO q8h (capsule)
- with or without food
C/I in severe hepatic impairment
- rarely used due to hepatotoxicity risk
short t1/2 (~8 hours) requires TID dosing
often combined with LHRH agonists
114
nilutamide dosing and adminstration
300 mg PO daily × 30 days, then 150 mg PO daily
- with or without food
C/I severe hepatic impairment
long t1/2 (38–59 hours) allows daily dosing
use in combination with surgical castration (orchiectomy)
115
flutamide BBW
increased risk of hepatic injury
~50% of cases occurred in first 3 months
- some resolve after d/c
NOT recommended if ALT > 2 x ULN
116
nilutamide BBW
increased risk of interstitial pneumonitis
most cases occurred in first 3 months
- most resolve after d/c
counsel patients to report new or worsening SOB
- d/c tx until relatedness determined
