Prostate carcinoma- hormonal therapy 1

Prostate carcinoma- hormonal therapy 1

1. Hormonal
Therapy in
Prostate Cancer
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

2. Androgen Signaling Pathway

3. Therapeutic Approaches
1. Ablation of androgen sources
2. Anti androgens
3. Inhibition of LHRH or LH
4. Inhibition of androgen synthesis

4. Ablation of Androgen sources
1. Bilateral orchidectomy (Total or subcapsular)
2. Bilateral adrenalectomy (Historical and Obsolete)

5. Bilateral orchidectomy
•Quickly reduces circulating testosterone levels to less
than 50 ng/dL (Castrate range).
•Classical castrate range – 50 ng/mL, now 15ng/mL
•Within 24 hours of surgical castration, testosterone
levels are reduced by greater than 90%.

6. Anti androgens
Steroidal:
1.Cyproterone acetate
Non steroidal:
1.Flutamide
2.Bicalutamide
3.Nilutamide
4.Enzalutamide
5.Apalutamide

7. Cyproterone acetate
•Classical steroidal antiandrogen with direct AR
blocking effects.
•Rapidly lowers testosterone levels to 70-80%
•Acts through progestational central inhibition.
•Dose 100 mg twice or thrice daily.
•Side effects:
Loss of libido,
Erectile dysfunction,
Lassitude.

8. Cyproterone acetate
•Cardiovascular complications in 10% of patients.
•Gynaecomastia in < 20% of patients.
•Used for the treatment of Hot flashes. Dose 50-100
mg/day.

9. Non steroidal antiandrogens
•Block testosterone feedback centrally.
•Cause LH and testosterone levels to increase.
•Testosterone levels reach 1.5 times the normal levels.
•Potency can be preserved. (< 20%)
•Peripheral aromatization to estradiol.
•Gynaecomastia and mastodynia.
•Liver toxicity requires periodic LFT monitoring

10. Flutamide
•First ‘Pure’ anti androgen.
•Half life 6 hrs.
•Dose 250 mg twice or thrice a day.
•Gastrointestinal toxicity – Diarrhoea is a common
complication.

11. Bicalutamide
•Half life 6 days
•Dose 150 mg once daily
•Equivalent efficacy to surgical or medical castration.
•Side effects: Gynaecomastia, mastalgia.

12. Nilutamide
•Half life 56 hours.
•Elimination via Cytochrome P450 system.
•Dose 300 mg daily for 1 month followed by 150 mg
daily.
•Adverse effects: Delayed adaptation to darkness
(25%), Interstitial pneumonitis (1%) progressing to
pulmonary fibrosis.

13. Enzalutamide
•AR antagonist inhibiting nuclear translocation and
DNA binding.
•Effective in castration resistant prostate cancer.
•Side effects: Fatigue, diarrhoea and hot flashes.
Seizures (1%)
•Indicated in patients with mCRPC.
•Efficacy equal to Abiraterone.
•Dose: 160 mg/day. (1 tab – 40 mg)

14. Apalutamide
•Oral, nonsteroidal antiandrogen
•Blocks the action of testosterone by binding to the
ligand-binding domain of the AR receptor.
•Used for the treatment of nonmetastatic CRPC.
•Adverse reactions: Fatigue, hypertension, rash, and
diarrhea.
•Dose: 240 mg/ day. ( 1 tab- 60 mg)

15. LHRH agonists
•Leuprolide
•Goserelin
•Triptorelin
•Histrelin

16. Leuprolide acetate
•Commonly used LHRH agonist
•Available as depot preparation for subcutaneous and
im injections.
•Lupron depot : Available with 1-,3-,4- and 6
th

monthly depot preparations with 7.5 mg, 22.5 mg,
30 mg and 45 mg for im injections.
•Eligard: Same dosage available for SC injections.
•Leuprolide acetate 1 mg/0.2 mL/day SC

17. Mechanism of Action
•Exploits sensitization of LHRH receptors in ant
pituitary following chronic exposure to LHRH.
•After initial flare up, downregulation of LHRH
receptor occurs.
•LH and testosterone production shut down.

18. Flare up phenomenon
•Testosterone surge or Flare up phenomenon
associated with upto 10 fold increase in LH.
•May last for 10-20 days.
•Co administration of an antiandrogen functionally
blocks the increased levels of testosterone.
•Antiandrogen administration required for 3-4 weeks.

19. LHRH antagonists
•Cetrorelix
•Abarelix
•Degarelix
•Relugolix

20. LHRH antagonists
•Competitively bind to LHRH receptors in the
pituitary, reducing LH concentrations by 84 % with in
24 hours.
•No LH and testosterone flare.
•No need for antiandrogen coadministration.

21. Abarelix
•Severe allergic reactions even after previous
uneventful treatment.
•Patient should be monitored for 30 minutes after
administration.
•Voluntarily withdrawn in 2005.

22. Degarelix
•No systemic allergic reactions.
•1-month SC dose, requiring two initial injections (2 ×
3 mL for 240 mg) followed by monthly doses of 4 mL
(80 mg).

23. Inhibition of Androgen Synthesis
1.Aminoglutethimide
2.Ketoconazole
3.Abiraterone

24. Aminoglutethimide
•Inhibits conversion of cholesterol to pregnenolone.
•Blocks production of aldosterone and cortisol also.
Hence should be replaced.
•Side effects: Anorexia, nausea, skin rash, lethargy,
vertigo, hypothyroidism and nystagmus.
•Dose: 1000 mg/day and Hydrocortisone acetate (40
mg/day).

25. Ketoconazole
•Interferes with two cytochrome P450 dependent
pathways.
•Blocks conversion of C21 to C19 steroids.
•Effect is rapid. Testosterone level drops to castrate
levels in 4 hours in some cases.
•Effect is immediately reversible.
•Dose: 400 mg 8 hrly. Usually with hydrocortisone 20
mg bd.

26. Ketoconazole
•With continuous use, testosterone levels begins to
rise and can reach low normal ranges with in 5
months of therapy.
•Used currently for castration resistant prostae cancer.
•Side effects:
–Gynaecomastia,
–lethargy, weakness,
–hepatic dysfunction, visual disturbance and
nausea.

27. Abiraterone
•Selective irreversible inhibitor of Cytochrome P17.
•Inhibits 17α hydroxylase and C17-20 lyase.
•Increase synthesis of aldosterone and its precursors.
•Suppress cortisol and increase ACTH secretion.
•Testosterone levels < 1 ng/mL.
•Side effects:
–Hypokalemia, hypertension, fluid overload.
•Dose: 1000 mg/day ( 1 tab – 250mg/500mg)

28. Abiraterone
•Co administration of prednisolone supresses ACTH.
•Can be used in Metastatic castration resistant
prostate cancer.

29. Drugs in Development
•Darolutamide
•Relugolix
•Orteronel (TAK-700)
•ARN-509

30. Darolutamide
•Oral, nonsteroidal antiandrogen with a similar mode
of action to enzalutamide and apalutamide.
Relugolix
• Oral, GnRH antagonist in phase 3 development.
• Reduced mean serum testosterone levels within 6 h of
dosing.
• However, a food effect reduced exposure by 50%

31. Orteronel (TAK-700)
•Mechanism of action similar to abiraterone.
•CYPP17 inhibitor with potentially greater 17,20 lyase
selectivity.
•Impairs androgen synthesis preferentially over
corticosteroid synthesis.

32. ARN-509
•Novel antiandrogen similar to enzalutamide
•Pure antagonist of AR while also inhibiting AR
nuclear translocation and DNA binding.
•Does not cross blood brain barrier. So no seizures.

33. Testosterone Testing
•Testosterone levels should be measured regularly to
ensure its suppression is being maintained to target.
•EAU guidelines recommendation: Test 3 months after
the first dose of ADT and repeated every 3−6 months
thereafter.

34. ADT and PSA Response
•Patients who had more than an 80% drop in PSA
within 1 month of initiating ADT survived significantly
longer free of disease progression.
•A rise in PSA, evidence of the emergence of
castration-resistant disease, preceded bone
metastatic progression by several months, with a
mean lead time of 7.3 months.

35. ADT and PSA Response
•In men with newly diagnosed metastatic prostate
cancer started on ADT, the absolute PSA level after 7
months of ADT was a strong, independent predictor
of survival.

36. Adverse Effects

37. Osteoporosis
•BMD criteria for osteopenia or osteoporosis-
–More than 2.5 standard deviations below an age
specific reference mean – Prior to the initiation of
ADT.
•After 5 yrs of ADT, fracture incidence 19.4 %.
•Over 15 years incidence 40%.
•4 years of ADT will place the average man in
osteopenia range.

38. Osteoporosis
•Treatment begins with recognition.
•BMD of the hip for all men anticipated on long term
ADT.
•Smoking cessation, weight bearing exercise, Vitamin
D and calcium supplementation.
•Bisphosphonate pamidronate can be used for
prevention as demonstrated in some studies.
•Bisphosphonates to be used when evidence of
osteopenia or osteoporosis emerge.

39. Osteoporosis
•Transdermal estradiol increases BMD in men with
prostate cancer.

40. Hot flashes
•Uncomfortable flushes of heat similar to that
experienced by women during menopause.
•Warmth in the upper torso and head followed by
objective perspiration.
•Experienced by 50-80% of patients.
•Mechanism: Increase in hypothalamic adrenergic
concentrations and alternations in endorphins and
CGRP acting on thermoregulating center in
hypothalamus.

41. Hot flashes
•Treatment reserved for bothersome patients.
•Megestrol acetate 20 mg bd can be used. Dose can
be reduced to 5 mg bd.
•Cyproterone acetate 50 mg/day titrated to 300
mg/day.
•DES and transdermal estradiol- Most effective.
•Clonidine – Centrally acting α agonist decreases
vascular reactivity.

42. Hot flashes
•Venlafaxime 12.5 mg bd can be used.
•Gabapentin decreased hot flashes to a moderate
degree in some studies.

43. Sexual Dysfunction
•20% men on ADT have some sexual activity.
•10-17% of men can have some erection adequate for
intercourse.
•Libido is highly compromised. Only 5% of men
maintain high level of sexual interest.
•Loss of penile volume and penile length loss of
noctural penile tumescence and loss of testicular
volume noted.

44. Sexual Dysfunction
•Treatment of libido is difficult.
•PDE 5 inhibitors or intracavernosal injections of
alprostadil can be used for erective dysfunction.

45. Cognitive function
•Hypogonadal state is associated with declines in
cognitive functioning.
•Short course of ADT is associated with increased
depression and anxiety scores.
•Major depressive disorder in 12.8% of men with ADT.
•Testosterone supplementation improves verbal
fluency.

46. Body Habitus
•Loss of muscle mass and increase in percent fat body
mass is common.
•More pronounced with initiation of ADT.
•Weight gain due to increase in body fat mass. (1.8-
3.8% increase in one year)
•Regular vigorous exercise may help to limit
accumulation of fat.

47. Diabetes and metabolic syndrome
•Present in 50% of men undergoing longterm ADT.
•Unlike visceral fat accumulation in classical metabolic
syndrome, fat accumulates in subcutaneous regions.
•HDL level is increased.
•Insulin sensitivity decreased.

48. Cardiovascular morbidity and
Mortality
•Effect more in low risk prostate cancer patients on
ADT.
•At 1 year of ADT, 20% higher risk of cardiovascular
morbidity compared to normal men.

49. Gynaecomastia
•Peripheral conversion of testosterone to estradiol
induces gynaecomastia and mastodynia.
•Bicalutamide: 66.3% Gynaecomastia, 72.7%
Mastodynia.
•Prophylactic radiation therapy (10 Gy) can be used to
prevent or reduce painful gynaecomastia.
•Liposuction and subcutaneous mastectomy can be
used for established gynaecomastia.
•Tamoxifen can be used for mastodynia.

50. Anaemia
•Normochromic, normocytic anaemia
•Decline in hemoglobin begin within 1 month of ADT
initiation. It continues for 24 months.
•Secondary to lack of testosterone stimulation of
erythroid precursors and decrease in erythropoietin
production.
•Recombinant erythropoietin can be used.
•After stopping ADT, anaemia reversal may take upto
1 year.

51. ADT Indications

52. ADT Indications
1.In Localised Ca prostate
2.In Locally advanced Ca prostate
3.In Biochemical recurrence
4.In metastatic Ca prostate

53. ADT in Localised Prostate Cancer
•Preoperative ADT before RP
•Combination therapy ADT and RT
•Primary ADT (Obsolete)

54. Preoperative ADT before RP
•Preoperative ADT reduces the rate of positive
surgical margins.
•But there is no benefit in terms of progression free
survival.
•It may be beneficial in high risk disease.

55. Combination therapy ADT and RT
•Combination of ADT with external beam radiation
shows benefit in overall survival, cancer specific
survival or freedom from disease progression.
•Benefit noted in disease and/or high grade, high risk
disease.
•Low risk tumours have no benefit.

56. Combination therapy duration
•For high risk disease, Combination therapy with 3
years of ADT is superior to 6 months of ADT..
•For intermediate risk disease, 4-6 months of ADT
improves the survival relative to standard dose of
radiation alone.

57. Primary ADT
•Was used in the past extensively in the treatment of
localized prostate cancer in men with significant
comorbidities and those not willing for surgery.
•They did not live any longer than patients who
received no treatment.
•ADT as primary therapy for localised Ca prostate not
recommended.

58. ADT in Locally Advanced Ca Prostate
•Neoadjuvant ADT before RP
•Adjuvant ADT after RP
•Neoadjuvant and concurrent ADT and RT
•Adjuvant ADT and RT

59. Neoadjuvant ADT before RP
•Period was 3 months.
•Clinical downstaging of the tumour in 32% to 90%.
•Pathological downstaging observed in 8%-31%.
•Current data do not support a significant benefit of
NAD before surgery.

60. Adjuvant ADT after RP
•Not of much clinical significance.
•Recent studies shows benefit of early ADT after RP in
high risk men with locoregional disease spread.

61. Neoadjuvant ADT and RT
•2 months before and 2 months during RT (RTOG)
•Causes reduction in target volume and potential
cytotoxic synergy of radiation and hormone
manipulation.
•Appropriate in high risk patients.
•Improvement in local control, disease free survival
and cancer specific mortality.

62. Adjuvant ADT and RT
Timing of ADT:
•RTOG (Goserelin)- Last week of RT and continued
indefinitely or at the time of relapse. (RTOG).
•EORTC (Goserelin) – Beginning of RT and continuing
for 3 years.
•Beneficial in both intermediate risk and high risk
cancers.

63. ADT for Biochemical Recurrence
•After Radical prostatectomy
•After RT

64. After RP
•Underevaluated, PSA value to start not known.
•High risk features show benefit-
–Gleason 8 or more,
–PSA level 15 ng/mL,
–Pathologic stage T3b, T4 or N1,
–Gleason 7 with concomitant PSA > 10 ng/mL or
–Positive surgical margin

65. After RT
•May be due to local vs distant metastatic disease.
•For local disease salvage local therapy is advised.
•93.5% of men undergo ADT as second line therapy
after RT failure.
•PSA doubling time < 12 months- High risk of distant
failure - start ADT
•Early or delayed ADT? Unknown…Trials awaited.
•Continuous or Intermittent? May be intermittent.

66. Timing of ADT

67. Timing of Therapy
•Continuous androgen deprivation therapy
•Intermittent androgen deprivation therapy

68. Continuous ADT-
Immediate Vs Delayed
1.There is no survival benefit to immediate ADT in
low-risk, localized prostate cancer.
2.In locally advanced, asymptomatic metastatic and
clinically present but undefined prostate cancer
treated in a community setting with limited disease
monitoring, immediate ADT results in significantly
better prostate cancer–specific survival but not
better overall survival.

69. Continuous ADT-
Immediate Vs Delayed
3. On the other hand, in men deemed not suitable for
local treatment, immediate ADT improved overall
survival but not prostate cancer–specific survival.
4. In node-positive disease without primary treatment,
there is no significant advantage to immediate ADT.
5. In node-positive disease with radical prostatectomy,
there is a significant survival advantage favoring
immediate ADT, with a 2.6-year difference in median
overall survival.

70. Intermittent ADT - Rationale
•Intermittent ADT may lengthen the time to the
emergence of androgen-refractory cancer growth.
•Side effects of continuous ADT are severe.
•Intermittent ADT improves the quality of life of
patients.

71. Intermittent Vs Continuous ADT
•Intermittent
ADT is non
inferior to
continuous
ADT.

72. Combined Androgen Blockade
•Idea is to remove the testicular and non testicular
source of androgens.
•Combination of antiandrogen with either castration
or an LHRH agonist, the results are conflicting.

73. Combined Androgen Blockade

74. Thank You