Prostate carcinoma- locally advanced

Metastatic
Prostate Cancer
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

MODERATORS:
Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D. Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
DEPT OF UROLOGY,GRH ANDKMC,CHENNAI. 2

PROSTATE CANCER CLINICAL STATES
3
DEPT OF UROLOGY,GRH ANDKMC,CHENNAI.

BONE SCAN SCREENING FOR METASTASIS
PSA >20 ng/ml
Gleason score 8-10
Clinical stage T3 or T4
Clinical symptoms
4

RISK AND VOLUME
5

SWOG 9346 PROGNOSIS
6

PRESENTATION
1. Patient presents with metastatic disease
2. Patient on watchful waiting develops metastasis
3. Patient with biochemical recurrence over time develops metastasis
7

CHARLES HUGGINS – NOBEL PRIZE 1966
8

? COMBINED ANDROGEN BLOCKADE
9

METASTATIC PROSTATE CANCER
ADT is indicated in symptomatic, metastatic disease.
Which ADT??
Androgen suppression only
Androgen suppression + Anti androgen
10

Prostate cancer
trialists
collaborative group
Meta analysis of
maximal androgen
blockade versus
testosterone
androgen
suppressioin alone
No significant difference in overall survival curves
11

THERAPEUTIC APPROACHES
1. Ablation of androgen sources
2. Anti androgens
3. Inhibition of LHRH or LH
4. Inhibition of androgen synthesis
12

ANDROGEN SIGNALING PATHWAY
13

ABLATION OF ANDROGEN SOURCES
1. Bilateral orchidectomy (Total or subcapsular)
2. Bilateral adrenalectomy (Historical and Obsolete)
14

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%.
15

ANTI ANDROGENS
Steroidal:
1. Cyproterone acetate
Non steroidal:
1. Flutamide
2. Bicalutamide
3. Nilutamide
4. Enzalutamide
5. Apalutamide
16

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.
17

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.
18

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
19

FLUTAMIDE
First ‘Pure’ anti androgen.
Half life 6 hrs.
Dose 250 mg twice or thrice a day.
Gastrointestinal toxicity – Diarrhoea is a common complication.
20

BICALUTAMIDE
Half life 6 days
Dose 150 mg once daily
Equivalent efficacy to surgical or medical castration.
Side effects: Gynaecomastia, mastalgia.
21

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.
22

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)
23

ENZALUTAMIDE
24

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)
25

LHRH AGONISTS
Leuprolide
Goserelin
Triptorelin
Histrelin
26

LEUPROLIDE ACETATE
Commonly used LHRH agonist
Available as depot preparation for subcutaneous and im injections.
Lupron depot : Available with 1-,3-,4- and 6th 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
27

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.
28

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.
29

LHRH ANTAGONISTS
Cetrorelix
Abarelix
Degarelix
Relugolix
30

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.
31

ABARELIX
Severe allergic reactions even after previous uneventful treatment.
Patient should be monitored for 30 minutes after administration.
Voluntarily withdrawn in 2005.
32

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).
33

INHIBITION OF ANDROGEN SYNTHESIS
1. Aminoglutethimide
2. Ketoconazole
3. Abiraterone
34

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).
35

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.
36

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.
37

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)
38

ABIRATERONE
Co administration of prednisolone supresses ACTH.
Can be used in Metastatic castration resistant prostate cancer.
39

ABIRATERONE
40

DRUGS IN DEVELOPMENT
Darolutamide
Relugolix
Orteronel (TAK-700)
ARN-509
41

DAROLUTAMIDE
Oral, nonsteroidal antiandrogen
Similar mode of action to enzalutamide and
apalutamide.
42

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.
43

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%
44

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.
45

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.
46

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.
47

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.
48

ADVERSE EFFECTS
1. Osteoporosis
2. Hot flashes
3. Sexual dysfunction
4. Cognitive decline
5. Changes in body habitus
6. Diabetes and metabolic syndrome
7. Cardiovascular morbidity
8. Gynaecomastia and anemia
49

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.
50

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.
51

OSTEOPOROSIS
Transdermal estradiol increases BMD in men with prostate cancer.
52

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.
53

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.
54

HOT FLASHES
Venlafaxime 12.5 mg bd can be used.
Gabapentin decreased hot flashes to a moderate degree in some
studies.
55

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.
56

SEXUAL DYSFUNCTION
Treatment of libido is difficult.
PDE 5 inhibitors or intracavernosal injections of alprostadil can
be used for erective dysfunction.
57

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.
58

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.
59

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.
60

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.
61

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.
62

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.
63

CRPC AND CHEMOTHERAPY
Before Chemotherapy: 6-12 months
After Chemotherapy: 16-20 months
64

CRPC DEFINITION
Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either:
a. Biochemical progression: Three consecutive rises in PSA at least one week
apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL or
b. Radiological progression: The appearance of new lesions: either two or
more new bone lesions on bone scan or a soft tissue lesion using RECIST
(Response Evaluation Criteria in Solid Tumours).
Symptomatic progression alone must be questioned and subject to further
investigation. It is not sufficient to diagnose CRPC.
65

HISTORICALLY FAILED AGENTS
Doxorubicin
Carmustine
Lomustine
Cyclophosphamide
Cisplatin
Estracyst
5 Flurouracil
Hydroxyurea
Mithramycin
Mitomycin
Melphalan
Nitrogen mustard
Prednimustine
Vincristine
M-Amsacrine
Vindesine
66

MITOXANTHRONE
FIRST CLINICALLY
USEFUL
CYTOTOXIC AGENT
Mitoxanthrone
THE MOTHER OF ALL
67

TANNOCK ET AL, 1996
68

MITOXANTHRONE
69

MITOXANTRONE, TANNOCK ET AL, 1996
70

MITOXANTHRONE CURRENT STATUS
Replaced by Docetaxel and Carbazitaxel.
But, still useful for patients with docetaxel- and cabazitaxel-refractory disease, or
in those with a marginal performance status in which the more toxic taxane agents
may not be well tolerated.
71

HAZARD RATIO???
The hazard ratio is a comparison between the probability of events in a treatment
group, compared to the probability of events in a control group.
A hazard ratio of 3 means that three times the number of events are seen in the
treatment group at any point in time.
A hazard ratio of 1 means that both groups (treatment and control) are experiencing
an equal number of events at any point in time.
A hazard ratio of 0.333 tells you that the hazard rate in the treatment group is one
third of that in the control group.
72

DOCETAXEL
Mitoxanthrone
Docetaxel
73

BACKGROUND
Mitoxantrone plus prednisone reduces pain and improves the
quality of life in men with advanced, hormone-refractory
prostate cancer, but it does not improve survival.
AIM
To compare docetaxel (given either every three weeks or
weekly) plus daily prednisone with mitoxantrone plus
prednisone.
DURATION
2000-2002.
TAX327 Trial
Docetaxel plus
Prednisone or
Mitoxantrone plus
Prednisone for
Advanced Prostate
Cancer
74

OVERALL
SURVIVAL
75

PAIN
76

REDUCTION IN SERUM PSA
77

QUALITY OF LIFE
78

ADVERSE
REACTIONS
79

CONCLUSION
When given with prednisone, treatment with docetaxel every three weeks led to
superior survival and improved rates of response in terms of pain, serum PSA level,
and quality of life, as compared with mitoxantrone plus prednisone.
80

AIM
To assess whether concomitant treatment with ADT
plus docetaxel would result in longer overall survival
than that with ADT alone.
DURATION
Study designed by ECOG in 2005.
CHAARTED
Trial
ChemoHormonal
Therapy Versus
Androgen Ablation
Randomized Trial for
Extensive Disease in
Prostate Cancer
81

CHAARTED Trial-
STUDY PLAN
82

CHAARTED
TRIAL
83

CONCLUSION
Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer
resulted in significantly longer overall survival than that with ADT alone.
84

SHALL WE TRY
DOCETAXEL IN HORMONE SENSITIVE
METASTATIC PROSTATE CANCERS???
Logic:
1. Docetaxel is better in improving quality of
life in mCRPC.
2. Will early chemotherapy along with ADT
improve treatment outcomes in hormone
sensitive metastatic cancers too???
85

AIM
To investigate the effects of the addition of
docetaxel to androgen-deprivation therapy (ADT)
for patients with metastatic non-castrate prostate
cancer.
DURATION
2004-2008.
GETUG AFU
15 Trial
Hormone Therapy
and Docetaxel or
Hormone Therapy
Alone in Treating
Patients With
Metastatic Prostate
Cancer
Groupe d’Etude des Tumeurs Uro-Genital and Association
Francaise d’Urologie
86

OVERALL
SURVIVAL
87

PROGRESSION
FREE SURVIVAL
88

COMPLICATIONS
89

CONCLUSION
Docetaxel should not be used as part of first-line treatment for patients with non-
castrate metastatic prostate cancer due to increased incidence of adverse events.
90

GETUT AFU VS STAMPEDE
91

AIM
Evaluate multiple therapeutic strategies in the
management of high-risk locally advanced and
metastatic hormone-naïve prostate cancer.
Each novel treatment strategy is compared against a
single, contemporaneous control arm.
DURATION
Open since 2005.
STAMPEDE
Trial
Systemic Therapy
in Advancing or
Metastatic Prostate
Cancer: Evaluation
of Drug Efficacy
92

STAMPEDE TRIAL
2008
5 ORIGINAL
COMPARISONS
93

94

ARM B - ZOLEDRONIC ACID
Prostate cancer cells can spread to bones and weaken them. Zoledronic acid is a
drug that reduces bone destruction and hardens bones.
The results of STAMPEDE show that the addition of zoledronic acid alone does not
prolong life expectancy.
95

ARM C - DOCETAXEL
Addition of docetaxel to hormone treatment does improve life expectancy, most
markedly in people with metastatic disease.
Delays time to progression or relapse for people with locally-advanced and
metastatic disease.
Docetaxel may now be given as part of standard treatment to all suitable people
entering STAMPEDE (from protocol v14.0).
96

ARM D - CELECOXIB
Recruitment stopped early as an earlier analysis failed to demonstrate sufficient
benefit.
Celecoxib does not improve life expectancy.
97

ARM E – DOCETAXEL + ZOLEDRONIC ACID
Zoledronic acid did not provide additional benefit when combined with docetaxel.
ARM E – CELECOXIB + ZOLEDRONIC ACID
No benefit overall.
98

STAMPEDE
Trial -
Current
99

Docetaxel
THE KING
STANDARD OF
CARE
100

CRPC WITH DOCETAXEL DISEASE COURSE
101

DOCETAXEL
RESISTANCE
102

CARBAZITAXEL
103

AIM
To comparing the safety and efficacy of
XRP6258(Carbazitaxel) plus prednisone to
mitoxantrone plus prednisone in the treatment of
hormone refractory metastatic prostate cancer
previously treated with a Taxotere® (Docetaxel)-
containing regimen.
DURATION
2007-2009.
TROPIC Trial
XRP6258
(Cabazitaxel) Plus
Prednisone
Compared to
Mitoxantrone Plus
Prednisone in
Hormone
Refractory
Metastatic Prostate
Cancer
104

TROPIC
TRIAL
105

CONCLUSION
Cabazitaxel prolongs OS at 2 years versus
mitoxantrone and has low rates of
peripheral neuropathy.
Palliation benefits of cabazitaxel were
comparable to those of mitoxantrone.
Docetaxel
THE QUEEN 106

DOCETAXEL
VS
CARBAZITAXEL
Docetaxel
107

AIM
To demonstrate the superiority of cabazitaxel plus
prednisone versus docetaxel plus prednisone in term
of overall survival (OS) in participants with
metastatic castration resistant prostate cancer
(mCRPC) and not previously treated with
chemotherapy.
DURATION
2011-2013.
FIRSTANA
Trial
Cabazitaxel Versus
Docetaxel Both
With Prednisone in
Patients With
Metastatic
Castration Resistant
Prostate Cancer
108

CONCLUSION
C20 and C25 did not demonstrate superiority for
OS versus D75 in patients with chemotherapy-naïve
mCRPC.
Tumor response was numerically higher with C25
versus D75; pain PFS was numerically improved with
D75 versus C25.
Cabazitaxel 20 mg/m2 (C20)
Cabazitaxel 25 mg/m2 (C25)
Docetaxel 75 mg/m2 (D75)
Carbazitaxel
Docetaxel
109

NEW UNDERSTANDINGS
LEADS TO
NEW THERAPIES
110

ANDROGEN INDEPENDENCY
111

ABIRATERONE
Abiraterone
112

ABIRATERONE
113

AIM
To compare the clinical benefit of abiraterone
acetate plus prednisone with placebo plus
prednisone in patients with metastatic castration-
resistant prostate cancer (CRPC) who have failed
one or two chemotherapy regimens.
At least one of the previous chemotherapies must
have contained docetaxel. (Docetaxel resistant).
DURATION
2008-2012.
COU AA 301
Trial
Abiraterone Acetate
in Castration-
Resistant Prostate
Cancer Previously
Treated With
Docetaxel-Based
Chemotherapy
114

OVERALL
SURVIVAL
115

CONCLUSION
Abiraterone acetate significantly prolongs overall survival in patients with metastatic
castration-resistant prostate cancer who have progressed after docetaxel treatment.
Carbazitaxel
Docetaxel
116

WILL ABIRATERONE KILL DOCETAXEL?
117

OBJECTIVE
To determine if newly diagnosed (within previous 3
months) participants with metastatic hormone-naive
prostate cancer (mHNPC),
who have high-risk prognostic factors will benefit
from,
the addition of abiraterone acetate and low-dose
prednisone to androgen deprivation therapy.
DURATION
Study started in 2013.
LATITUDE
Trial
A Study of Abiraterone
Acetate Plus Low-Dose
Prednisone Plus
Androgen Deprivation
Therapy (ADT) Versus
ADT Alone in Newly
Diagnosed Participants
With High-Risk,
Metastatic Hormone-
Naive Prostate Cancer
118

OVERALL SURVIVAL
119

INTERIUM ANALYSIS- CONCLUSION
The addition of abiraterone acetate and
prednisone to ADT significantly
increased:
overall survival and
radiographic progression-free survival
in men with newly diagnosed, metastatic,
castration-sensitive prostate cancer.
120

STAMPEDE - ABIRATERONE
121

ENZALUTAMIDE
122

ENZALUTAMIDE
123

AIM
To compare the clinical benefit of Enzalutamide
versus placebo in patients with castration-resistant
prostate cancer who have been previously treated
with docetaxel-based chemotherapy. (Docetaxel
Resistant)
DURATION
2009-2010.
AFFIRM Trial
Safety and Efficacy
Study of
Enzalutamide in
Patients With
Castration-
Resistant Prostate
Cancer Who Have
Been Previously
Treated With
Docetaxel-based
Chemotherapy
124

CONCLUSION
In addition to improving overall survival, enzalutamide improves wellbeing and everyday
functioning of patients with metastatic castration-resistant prostate cancer.
125

OBJECTIVE
To determine the benefit of enzalutamide versus
placebo as assessed by overall survival and
progression-free survival in patients with progressive
metastatic prostate cancer who have failed
androgen deprivation therapy but not yet received
chemotherapy. (Chemotherapy naïve)
DURATION
2010-2019.
PREVAIL Trial
Enzalutamide in Men
with Chemotherapy-
naïve Metastatic
Castration-resistant
Prostate Cancer
126

CONCLUSION
Enzalutamide provided clinically significant benefits in men:
with chemotherapy-naive metastatic castration-resistant prostate cancer,
with or without visceral disease,
low- or high-volume bone disease, or lymph node only disease.
127

AIM
To determine the efficacy and safety of oral
enzalutamide compared to bicalutamide in castrate
men with metastatic prostate cancer who have
progressed while on Luteinizing Hormone Receptor
Hormone (LHRH) agonist/antagonist or after
receiving a bilateral orchiectomy.
DURATION
Estimated completion in 2017.
TERRAIN
Trial
Efficacy and Safety
Study of
Enzalutamide Versus
Bicalutamide in
Castrate Men With
Metastatic Prostate
Cancer
128

PROGRESSION
FREE SURVIVAL
129

PROGRESSION
EVENTS
130

CONCLUSION
Enzalutamide is a more effective treatment than bicalutamide for patients with
metastatic prostate cancer who progress on ADT.
TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients
with asymptomatic or mildly symptomatic metastatic castration-resistant prostate
cancer.
131

AIM
To determine the safety and efficacy of
enzalutamide vs bicalutamide in asymptomatic or
mildly symptomatic patients with prostate cancer
who have disease progression despite primary
androgen deprivation therapy.
DURATION
2012-2018
STRIVE
Trial
Safety and Efficacy
Study of
Enzalutamide Versus
Bicalutamide in Men
With Prostate Cancer
132

PROGRESSION
FREE SURVIVAL
133

CONCLUSION
Enzalutamide significantly reduced risk of prostate cancer progression or death
compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
134

APALUTAMIDE
135

AIM
To determine if the addition of apalutamide to ADT
provides superior efficacy in improving radiographic
progression-free survival (rPFS) or overall survival (OS) for
participants with mHSPC.
DURATION
TITAN Trial
A Study of
Apalutamide Plus
Androgen
Deprivation
Therapy (ADT)
Versus ADT in
Participants With
mHSPC (TITAN)
136

AIM
To evaluate the efficacy and safety of apalutamide in
adult men with high-risk non-metastatic castration-resistant
prostate cancer.
DURATION
SPARTAN
Trial
A Study of
Apalutamide (ARN-
509) in Men With
Non-Metastatic
Castration-
Resistant Prostate
Cancer (SPARTAN)
137

METASTASIS
FREE SURVIVAL
138

CONCLUSION
Among men with nonmetastatic castration-resistant prostate cancer, metastasis free
survival and time to symptomatic progression were significantly longer with
apalutamide than with placebo.
139

ENZAMET AND TITAN
140

APPROVED IN EUROPE FOR METASTATIC CRPC
Docetaxel,
Abiraterone/prednisolone,
Enzalutamide,
Cabazitaxel and
Radium-223.
141

COMMON DRUGS SUMMARY
142

IMMUNOTHERAPY
143

AIM
To assess the efficacy of Sipuleucel-T
Immunotherapy for Castration-Resistant Prostate
Cancer.
DURATION
2012-2017.
IMPACT
Trial
Sipuleucel-T
Immunotherapy for
Castration-
Resistant Prostate
Cancer
144

SIPULEUCEL T
145

PRIMARY
EFFICACY
HR 0.67
146

DOCETAXEL
EFFECT
147

CONCLUSION
The use of sipuleucel-T prolonged overall survival among men with metastatic
castration-resistant prostate cancer.
No effect on the time to disease progression was observed.
148

PROSTVAC VF
PSA targeted poxviral based vaccine.
Not a personalized product.
Administered by repeated subcutaneous injections over several months.
Improved overall survival in mCRPC compared to placebo. (HR 0.56).
Produce survival benefit without altering radiographic progression.
149

PROSTVAC VF
150

PROSTVAC
151

IPILIMUMAB
Blockade of immune checkpoint molecule CTLR 4 inhibit immunogenic evasion by
tumour tumour cells.
Reduction in PSA is noted in mCRPC.
Side effects:
Colitis
Hepatitis
Adrenal insufficiency and other endocrinopathies,
Dermatitis/vitiligo even hypophysitis.
152

ASCO GU 2018
POST CHEMO
SETTING
NOT
SIGNIFICANT
153

PEMBROLIZUMAB
Used in treatment of patients with “unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors
who have progressed on prior treatments and who have no satisfactory alternative
treatment options.
The recommended adult dosage is 200 mg given intravenously once every 3 weeks.
154

PEMBRLIZUMAB - MECHANISM OF ACTION
PD 1
PD-L 1
155

CABOZANTINIB
Tyrosine kinase inhibitor
Blocks C-Met and VEGFR2 receptors
Tried in mCRPC progressing with docetaxel and enzalutamide/abiraterone therapy.
Dose : 100 mg daily (In trial settings)
Adverse effects: Hand foot syndrome, Mucositis, elevation of liver enzymes.
Unprecendented Improvements in Bone scans.
12% of patients showed complete resolution in bone metastasis in bone scans.
156

MECHANISM OF ACTION
157

CLUSTERIN AND CUSTIRSEN
Clusterin is anti apoptotic chaperone.
Increased expression in castration resistant prostatic cancer.
Custirsen is an oligonucleotide administered intravenously.
Inhibits clusterin in mRNA level.
Increases sensitivity to androgen deprivation and chemotherapy.
158

CLUSTERIN
159

PARP INHIBITORS
Poly ADP Ribose Polymerase (PARP) is involved in repair of single strand DNA repair.
In the presence of associated with BRCA mutations in cancer cells, PARP inhibitors leads
to apoptosis of cancer cells.
Olaparib (400 mg bd) has been tried.
Rucaparib, Niraparib, and Talazoparib are being tested.
Toxicities: Nausea, fatigue, myelosuppression, and a 1% risk of myelodysplastic
syndrome or acute myeloid leukemia.
160

PARP INHIBITORS
161

EMERGING
PATHWAYS
SUMMARY
162

RADIATION THERAPY FOR PALLIATION
Hallmark of bone metastasis is pain – frequently continuous and severe.
Spinal cord compression is serious complication.
Single fraction 800 cGy x1
Pathological fracture is painful and disabling.
Prophylactic surgical fixation:
1. An intramedullary lytic lesion 50% or greater of the cross sectional diameter of
the bone.
2. A lytic lesion involving a length of cortex equal to or greater than the cross
sectional diameter of the bone or greater than 2.5 cm in axial length.
163

SPINAL CORD COMPRESSION
Medical emergency can lead to paraplegia and autonomic dysfunction.
Pain precedes compression by 4 months.
Neurological dysfunction can happen in hours to days.
MRI is the investigation of choice.
Once diagnosed – Inj Dexamethasone 4-10 mg loading dose followed by a
maintenance dose of 4 to 24 mg every 6 hours.
Surgery might be needed.
164

AIM
To assess the benefit of Metastasis Directed Therapy
(MDT - surgery or stereotactic body radiotherapy)
for oligorecurrent prostate cancer (PCa).
DURATION
2012-2017.
STOMP
Trial
Salvage Treatment
or Active Clinical
Surveillance for
Oligometastatic
Prostate Cancer
165

ADT FREE
SURVIVAL
166

CONCLUSION
ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent
PCa, suggesting that MDT should be explored further in phase III trials.
167

AIM
To assess the safety and efficacy of stereotactic
ablative radiotherapy (SABR) for hormone-sensitive
oligometastatic prostate adenocarcinoma, and
To describe the biology of the oligometastatic state
using immunologic, cellular, molecular, and functional
imaging correlates.
DURATION
ORIOLE
Trial
Observation Versus
Stereotactic
Ablative RadiatIOn
for OLigometastatic
Prostate CancEr
168

BISPHOSPHONATES
Zoledronate is intravenous bisphosphonate widely used.
Inhibits osteoclast activity and proliferation.
Reduce the skeletal related events and increase bone mineral density.
At present, zoledronate is indicated for the treatment of patients with progressive
CRPC with evidence of bone metastasis, and it is administered at a dose of 4 mg
intravenously repeated at intervals of 4 weeks for several months
169

BISPHOSPHONATES
170

BISPHOSPHONATES – SIDE EFFECTS
Fatigue
Myalgia
Fever
Anemia
Hypocalcemia (Noted with zoledronate) - concomitant administration of oral calcium
supplements (1000 mg/day) and vitamin D (800 units/day) is often recommended.
Osteonecrosis of jaw (Rare but severe complication with zoledronate)
Zoledronate should not be administered in patients with chronic dental problems and
poor dentition.
171

VICIOUS CYCLE
OF BONE
DESTRUCTION
172

DENOSUMAB
173

DENOSUMAB
174

RADIOPHARMACEUTICALS
Strontium-89 (89Sr) and Samarium-153 (153Sm) – Beta emitters.
Radium 223 novel alpha emitter.
175

AIM
To compare, in patients with symptomatic hormone
refractory prostate cancer (HRPC) and skeletal
metastases, the efficacy of best standard of care
plus Radium-223 dichloride versus best standard of
care plus placebo, with the primary efficacy
endpoint being overall survival (OS).
DURATION
2008-2014.
ALSYMPCA
Trial
ALpharadin in
SYMPtomatic
Prostate CAncer
176

OVERALL
SURVIVAL
177

CONCLUSION
Radium-223 should be considered as a treatment option for patients with castration-
resistant prostate cancer and symptomatic bone metastases.
178

RADIUM 223
For castrate resistant and painful bone metastasis.
No soft tissue metastasis.
Alpha particles range < 1 mm.
6 cycles used.
179

RADIUM 223
180

ONGOING
TRIALS
181

OBJECTIVE
To study how well the estrogen skin patch works
compared with luteinizing hormone-releasing
hormone agonist injections in treating patients with
locally advanced or metastatic prostate cancer.
DURATION
PATCH Trial
Prostate
Adenocarcinoma
TransCutaneous
Hormones
182

METASTATIC DISEASE FIRST LINE SETTING
183

METASTATIC DISEASE FIRSTLINE SETTING
184

LIFE PROLONGING DISEASE CRPC
185

CYTOTOXIC TREATMENT CRPC
186

SUPPORTIVE CARE CRPC
187

THANK YOU
188

Prostate carcinoma- locally advanced

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