hormonal agents for therapy in oncology

1. Hormonal Agents
Reference : Devita 12th Edition
Presentor : Dr Parnian Boroonsara

2. Introduction
• Hormonal agents are commonly used to treat hormonally
responsive cancers, such as breast, prostate, or endometrial
carcinomas. Other uses of hormonal therapies include
treatment of paraneoplastic syndromes (e.g., carcinoid
syndrome) and symptoms caused by cancer, including
anorexia.

4. Selective Estrogen Receptor
Modulators

5. Tamoxifen
• Tamoxifen remains an important hormonal therapy for the
prevention and treatment of breast cancer. It is the only
hormonal agent approved by the U.S. Food and Drug
Administration (FDA) for the prevention of estrogen receptor
(ER)–positive premenopausal breast cancer and the treatment
of ER-positive ductal carcinoma in situ (DCIS). Tamoxifen is
also used in the adjuvant treatment of surgically resected
premenopausal ER–positive breast cancer and to treat ER-
positive metastatic breast cancer (MBC).

6. • The standard daily dose : 20 mg
• the optimal duration :depends on the clinical setting
• the recommended duration in the prevention and DCIS settings
is 5 years, prospective studies demonstrated that 10 years
(compared to 5 years) improved breast cancer mortality and
overall survival for the adjuvant treatment of breast cancer.

7. Side Effects of Tamoxifen
• Positive estrogenic effects : decrease in total cholesterol and the
preservation of bone density in postmenopausal women.
• In premenopausal women, tamoxifen has a negative effect on bone
density.
• most common side effect : hot flashes
• In 50% of patients.
• Hot flashes vary in intensity and duration, plateauing after the first 3
months of treatment.
• Ameliorators of symptoms : low dose megestrol; antidepressants
such as venlafaxine, desvenlafaxine, citalopram, escitalopram, and
paroxetine; and the anticonvulsant drugs gabapentin and pregabalin.
• Some drugs such as paroxetine potently inhibit the CYP2D6 enzyme (thus
lowering the concentrations of the active metabolite, endoxifen).

8. • increases the incidence of endometrial cancer in
postmenopausal (but not premenopausal) women
(commensurate with the duration of tamoxifen use)
-Thromboembolic phenomena.
-Although most patients do not experience vaginal symptoms,
some complain of vaginal dryness, whereas others have
increased vaginal secretions.
-Cataracts

9. Pharmacology
• extensively metabolized predominantly by the cytochrome P450
(CYP) system
• Blocking estrogen stimulation of breast cancer cells,
inhibiting both translocation and nuclear binding of the ER.
• Tamoxifen has agonistic, partial agonistic, or antagonistic
effects depending on the species, tissue, or end points
assessed.

10. • .The two most active tamoxifen metabolites :
(4-hydroxytamoxifen (4-OH tamoxifen) and 4-OH-N-
desmethyltamoxifen (endoxifen))
inhibit estrogen-induced proliferation up to 100 times greater than
tamoxifen.

15. • In women taking tamoxifen (20 mg daily), plasma endoxifen steady-state
concentrations
(Css) are up to 10 times higher than 4-hydroxytamoxifen. While tamoxifen
metabolism
to 4-OH-tamoxifen is catalyzed by multiple enzymes, endoxifen is formed
predominantly
by the CYP2D6-mediated oxidation of N-desmethyltamoxifen.
• Peak tamoxifen levels (maximum concentration [Cmax]) are seen 3 to 7 hours
after oral
administration.
• The terminal half-life of tamoxifen ranges between 4 and 9 days.
• The drug's distribution in tissues is extensive and tamoxifen concentrations in
liver, lungs,
brain, pancreas, skin, and bones are up to 60-fold higher than plasma steady

16. • CYP2D6 genetic variation or drug-induced inhibition of CYP2D6
result in
lower endoxifen Css in tamoxifen-treated patients.
• In the metastatic setting, a prospective study demonstrated no association
between Z-endoxifen exposure and 6 month progression-free survival
(PFS). In
contrast, in the adjuvant setting, the association
between CYP2D6polymorphisms
and recurrence is controversial.
• The Clinical Pharmacogenetics Implementation Consortium published
recommendations for the use of tamoxifen in the adjuvant setting based
on CYP2D6 genotype. These recommendations include alternative
hormonal therapy for patients with CYP2D6 genotypes associated with
reduced CYP2D6 enzyme activity or (for those who must remain on
tamoxifen) dose escalation from 20 to 40 mg per day.

17. • Many drugs inhibit CYP2D6. Similar to the CYP2D6genotype
data, data surrounding CYP2D6 inhibitors and breast cancer
outcomes are controversial. In the absence of prospective data,
clinicians should avoid prolonged coadministration of drugs that
potently inhibit CYP2D6. Furthermore, drugs that induce phase
I and II enzymes (e.g., rifampicin) should be avoided.

21. Endoxifen
• Two phase I studies of oral Z-endoxifen have been reported.
• Endoxifen clearance was unaffected by CYP2D6 genotype. At the
80
mg/day dose, Z-endoxifen Css were 50 to 100 times higher (>2 µM)
than
achieved with TAM (20 mg/day). A randomized phase II study
(A011203)
compared Z-endoxifen (80 mg/day) to tamoxifen (20 mg/day) in
patients
with ER+ MBC who progressed on aromatase inhibitors.Endoxifen
did not
improve PFS overall

22. • Development of Z-endoxifen is ongoing in premenopausal
breast
• cancer patients with ER+/HER2- breast cancer.

25. Toremifene
• an antiestrogen similar to tamoxifen.
• It is available in the United States for the treatment of MBC and
approved in other countries for The adjuvant treatment of ER-positive
breast cancer.
• Clinical trials have demonstrated no difference in either disease-
free or overall survival when toremifene was compared with
tamoxifen.
• evidence exists for major cross-resistance between tamoxifen and
toremifene.

26. Pharmacology
• Toremifene's chemical structure
differs from tamoxifen by the
substitution of a chlorine for a
hydrogen atom that is retained
when toremifene undergoes
metabolism.

27. • Like tamoxifen, toremifene is metabolized by CYP3A, with secondary
metabolism forming hydroxylated metabolites with similar binding
affinities to 4-OH tamoxifen. As with tamoxifen, tissue concentrations
of toremifene are higher compared to plasma. Seventy percent of the
drug is excreted in feces as metabolites.
• hepatic dysfunction decreases the toremifene clearance.
• Conversely, patients on anticonvulsants had increased clearance

28. Raloxifene
• Raloxifene is a SERM originally developed to treat
osteoporosis.
• Large placebo-controlled randomized trials demonstrated
reduced
rates of osteoporosis and a reduction in new breast cancers.
• The National Surgical Adjuvant Breast and Bowel Project
(NSABP) P2 trial demonstrated that tamoxifen was superior to
raloxifene in terms of invasive and noninvasive cancer events.
•BUT raloxifene exhibited fewer thromboembolic events and
endometrial cancer.

29. Pharmacology
• Raloxifene is partially estrogenic in bone, antiestrogenic in
mammary tissue, and less estrogenic in uterine tissue
compared to tamoxifen.
• The plasma elimination half-life of raloxifene averages 27.7
hours.
excreted principally in feces as an unabsorbed drug.
The metabolism of raloxifene does not appear to be mediated by
CYP enzymes.

30. • ‫رالوکا‬ ‫قرص‬
60
‫گرم‬ ‫میلی‬
• EVISTA Tablet 60 mg

31. Lasofoxifene
• Lasofoxifene is a third-generation SERM originally developed for
• treatment of postmenopausal vaginal atrophy and osteoporosis.
• In the Postmenopausal Evaluation and Risk-Reduction with
Lasofoxifene (PEARL) trial, 5 years of lasofoxifene (0.5 mg/day)
reduced the risk of invasive ER+ breast cancer by 83% and had
positive effects on vertebral and nonvertebral fractures, coronary
heart disease events, and stroke.

32. Pharmacology
• After oral administration, lasofoxifene selectively binds to both ERα
and Erβ with high affinity with differing agonist and antagonist effects
in ER-expressing tissues. After ingestion, Cmax is achieved in ∼6.0 to
7.3 hours.
Phase I oxidation via CYP3A4/CYP3A5 and CYP2D6 accounts for ∼ 50%
of lasofoxifene metabolism. Phase II conjugation reactions include
glucuronidation and sulfation. The former is catalyzed by UGTs.

33. Fulvestrant
• a selective ER degrader (SERD) that results in ER
downregulation without agonist activity.
• competitively binds to the ER with ∼100 times greater affinity
than
• tamoxifen. Prospective studies demonstrated that 500
mg/month
(along with an extra loading dose in the first month) is superior
to the
250-mg dose in the metastatic setting.
In endocrine-naïve advanced hormone receptor–positive breast
cancer, fulvestrant (500-mg dose) was superior to anastrozole.

34. Side Effects
• well tolerated
• most common drug-related events (>10% incidence) is injection site
reactions and hot flashes.
• Common events (incidence of 1% to 10%) included asthenia,
headache, and gastrointestinal disturbances (nausea, vomiting, and
diarrhea).

35. Pharmacology
• Fulvestrant is a steroidal molecule derived from estradiol (E2) with an
alkylsulfonyl side chain in the 7-α position.
• administered via an intramuscular formulation that provides prolonged
release of the drug over several weeks.
• After a single intramuscular injection, the time of maximal concentration (t
max) ranged from 2 to 19 days.
• Pharmacokinetic modeling of pooled data from the 250-mg cohort was
best described by a two-compartment model in which a longer terminal
phase began 3 weeks after administration. By adding a loading dose at 14
days, steady-state levels are achieved within 1 month of treatment
initiation.

36. • Fulvestrant acts through a selective downregulation of the estrogen
receptor, which is competitively bound. The binding established
between fulvestrant and ER inhibits the dimerization of the estrogen
receptor and blocks the nuclear localization of the receptor itself

39. Elacestrant
• Elacestrant is one of many emerging oral SERDs. Based on
encouraging data from early phase trials, the phase III EMERALD trial
randomized 477 postmenopausal women with ER-positive/HER2-
negative MBC to elacestrant or standard of care (fulvestrant or an
aromatase inhibitor). Compared to SOC, elacestrant signifficantly
improved PFS (median PFS 2.79 vs 1.91 months; p = 0.0018).

40. Pharmacology
• Elacestrant is a nonsteroidal, orally bioavailable SERD that inhibits
estradioldependent induction of target gene transcription and cell
proliferation in breast cancer cell lines and induces proteasome-
dependent ER degradation.
• In a phase I study, no DLTs (using doses up to 600 mg/day) were
reported; however, grade 1–2 nausea, vomiting, dyspepsia,
esophageal pain, and gastroesophageal reflux disease were
concerning for long-term tolerability at 600 mg. At 400 mg/day, the
most common treatment-emergent AEs were nausea (50.0%),
dyspepsia (32.0%), vomiting (30.0%), and fatigue (28.0%).

41. Aromatase Inhibitors

42. Aromatase Inhibitors
• The synthesis of ovarian hormones ceases at menopause. However,
estrogen continues to be converted from androgens (produced by
the adrenal glands) by aromatase, an enzyme of the cytochrome
P450 (CYP) superfamily.
• Aromatase is the enzyme complex responsible for the final step in
estrogen synthesis via the conversion of androgens,
androstenedione and testosterone, to estrogens, E1 (estrone) and E2
(estradiol) .
• This pathway was used to develop the antiaromatase class of
compounds. Alterations in aromatase expression have been
implicated in the pathogenesis of breast cancer, endometrial cancer,
and endometriosis. Aromatase (cytochrome P450 19 [CYP19]) is
encoded by the highly polymorphic CYP19 gene.

45. • Aromatase inhibitors have been classified in several ways,
including first, second, and third generation; steroidal and
nonsteroidal; and reversible (ionic binding) and irreversible
(suicide inhibitor, covalent binding).
• The nonsteroidal aromatase inhibitors include
aminoglutethimide (first generation); rogletimide and fadrozole
(second generation); and anastrozole, letrozole, and vorozole
(third generation).
• The steroidal aromatase inhibitors include formestane (second
generation) and exemestane (third generation).

46. • Steroidal inhibitors compete with the endogenous substrates,
androstenedione and testosterone, for the active site of the
enzyme and are processed into intermediates that irreversibly
bind to the active site, causing irreversible enzyme inhibition.
• Nonsteroidal inhibitors also compete with the endogenous
substrates for access to the active site, where they then form a
reversible bond to the heme iron atom so that enzyme activity
can recover if the inhibitor is removed.

47. Letrozole and Anastrozole
• Both letrozole and anastrozole have been extensively studied in
the metastatic and adjuvant settings.
• Compared to tamoxifen, both drugs have superior response
rates and PFS in the metastatic setting.
• In the adjuvant setting, a meta-analysis demonstrated their
superiority to tamoxifen in terms of relapse-free survival and
overall survival.
• In postmenopausal women at high risk for developing breast
cancer, anastrozole significantly reduced the incidence of
invasive breast cancer.

48. Side Effects of Anastrozole and Letrozole
similar
arthralgias and myalgias in ≤50% of patients.
Both drugs are associated with a higher rate of fractures compared
with tamoxifen.
Therefore, when prescribing anastrozole for extended periods of time
to patients with early breast cancer, bone density should be
monitored.
Prospective studies demonstrated that bisphosphonates prevent
aromatase inhibitor–induced bone loss, and a meta-analysis
demonstrated that bisphosphonates reduce bone recurrences and
prolong overall survival

49. • A meta-analysis of toxicities comparing aromatase inhibitors
with tamoxifen demonstrated a 30% increase in grade 3 and 4
cardiac events and hypercholesterolemia with aromatase
inhibitors.
• However, prospective data demonstrated no differences in
myocardial events comparing anastrozole with placebo,
although an increase in hypertension was observed.

50. Pharmacology
• Letrozole is a nonsteroidal aromatase inhibitor with a high
specificity for the inhibition of estrogen production.
• After 2 weeks of treatment with letrozole, E2, E1, and estrone
sulfate were suppressed ≥95% from baseline.
• In postmenopausal women with advanced breast cancer, the
drug had no effect on (FSH), (LH), (TSH), cortisol, 17-α-
hydroxyprogesterone, androstenedione, or aldosterone blood
concentrations

51. • Anastrozole is a nonsteroidal aromatase inhibitor 200-fold more
potent than aminoglutethimide.
• tmax is 2 to 3 hours after oral ingestion.
• Elimination is primarily via hepatic metabolism and only 10% is
excreted unchanged in urine.
• The terminal half-life is ∼50 hours, and steady-state
concentrations are achieved in ∼10 days with once daily
dosing.
• In one study, anastrozole 1 mg and 10 mg daily inhibited in vivo
aromatization by 96.7% and 98.1%, respectively, and plasma
E1and E2 levels were suppressed 86.5% and 83.5%,
respectively, regardless of dose.
• Thus, 1 mg of anastrozole achieves near-maximal aromatase
inhibition and plasma estrogen suppression in breast cancer
patients

55. Exemestane
•
steroidal structure
• classified as a type 1 aromatase inhibitor, also known as an aromatase
inactivator because it irreversibly binds with and permanently inactivates
the enzyme.
• In a phase III trial evaluating first-line treatment of hormone receptor–
positive MBC, exemestane improved median PFS and response rates
compared with tamoxifen.
• In the adjuvant setting, exemestane has been compared with anastrozole
in the treatment of ER-positive breast cancer, and there were no
differences in disease-free or overall survival.
• Finally, a significant reduction in the risk of developing invasive breast
cancer was observed when patients at increased risk of breast cancer
received exemestane versus placebo.

56. Side Effects of Exemestane
• side effects are similar to the other aromatase inhibitors.
• no impact on either cortisol or aldosterone levels
• Finally, exemestane has weak androgenic properties, and use
at higher doses has been associated with steroidal-like side
effects, such as weight gain and acne.
• However, these side effects have not been observed with the
FDA-approved dose (25 mg per day).

57. Pharmacology
• Exemestane is administered once daily by mouth, with the
recommended daily dose being 25 mg.
• Exemestane suppresses estrogen concentrations by 52% to
72%, comparable to that produced by the nonsteroidal
aromatase inhibitors anastrozole and letrozole.
• Maximal E2 suppression is achieved in 3 days.
• Exemestane is metabolized by CYP3A4.

60. RESISTANCE TO ENDOCRINE-
TARGETED THERAPY IN BREAST
CANCER

61. • Resistance to SERMs or aromatase inhibitors, whether intrinsic or acquired,
inevitably develops over time through multiple mechanisms.
• An important factor is the level of ER, which is highly predictive for endocrine
therapy response. In ∼10% of cases, resistance may result from a decrease or loss
of ER expression.
• Although alterations in ESR1, the gene that encodes ERα, are rare in newly
diagnosed breast cancer; activating ER point mutations are present in 30% to 40%
of recurrent breast cancers.
• These mutations lead to a conformational change in the ligand-binding domain
that mimics the conformation of the activated ligand-bound receptor and
generates constitutive, ligand-independent transcriptional activity, resulting in
hormonal therapy resistance.

62. • ESR1 translocations have also been described; several yield fusion proteins
that render ER-positive cells insensitive to endocrine therapy. ESR1
ampliffication has been more commonly observed in tumors resistant to
aromatase inhibitors.
• Dysregulation in multiple growth factor signaling pathways is associated
with resistance to endocrine therapy.
• ER-positive breast cancers that overexpress HER2 may be less responsive
to hormonal therapy. Overexpression or ampliffication in multiple growth
factor receptors, including epidermal growth factor receptor (EGFR),
human epidermal growth factor receptor 2 (HER2), human epidermal
growth factor receptor 3 (HER3), insulin-like growth factor 1 receptor
(IGF1R), and fibroblast growth factor receptor 1 (FGFR1), contributes to
endocrine resistance.

63. • These mitogenic pathways converge on the mitogen-activated protein
kinase (MAPK) and mammalian target of rapamycin (mTOR)
pathways. The expression of AIB1, an estrogen- receptor coactivator,
has been associated with tamoxifen resistance in patients whose
breast cancers overexpress HER2.
• Finally, mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR
pathway are frequently observed in ER-positive breast tumors.

64. • Impaired regulation of the cell-cycle progression through
abnormalities in key regulatory checkpoints can lead to endocrine
insensitivity as well. Abnormalities in the cyclin, cyclin-dependent
kinase (CDK) family, or retinoblastoma (Rb) pathways were frequently
observed in ER-positive breast cancers. Cyclin D1 (CCND1)
ampliffication, gain of CDK4, and loss of negative regulators have
been associated with estrogen-independent growth.

66. • Mechanism 1: Loss of wtER expression may lead to estrogen-independent
growth.
• Mechanism 2: Essential components of the ESR1 gene include activation function
1 (AF1), the DNA-binding domain (DBD), hinge, and the ligand-binding domain
(LBD). ESR1 activating point mutations have been reported in the LBD (red
lightning bolts), resulting in constitutively active mutant ER (mutER).
• Mechanism 3: Overexpression or ampliffcation of growth factor receptors,
including epidermal growth factor receptor (EGFR), human epidermal growth
factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3),
insulin-like growth factor 1 receptor (IGF1R), and fibroblast growth factor
receptor 1 (FGFR1), contributes to endocrine resistance.
• Mechanism 4: In the absence of stimulatory signaling, the retinoblastoma (Rb)
protein sequesters the transcription factor E2F, preventing progression of the cell
cycle. Increased activity of cyclin D1 or cyclin-dependent kinases (CDKs) 4 and 6
or loss of the Rb protein facilitates entry into the cell cycle.

67. mTOR Inhibitors
• . In patients resistant to anastrozole or letrozole, adding
everolimus (an mTOR inhibitor) to exemestane improved PFS.
• The benefit of mTOR inhibitors may be confined to patients who
exhibit secondary endocrine resistance, as no improvement in
PFS was noted when this class of drugs was added to
aromatase inhibitors in the first-line setting.
• The side effect profile of everolimus includes stomatitis,
hyperglycemia, anemia, and, rarely, drug-related pneumonitis.

70. uptodate
• Dosage 10 mg oral once daily
• Child pugh B = 5 mg daily
• Child pugh c = use not recommended
• Renal impairment = dosage adjustment not required

71. CDK4/6 Inhibitors
•
The cell-cycle progression for multiple growth factor or
proliferation signaling pathways is regulated by CDK4 or CDK6.
• CDK4/6 inhibition activates Rb and inhibits growth in both
estrogen-sensitive and estrogen-resistant models.
• Three highly selective CDK4/6 inhibitors have demonstrated
efficacy and are approved for the metastatic treatment of ER-
positive breast cancer: palbociclib, ribociclib, and abemaciclib

72. • Combinations of palbociclib, ribociclib, or abemaciclib with either letrozole or
fulvestrant demonstrated similar and substantial improvement in PFS in
premenopausalor postmenopausal women with metastatic hormone receptor–
positive breast cancer.
• While palbociclib did not improve DFS in the adjuvant setting, abemaciclib plus
endocrine therapy improved DFS compared with endocrine therapy alone in
patients with lymph node–positive, high-risk ER+ HER2- early breast cancer.
• Palbociclib and ribociclib share a similar toxicity profile, including
myelosuppression and fatigue. Notably, although neutropenia is commonly
observed, neutropenic fever is infrequent. Prolongation of the QT interval has
been reported with ribociclib, and electrocardiogram monitoring is recommended.
• Abemaciclib more potently inhibits CDK4 compared to CDK6. Unlike other
CDK4/6 inhibitors, abemaciclib has significant single-agent activity in hormone-
refractory and chemotherapy-refractory metastatic ER-positive breast cancer.
• Although myelosuppression can occur, the most common adverse event is
diarrhea.

75. uptodate
• Palbocilib
• 125 mg once daily for 21 days followed by 7 days iff repeat every 28
days ( in combination aromatase inhibitor therapy)
• Countinue until diseas progresseion or unacceptable toxicity
• Missed dose????????? An additional dose should not be taken
First reduction dose 125 mg
Seconde and last reduction dose 75 mg

78. PI3K Inhibitors *
• Mutations in PIK3CA, the gene encoding the p110α catalytic subunit
of PI3K, are encountered in ∼40% of patients with HR-positive HER2-
neagtive breast cancer.
• Alpelisib is an oral phosphatidylinositol 3-kinase (PI3K) inhibitor
targeting PI3K-alpha (PI3Kα).
• In the SOLAR-1 study, alpelisib (300 mg once daily) plus fulvestrant
improved PFS (11 vs 5.7 months) compared with fulvestrant/placebo
for postmenopausal women and men with PIK3CAmutated ER-
positive HER2-negative MBC following progression on hormonal
therapy.

79. • The most common grade 3 or 4 adverse events were hyperglycemia
and rash
• In the follow-up BYLIEVE study, alpelisib plus endocrine therapy
confirmed antitumor activity in PIK3CAmutated, hormone receptor-
positive, HER2-negative advanced breast cancer after progression on
a CDK4/6i plus an aromatase inhibitor.

80. GnRH(Gonadotropin-Releasing Hormone
Analogs)
• Gonadotropin-releasing hormone (GnRH) analogs result in a
medical orchiectomy in men and can provide androgen ablation
for hormone-sensitive and castration-refractory metastatic
prostate cancer.
• Because the initial agonist activity of GnRH analogs can cause
a tumor flare from temporarily increased androgen levels,
concomitant use of the antiandrogen flutamide or bicalutamide
has been used to prevent this effect.

81. • Can cause tumor regressions in hormonally responsive breast
cancers and have received FDA approval for the treatment of
MBC in premenopausal women.
• The benefit of combining these drugs with tamoxifen,
anastrozole, or exemestane in the adjuvant treatment of
premenopausal women with primary ER+ breast cancer has
been established in multiple large clinical trials.

82. • The primary toxicities of GnRH analogs are secondary to the
ablation
of sex steroid concentrations and include hot flashes, sweating,
and
loss of libido.

83. • goserelin and leuprolide
available in depot intramuscular preparations to be given at monthly
intervals.
recommended monthly dose of leuprolide is 7.5 mg and of goserelin is
3.6 mg.
There are also longer acting depot preparations to be administered
every 3, 4, 6, and 12 months.

86. Pharmacology
• Initial administration of these compounds stimulates gonadotropin
release. However, prolonged administration can lead to profound
inhibition of the pituitary–gonadal axis.
• Plasma E2 and progesterone are consistently suppressed to
postmenopausal or castrate levels after 2 to 4 weeks of treatment.
• administered intramuscularly or subcutaneously
• .

87. • Leuprolide is 80 to 100 times more potent than endogenous GnRH. It
induces castrate levels of testosterone in men with prostate cancer
within 3 to 4 weeks of drug administration.
• The mechanisms of action include pituitary desensitization after a
reduction in pituitary GnRH receptor binding sites and possibly a
direct antitumor effect in ER-positive human breast cancer cells.
• The parenteral bioavailability of subcutaneously injected leuprolide is
94%.
• Urinary excretion

88. • Goserelin is 100 times more potent than naturally occurring GnRH. In
women, goserelin inhibits ovarian androgen production, but serum
levels of dehydroepiandrosterone sulfate and, to a lesser extent,
androstenedione, are preserved.
• Urinary excretion

89. Gonadotropin-Releasing Hormone
Antagonists
• Degarelix is a synthetically modified compound with GnRH antagonist
activity.
• Degarelix blocks the GnRH receptor, thereby preventing the trigger for
LH production that mediates androgen synthesis.
In contrast to GnRH analogs, degarelix does not cause tumor fare
symptoms secondary to temporary increased androgen production.
The most common side effects are hot flashes and pain at the injection
site.

90. Pharmacology
• The recommended loading dose of degarelix is 240 mg, administered
as two injections of 120 mg each subcutaneously.
• Monthly maintenance doses of 80 mg as a 20 mg/mL solution are
started 28 days after the loading dose.
• In 60 healthy males, after a single subcutaneous dose of degarelix, a
terminal halflife of 47 days was observed.

91. Antiandrogens

92. Flutamide
•
The antiandrogen flutamide is used in men with metastatic prostate cancer
either as initial therapy, combined with GnRH analog administration, or
when the metastatic prostate cancer is unresponsive despite androgen
ablation therapy.
• The recommended dose is 250 mg by mouth three times a day.
• In patients whose prostate cancer is growing despite flutamide use,
stopping flutamide can sometimes cause a flutamide withdrawal response.
• The most common toxicity seen with flutamide is diarrhea, with or without
abdominal discomfort. Gynecomastia, which can be tender, frequently
occurs in men who are not receiving concomitant androgen ablation
therapy.
• Flutamide can rarely cause hepatotoxicity, a condition that is reversible if
detected early, but this toxicity can also be fatal.

93. Pharmacology
• Flutamide has no intrinsic steroidal activity
• acts as an androgen receptor antagonist by preventing binding
of dihydrotestosterone and its subsequent translocation of the
androgen–receptor complex into the nuclei.
• The administration of flutamide alone leads to increased LH and
FSH production and a concomitant increase in plasma
testosterone and E2 levels. When the drug is administered
three times a day, steady-state levels are achieved by day 6.

95. Bicalutamide
• a nonsteroidal antiandrogen approved for use in the United
States. The recommended dose is one 50 mg tablet per day.
• Bicalutamide monotherapy is not recommended as a first-line
therapy for the management of prostate cancer in the advent of
second-generation androgen receptor signaling inhibitors.
• It can be considered in patients unable to tolerate castration
therapy or with a poor performance status.
• Bicalutamide is commonly associated with gynecomastia and
elevated transaminase levels requiring frequent monitoring.

96. Enzalutamide *
•
Enzalutamide is a diarylthiohydantoin compound that binds AR
with an affinity that is several-fold greater than the
antiandrogens bicalutamide and flutamide.
• This class of novel AR inhibitor also disrupts the nuclear
translocation of AR and impairs DNA binding to androgen
response elements and the recruitment of coactivators.
• Enzalutamide is approved for the treatment of metastatic
castrate-resistant prostate cancer both before and after
chemotherapy.
• Side effects include hot flashes, fatigue, diarrhea, and rarely,
seizures.

97. Pharmacology
• Enzalutamide binds to the AR with an eightfold higher affinity than
bicalutamide
• The standard dose of enzalutamide is 160 mg once daily
• reached peak concentrations between 30 minutes and 4 hours after
administration.
• Steady-state plasma levels of enzalutamide are reached after 1
month of daily treatment.

99. • Xtandi contains an androgen receptor antagonist.
• The drug works by inhibiting androgen binding to androgen receptors,
and restrains androgen receptor nuclear translocation and interaction
with DNA.

100. • The mechanism of action of XTANDI resulted in:
• Decreased proliferation*†
• Tumor cell death*†
• Reduced tumor volume*‡

101. • The FDA approval for Xtandi was based on a Phase III clinical study
known as AFFIRM.
• It was conducted between September 2009 and July 2012. The
randomised, global, placebo-controlled study enrolled 1,199 patients
with mCRPC. Patients who were administered with docetaxel were
randomly given Xtandi 160mg oral dose or placebo once daily.

102. • The results:
• patients administered with Xtandi showed statistically significant
improvement in median OS, when compared to the patients treated
with placebo. 18.4 months against 13.6 months
• The number of deaths reported in the Xtandi arm was 38.5% while it
was 53.1% in the placebo arm .

103. Apalutamide *
• oral nonsteroidal antiandrogen that binds to the ligand binding
domain of the androgen-receptor preventing its subsequent
translocation and DNA binding.
• In men with non-metastatic castrationresistant prostate cancer,
apalutamide improved metastasis-free survival time and time to
symptomatic progression.
• In the metastatic castration-sensitive prostate cancer setting, when
combined with ADT, apalutamide improved overall survival and
radiographic PFS.
• 240 mg orally once daily.

104. Darolutamide *
• Darolutamide is a novel high affinity nonsteroidal androgen receptor
antagonist approved by the FDA in 2019 for the treatment of
nonmetastatic castrate-resistant prostate cancer.
• In men with nonmetastatic castrate-resistant prostate cancer on ADT,
darolutamide prolonged metastasis-free survival compared to ADT
alone.
• The most common adverse reactions were fatigue, rash, and pain in
the extremities. however, CNS-related adverse events such as mental
impairment, dizziness, and seizures were similar to placebo that may
be linked to its low penetration of the blood–brain barrier.

105. Abiraterone Acetate
• After the failure of initial androgen manipulation, prostate cancer continues
to respond to a variety of second- and third-line hormonal interventions.
• Based on this observation, CYP17, a key enzyme in androgen and
estrogen synthesis, was targeted using ketoconazole, which is a weak,
reversible, and nonspecific inhibitor of CYP17, resulting in modest
antitumor activity of short durability. Abiraterone acetate, a selective,
irreversible inhibitor of CYP17 that is 20 times more potent than
ketoconazole, prolonged overall survival in castration-resistant prostate
cancer.
• In men with newly diagnosed, metastatic, castration-sensitive prostate
cancer, combining abiraterone acetate with ADT was superior to ADT
alone, as evidenced by doubling of PFS.
• Earlier use of abiraterone acetate was further supported in another phase
III study demonstrating that adding abiraterone acetate to androgen
deprivation lowered the relative risk of death compared to androgen
deprivation alone.

106. Pharmacology
• Abiraterone acetate is a 3-pyridyl steroid pregnenolone-derived
compound available as an oral prodrug. Its main toxicity is
mineralocorticoid excess (including hypokalemia, hypertension,
and fluid overload) because continuous CYP17 blockade raises
adrenocorticotrophic hormone (ACTH) levels that increase
upstream levels of CYP17, including corticosterone and
deoxycorticosterone.
• These adverse effects can be lessened by coadministration of
steroids.

107. • The established dose of abiraterone is 1,000 mg per day.
• . Abiraterone is converted into two inactive metabolites, N-oxide
abiraterone sulfate and abiraterone sulfate. Abiraterone not only
inhibits several CYP enzymes, including CYP2D6, CYP1A2,
and CYP3A4, but also inhibits a CYP3A4 substrate

108. • Steroid biosynthesis pathways and
mechanism of action of abiraterone
acetate. CYP17 has two sequential
enzymatic activities. The 17α-
hydroxylase activity is critical to
production of cortisol. The C17,20-lyase
activity is required for synthesis of
testosterone and estradiol. Thus,
inhibition of C17,20-lyase function is the
desired function of abiraterone as it is
this enzymatic activity that is
responsible for androgen production.
• Red arrows indicate the direction and
degree of change in hormone levels
from abiraterone. Blue arrows indicate
the change in hormone levels when
corticosteroids are administered with
abiraterone.

111. Medroxyprogesterone and Megestrol
• Medroxyprogesterone and megestrol are 17-OH-progesterone
derivatives.
• Historically, megestrol was used as a hormonal agent for patients
with advanced breast cancer or advanced prostate cancer, usually at a
dose of 160 mg. It is still used for the treatment of hormonally
responsive metastatic endometrial cancer.
• Varying doses of megestrol have also been evaluated for the
treatment of anorexia/cachexia related to cancer or AIDS.
• Low dosages of megestrol (20 to 40 mg per day) can effectively
reduce hot flashes in women with breast cancer and in men who
have undergone androgen ablation therapy.

112. • well tolerated
• with its most prominent side effects being appetite stimulation and
resultant weight gain.
• Another side effect is the suppression of adrenal steroid production
by suppression of the pituitary–adrenal axis.
• This adrenal suppression can cause clinical problems in some
patients.
• slightly increased incidence of thromboembolic phenomena

113. • menstrual irregularities in women
• impotence in men although these side effects are typically reversible.
• antiemetic properties.
• Medroxyprogestrone :
• Dosing for the treatment of metastatic breast or prostate cancer has
commonly been 400 mg per week or more and 1,000 mg per week or
more for metastatic endometrial cancer.
• Injectable or daily oral doses have been used for controlling hot
flashes.

114. Octreotide
• Octreotide and lanreotide are somatostatin analogs used to treat
carcinoid syndrome and other hormonal excess syndromes associated
with some pancreatic islet cell cancers and acromegaly.
• In enteropancreatic and midgut neuroendocrine tumors,
somatostatin analogs improve tumor control
• Octreotide and lanreotide are generally well tolerated overall.
• More toxicity is observed in acromegalic patients, with such problems
as bradycardia, diarrhea, hypoglycemia, hyperglycemia,
hypothyroidism, and cholelithiasis.

115. Pharmacology
• Octreotide is an 8–amino acid synthetic analog of the 14–amino acid
peptide somatostatin.
• Octreotide can be administered intravenously or subcutaneously.
• Octreotide inhibits insulin, glucagon, pancreatic polypeptide, gastric
inhibitory polypeptide, and gastrin secretion.
• Whereas the half-life of somatostatin is only 2 to 3 minutes,
octreotide has a half-life of 90 to 120 minutes, and the pharmacologic
duration of action lasts up to 12 hours (when administered
subcutaneously).

116. • Because of the short half-life of classic octreotide, classic octreotide
initial doses of 50 μg are given two to three times on the first day.
• The dose is titrated upward, with a usual daily dose of 300 to 450 μg
per day for most patients.
• A slow-release form of octreotide, designed for once-permonth
administration, controls the symptoms of carcinoid syndrome at least
as well as three-times-per-day octreotide.
•