Overview and Pharmacotherapy of Prostate Cancer (based on NCCN 2012 guidelines for prostate cancer)

PROSTATE CANCER
Clinical Immunology/Hematology/Oncology Therapeutics
Hyun Ik Kim
PharmD Candidate, Class of 2013
Ernest Mario School of Pharmacy
hyunik@eden.rutgers.edu

Objectives
 Define prostate cancer
 Discuss potential etiology, risk factors, signs
and symptoms for prostate cancer
 Identify diagnosis and screening guidelines,
and possible prevention of prostate cancer
 Recommend appropriate treatments based on
the characteristics of the tumor and
information specific to the patient
2

Epidemiology
 Prostate cancer is the most common cancer in
men in the United States
 In 2012, 241,740 new cases and 28,170
deaths are predicted
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
pdf.pdf. Accessed November 25, 2012.
3

Normal Prostate
 Prostate is a gland
 About the size of a walnut
 Divided into lobes: base, apex, and left and right lateral
 Gland cells produce prostate-specific antigen (PSA)
Wikipedia Commons. Prostatelead. Wikipedia Web site. Available at: http://en.wikipedia.org/wiki/File:Prostatelead.jpg. Accessed November 25, 2012.
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134-pdf.pdf.
Accessed November 25, 2012.
Anatomy of the prostate. National Cancer Institute Web site. Available at: http://training.seer.cancer.gov/prostate/anatomy/. Accessed November 25, 2012.
4

Where It All Goes Wrong…
 Etiology: unknown; may involve several factors…
 Most (~95%) cases of prostate cancer are
adenocarcinomas, or arise from gland cells
 Inflammation
 Unknown cause; may include infection or trauma
 Sexually transmitted infections
 Physical/chemical trauma
De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256-269.
College of American Pathologists. Prostate cancer. College of American Pathologists Web site. Available at::
http://www.cap.org/apps/docs/reference/myBiopsy/ProstateAdenocarcinoma.pdf. Accessed November 25, 2012.
5

Gene Mutations in Prostate Cancer
 Gene mutations that have been associated:
 Bcl-2: encodes proteins that suppress apoptosis
 May be overexpressed
 Androgen receptor (AR): encodes androgen receptor,
which binds testosterone and dihydrotestosterone
(DHT)
 Testosterone and DHT promote cell growth; DHT is primarily
responsible in prostate
 Mutations have been found
 SRD5A2: encodes 5-alpha reductase, the enzyme that
converts testosterone  dihydrotestosterone (DHT)
 Polymorphisms have been found; may raise enzyme activity
Steers. Urology. 2001;58:17-24.
6

Progression to Prostate Cancer
 Supposed, precancerous lesions develop from injury:
 Proliferative inflammatory atrophy (PIA): increased
proliferation of gland cells in areas of atrophy
 Prostatic intraepithelial neoplasia (PIN): presence
of abnormal, high grade gland cells
 Unreversed damage leads to prostate cancer
 Process: inflammation (?)  gene mutations 
cancer
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
7

Risk Factors
 The following increase risk of prostate cancer:
 Family history
 1st degree relative (father or brother)
 Age: rarely occurs before age 40
 Median age at diagnosis: ~67 years old
 Median age at death: ~80 years old
 ~2 of 3 prostate cancers are in men > 65 years old
 Race: more common in African Americans
 Not known why; historically, proposed to have higher
testosterone levels, but evidence is lacking
1. American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
1. Rohrmann S, Nelson WG, Rifai N, et al. J Clin Endocrinol Metab. 2007;92:2519-25.
SEER stat fact sheets: prostate. National Cancer Institute Web site. Available at: http://seer.cancer.gov/statfacts/html/prost.html. Accessed November 25, 2012.
8

Possible Risk Factors
 Indefinite risk factors: diet, obesity, gene
mutations, smoking, inflammation of prostate,
sexually transmitted infections
 Definite correlation has not been established
9

Signs/Symptoms of Prostate Cancer
 May be asymptomatic, especially in early stages
 Otherwise, symptoms include:
 Difficult/painful/frequent urination
 Blood in urine/semen
 And also…
 Pain in back, hips, or upper thighs
 Weakness/numbness in legs and feet, incontinence
 Fractures
 Why these?
10

Metastatic Prostate Cancer
 Prostate cancer (and others) commonly
metastasizes to bone
 Higher mortality and morbidities associated with
bone metastasis in prostate cancer
Sathiakumar N, Delzell E, Morrisey MA, et al. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-
based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer Prostatic Dis. 2011;14:177-183.
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
11

The Vicious Cycle of Bone Metastasis
Tumor releases:
 Parathyroid hormone-
related peptide
(PTHrP)
Osteoblasts release:
 Transforming growth factor (TGF)
 Insulin-like growth factor (IGF)
13. Janssens K, ten Dijke P, Janssens S, et al. Transforming growth factor-β1 to the bone. Endocr Rev. 2005;26:743-774.
14. Ara T, DeClerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223-1231.
…Hence, the pain, weakness, and fractures
Osteoclasts cause bone resorption:
 PTHrP binds to osteoblasts,
increasing expression of RANKL
 RANKL binds to RANK, leading
to excess osteoclast activation
12

 There are several methods to diagnosis:
 Prostate-specific antigen (PSA) blood test:
 Not specific for prostate cancer; surgery, urinary tract
infection and benign prostatic hyperplasia (BPH) can
also raise PSA levels
 No consensus on “normal” levels, but generally, < 4.0
ng/mL
 PSA velocity: measurement of change in PSA levels
over time
 Digital rectal exam (DRE):
 Not specific for prostate cancer (may indicate BPH)
 Normal prostate is hard (like the tip of your nose);
prostate cancer is soft (like your chin)
Diagnosis of Prostate Cancer
Prostate-Specific Antigen (PSA) test. National Cancer Institute Web site. Available at: http://www.cancer.gov/cancertopics/factsheet/Detection/PSA. Accessed
November 25, 2012.
13

Diagnosis of Prostate Cancer
 Diagnostic methods continued:
 Transrectal ultrasound (TRUS)
 Done as follow up after PSA and DRE
 Probe inserted into rectum
 Biopsy: the only definitive method
 Prostate tissue is removed with needles and examined
 For metastasis/lymph node involvement:
 Bone scan/CT scan/MRI
14

Screening for Prostate Cancer
 When should men be screened?
 Remains controversial and without consensus
 Should be ongoing discussion between patient and
physician
 Know the NCCN recommendations:
 Obtain initial screening (PSA level and DRE) at age 40
 Individualize screening for men over 75 years old
 Get baseline evaluation
 Family history, race, history of prostate disease and screening
(previous biopsies, PSA tests, etc.), medication use
15

 Adapted from NCCN:
Prostate Cancer Screening Guidelines
Initial
PSA and
DRE
Men at least 40
years old
• Not at risk
• At risk:
- African American
- Family history
- PSA ≥ 1.0 ng/mL
- Taking 5-alpha-
reductase
inhibitors
Repeat
annually
Repeat at
age 45
Repeat at
age 50, then
annually
PSA > 1
ng/mL
DRE negative
PSA ≤ 1
ng/mL
DRE negative
PSA ≤ 1
ng/mL
DRE negative
If PSA > 2.6 ng/mL or
DRE is positive at any
exam, obtain biopsy
PSA > 1
ng/mL
DRE negative
16

Prostate Cancer Screening Guidelines
 Summary of NCCN recommendations:
 Start screening with PSA and DRE at age 40
 If PSA ≤ 1 ng/mL, screen at age 45 and 50, then
annually thereafter
 If PSA > 1 ng/mL at any point, screen annually
 If PSA > 2.6 ng/mL or DRE positive at any point,
obtain a biopsy
 Just know the above (if you want more details,
read NCCN guidelines)
17

Why 5-alpha reductase inhibitors?
 5-alpha reductase inhibitors (dutasteride and
finasteride) reduce prostate size
 Mechanism of action:
 They also lower PSA Levels
 Therefore, may cause false-negative due to lowered
PSA level when there is cancer
 Hence, screening evaluation includes medication use
5-alpha reductase inhibitor
Testosterone Dihydrotestosterone (DHT)
18

Prevention of Prostate Cancer
 5-alpha reductase inhibitors were studied in
two major trials: PCPT and REDUCE
 Objective: Determine if 5-alpha reductase
inhibitors reduce risk of prostate cancer
 Rationale for studies: mechanism of action
 Trial results: fewer cases of cancer, but a larger
rate of cancers were higher grade (more
aggressive) compared to those in placebo group
 Not truly prophylactic
 Selenium and vitamin E were also studied
 They don’t work
Dutasteride decreases prostate cancer risk. National Cancer Institute Web site. Available at: http://www.cancer.gov/clinicaltrials/results/summary/2010/prostate-
chemoprevention0410. Accessed November 25, 2012.
19

Determining Treatment
 Treatment depends on “recurrence risk” of cancer
 Recurrence risk = life expectancy + prognostic group
 Life expectancy is estimated using period life table from
US Social Security Administration (SSA)
20

Grouping of Prostate Cancer
 Prognostic group is determined from TNM
classification, Gleason score, and PSA levels:
 PSA levels:
 Not specific to prostate cancer, but generally < 4 ng/mL
 TNM classification:
 T: size of primary tumor
 N: metastasis to regional lymph nodes
 M: metastasis to distant organs/lymph nodes
 Gleason score:
 Histologic grade (from 1 to 5) is assigned to two areas that
comprise majority of tumor for score between 2 and 10
 Higher score = worse prognosis
21

TNM Staging
 T1: Tumor is not palpable with DRE or visible
with imaging
 T2: Tumor is palpable with DRE or visible with
imaging, and still confined to prostate
 T3: Tumor has spread beyond prostate up to
seminal vesicles
 T4: Tumor has spread beyond seminal
vesicles to nearby organs
22

T1
 T1: Tumor is not palpable with DRE or visible
with imaging
 Found through needle biopsy or tissue removal for
other reasons (like benign prostatic hypertrophy)
23

T2
 T2: Tumor is palpable with DRE or visible with
imaging, and still confined to prostate
 T2a: Tumor is on at most, one half of one side
 T2b: Tumor is on more than one half of one side
 T2c: Tumor is on both sides of prostate
24

T3
 T3: Tumor has spread beyond prostate up to
seminal vesicles
 T3a: Extends beyond prostate but not seminal vesicles
 T3b: Spreads to seminal vesicles
25

T4
 T4: Tumor has spread beyond seminal
vesicles to adjacent structures like bladder,
levator muscles, or pelvic wall
26

Gleason Score
 Two grades are assigned from 1 – 5, to total a
score between 2 and 10
Figure: Gleason score
for prostate
adenocarcinoma
(majority of cancers
arise from glands)
27

Recurrence Risk Determines Treatment
 Appropriate treatment is based on patient’s
health and tumor characteristics
 Recurrence risk = life expectancy + prognostic group
 Divided into three main categories:
 Life expectancy is only used if clinically localized
Recurrence Risk Life
Expectancy
Primary Tumor Gleason Score PSA Level
Clinically
Localized
< or ≥
10 or 20 years
T1 – T3a Up to 10 Up to 20
ng/mL or
greater
Locally Advanced Any T3b – T4 Any Any
Metastatic Any Any T, N1, M0
Any T, Any N, M1
Any Any
28

Tips for Studying
 For your exam, know the treatments given:
 The type of recurrence risk (clinically localized,
locally advanced, or metastatic)
 Life expectancy
 Still need to understand T stage, Gleason score, and
PSA levels, but not for identifying risk
Recurrence Risk Life
Expectancy
Primary Tumor Gleason Score PSA Level
Clinically
Localized
< or ≥
10 or 20 years
T1 – T3a Up to 10 Up to 20
ng/mL or
greater
Locally Advanced Any T3b – T4 Any Any
Metastatic Any Any T, N1, M0
Any T, Any N, M1
Any Any
29

Prostate Cancer Treatment Guidelines
Treatment by Recurrence Risk
Clinically Localized Expected Survival Therapy
Very Low - T1c
- Gleason score ≤ 6
- PSA < 10 ng/mL
- Fewer than 3
prostate biopsy cores
positive
- PSA density < 0.15
ng/mL/g
< 20 years
≥ 20 years
• Active surveillance
• Refer to therapy for “Low” recurrence risk
Low - T1 – T2a
- Gleason score ≤ 6
- PSA < 10 ng/mL
< 10 years
≥ 10 years
• Radiation therapy
• Radical prostatectomy +/- Pelvic lymph node dissection
Intermediate - T2b-T2c
- Gleason score = 7
- PSA = 10 – 20 ng/mL
< 10 years
≥ 10 years
• Radiation therapy +/- Androgen deprivation therapy (4 to
6 months) +/- Brachytherapy
• Radical Prostatectomy +/- Pelvic lymph node dissection
• Radiation therapy +/- Androgen deprivation therapy (4 to
6 months) or Brachytherapy
30

Prostate Cancer Treatment Guidelines
Clinically Localized Therapy
High - T3a
- Gleason score 8 - 10
- PSA > 20 ng/mL
• Radiation therapy + Androgen deprivation therapy (2 – 3 years)
• Radiation therapy + Brachytherapy +/- Androgen deprivation therapy (4 to
6 months)
• Radical prostatectomy + Pelvic lymph node dissection (in select patients)
Locally Advanced Therapy
T3b – T4 with any Gleason
score or PSA level
• Radiation therapy + Brachytherapy +/- Androgen deprivation therapy (4 to 6
months)
• Radical prostatectomy + Pelvic lymph node dissection (in select patients)
• Androgen deprivation therapy (in select patients)
Metastatic Therapy
Any T, N1, M0
Any T, N, M1
• Androgen deprivation therapy
• Androgen deprivation therapy
31

Treatments for Prostate Cancer
 Active Surveillance
 Radiation Therapy
 Radical Prostatectomy
 Androgen Deprivation Therapy
32

How to Monitor Treatments
33
 Once therapy is initiated, monitor for
progression/relapse:
 For non-metastatic cases: obtain PSA every 6 –
12 months and DRE every year (optional if PSA
levels are undetectable)
 For metastatic cases (N1 or M1): get physical
exam, PSA, and DRE every 3 – 6 months
 Definition of relapse is specific to each
treatment

Overview: Active Surveillance
 Active Surveillance (also called “observation”)
 Active monitoring of disease with expectation to
intervene if the cancer progresses
 What “active” means: periodic PSA, DRE, and/or
biopsy tests:
 PSA at least every 6 months
 DRE and/or biopsy at least every 12 months
 Disadvantages/Adverse effects:
 Anxiety (I’m just watching a tumor inside me…)
 Cancer may progress/metastasize, cost more to treat
later, and cause more side effects
 May miss a chance to cure
34

Active Surveillance Indications
Very low
< 20 years
≥ 20 years
Low
Active surveillance
Active surveillance
(or Radiation therapy, Radical prostatectomy
+/- Pelvic lymph node dissection
< 10 years
≥ 10 years
Active surveillance
Intermediate
< 10 years
Active surveillance
(or Radiation therapy +/- short-term Androgen
deprivation therapy (4 – 6 months) +/-
Brachytherapy
35

Active Surveillance
 Only for clinically localized recurrence risk
 Not done beyond intermediate risk and ≥ 10 years
life expectancy
 Discontinue active surveillance when:
Patient experiences:
- Symptoms
- Increase In PSA
- Positive DRE
- Suspicious biopsy
Repeat clinical assessment
36

Overview: Radiation Therapy
 Radiation Therapy (RT)
 External beam radiation therapy: ionizing radiation
using X-ray beams of protons22,23
 Radionuclide therapy: beta particles
 Brachytherapy: Radiation is injected directly into tumor site
External beam radiation therapy Radionuclide therapy
Disadvantages Time-consuming Beta particles have a wide range
of effect (hence the side effects)
Adverse
effects
Sexual dysfunction, proctitis,
urinary and bowel problems24
Myelosuppression
37

Low
≥ 10 years Radiation therapy
(or Active surveillance, Radical prostatectomy +/-
Pelvic lymph node dissection
Intermediate
Radiation therapy +/- short-term Androgen
deprivation therapy (4 – 6 months) or +/-
Brachytherapy
High Radiation therapy + long-term Androgen deprivation
therapy (2 – 3 years)
OR
Radiation therapy + Brachytherapy +/- short-term
Androgen deprivation therapy (4 – 6 months)
(regardless of
expected survival)
Radiation Therapy Indications
38

 Indications beyond clinically localized risk:
 Locally advanced:
 Used with either: long-term Androgen deprivation
therapy (2 – 3 years) or Brachytherapy +/- short-term
Androgen deprivation therapy (4 – 6 months)
 Metastatic (to lymph nodes [N1]):
 Used with long-term Androgen deprivation therapy (2
– 3 years)
 Summary: indicated for all cases except very
low risk, and distant metastasis
Radiation Therapy Indications
39

Relapse in Radiation Therapy
 Next treatment after relapse depends on metastasis
 Relapse = increase in PSA ≥ 2 ng/mL or positive DRE
Relapse
Distant metastasis
No distant metastasis
Radiation therapy Androgen deprivation therapy
OR
Observation
OR
Clinical trial
Radical prostatectomy
OR
Observation
OR
Cryosurgery
OR
Brachytherapy
Androgen deprivation therapy
OR
Observation
Biopsy +
for cancer
Get biopsy
Biopsy -
for cancer
40

Overview: Radical Prostatectomy
 Radiation Therapy (RT)
 Surgical removal of prostate
 Done with pelvic lymph node dissection for certain
risks, or if predicted probability of lymph node
metastasis > 2 %
 Adverse effects: Sexual dysfunction, proctitis,
urinary and bowel problems24
41

Radical Prostatectomy Indications
 Indications are similar to those for Radiation therapy,
 But not used in metastasis, or with Androgen deprivation
therapy
Recurrence Risk Expected Survival Therapy
Low
≥ 10 years
Radical Prostatectomy
(or Active surveillance, Radiation therapy)
Intermediate
Radical Prostatectomy +/- Pelvic lymph node
dissection
High /
Locally
Advanced
Radical Prostatectomy + Pelvic lymph node
dissection (in select patients with no fixation)
42
≥ 10 years

Relapse in Radical Prostatectomy
 Next treatment after relapse depends on metastasis
 Relapse = failure of PSA to reach undetectable
levels or detectable PSA that increases on two
subsequent measurements
Relapse
Distant metastasis
Androgen deprivation therapy
+/- Radiation therapy (to site of
metastasis/weight-bearing
bones/or symptomatic)
OR
Observation
Radical prostatectomy
Radiation therapy +/- Androgen
deprivation therapy
OR
Observation
43

Overview: Androgen Deprivation Therapy
 Radiation Therapy
 Androgen Deprivation Therapy (ADT)
 Bilateral orchiectomy (surgical castration of
testes)
 Luteinizing-hormone releasing hormone (LHRH)
agonist or antagonist (medical castration)
 It helps to review the hypothalamic-pituitary-adrenal
(HPA) axis to understand the rationale for ADT
44

Hypothalamic-Pituitary-Adrenal Axis
45
 Hypothalamus secretes
LHRH
 LHRH binds to receptors on
anterior pituitary
 Anterior pituitary secretes LH and
Follicle Stimulating Hormone
(FSH), and adrenalcorticotropic
hormone (ACTH)
 LH and FSH bind to receptors in
testes to produce androgens
 ACTH binds to receptors in adrenal
glands to produce androgens

LHRH Agonists/Antagonists in Detail
Drug class Drugs in
class
Mechanism of Action Adverse Effects
LHRH agonist Leuprolide
Goserelin
Triptorelin
Gonadotropin releasing
hormone (GnRH aka LHRH)
competitively binds to
pituitary receptors, releasing
FSH and LH
Hot flashes, impotence,
reduced libido,
gynecomastia, tumor flare
LHRH
antagonist
Degarelix Gonadotropin releasing
hormone (GnRH aka LHRH)
competitively binds to
pituitary receptors,
preventing release of FSH
and LH
reduced libido, gynecomastia
Antiandrogen Flutamide
Bicalutamide
Nilutamide
Competitively binds to
androgen receptors
reduced libido,
gynecomastia, hepatotoxicity
- Specific for nilutamide:
night blindness, pneumonitis
46

Optimal ADT
 Bilateral orchiectomy, LHRH agonist or antagonist?
 Pick any one; all are equally effective
 LHRH agonist should be used with antiandrogen
for at least one week
 LHRH agonist initially increases production of
testosterone before achieving castrate levels
 Initial increase is “tumor flare” and lasts ~1 week
 Antiandrogen blocks AR receptor, preventing surge
47

ADT Indications
 The only option for metastatic cases
 Use with Radiation therapy when possible (category 1)
Short-term ADT (4 – 6 months), used optionally
with Radiation therapy
Intermediate
(regardless of
expected survival)
Long-term ADT (2 – 3 years) + Radiation
therapy
OR
Short-term ADT (4 – 6 months), used optionally
with Radiation therapy + Brachytherapy
OR (for locally advanced only)
ADT alone (in select patients)
High
Metastasis
Long-term ADT (2 – 3 years) + Radiation
therapy
OR
ADT
Locally
Advanced
48

“Castration-Resistant” Prostate Cancer
 ADT is eventually used for prostate cancer
(whether due to relapse or recurrence risk)
 Prostate cancer becomes refractory to ADT
 Called “castration-resistant prostate cancer”
(CRPC)
 Occurs within 12 - 18 months; mechanisms
include:16
 Increased expression of AR
 Increased expression of enzymes that synthesize
androgens
 Utilization of other pathways to activate AR
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-92.
16. Amaral TMS, Macedo D, Fernandes I, et al. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate. 2012;2012:1-11.
49

Treatments for CRPC
 Determine whether CRPC has metastasized:
CRPC
Chemotherapy
Distant metastasis
Secondary hormone therapy
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
50

 First, maintain castrate levels of testosterone
 Continue using LHRH agonist/antagonist
 Secondary hormone therapy is an option; others
include observation and enrollment in a clinical trial
CRPC: Without Distant Metastasis
CRPC
Chemotherapy
Distant metastasis
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
51

CRPC: Secondary Hormone Therapy
52
 None have shown improvement in overall survival
 Decrease and maintain PSA response for a few months
Therapies Mechanism Adverse Effects
Antiandrogen Competitively binds to androgen
receptors
Hot flashes, impotence, reduced libido,
gynecomastia, hepatotoxicity (nilutamide;
night blindness, pneumonitis)
Antiandrogen
withdrawal
Unknown; may involve androgen
receptor mutation that uses
antiandrogen as an agonist
Withdrawal may allow some patients to
improve quality of life, and avoid adverse
effects of treatment
Ketoconazole Non-selective CYP17 inhibitor;
prevents androgen synthesis
Nausea, vomiting, hepatotoxicity, impotence,
reduced libido
Estrogen Prevents androgen synthesis by
inhibiting release of LHRH
Gynecomastia, weight gain, edema,
myocardial infarction, stroke

CRPC: Secondary Hormone Therapy
 Secondary hormone therapies continued:
Therapies Mechanism Adverse Effects
Corticosteroids
(prednisone,
dexamethasone)
Prevents androgen synthesis in
adrenal glands
Edema, hyperglycemia, mood/appetite
changes, hypertension, osteoporosis
Aminoglutethamide Non-selective aromatase
inhibitor, and prevents androgen
synthesis by inhibiting conversion
of cholesterol to pregnenolone
Drowsiness, skin rash, hepatotoxicity,
fever, adrenal insufficiency
Megestrol acetate Progesterone receptor agonist,
and prevents androgen synthesis
by inhibiting release of LHRH
Weight gain, insomnia, impotence,
reduced libido
53

Treatments for CRPC
 For metastatic or relapsing CRPC:
 Chemotherapy is used once PSA relapse or
metastasis occurs
CRPC
Chemotherapy
Distant metastasis
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
54

 First, maintain castrate levels of testosterone
 Continue using LHRH agonist/antagonist
 If bone metastasis, add denosumab or zoledronic
acid (recall the cycle of bone metastasis)
 Both inhibit osteoclasts to delay bone resorption
CRPC: With Distant Metastasis
55
Yes
Metastasis
to bone?
CRPC
with distant
metastasis
No
Add denosumab or
zoledronic acid
Maintain castrate
levels of
testosterone
Determine if patient
has symptoms

CRPC: With Distant Metastasis
 Then, pick a therapy based on whether patient
is symptomatic/asymptomatic:
Chemotherapy for CRPC with Distant Metastasis
Symptomatic Asymptomatic
Docetaxel (category 1) Sipuleucel-T (category 1)
Cabazitaxel Secondary hormone therapy
Abiraterone acetate Docetaxel
Mitoxanthrone Clinical trial
Radiation Therapy (palliative)
Clinical trial
56

Chemotherapy for Symptomatic CRPC
 Docetaxel is first line
 Demonstrated longest survival vs. others
Drug name Mechanism Adverse Effects Regimens
Docetaxel18,19
(category 1)
Antimitotic; binds to
tubulin, prevents
microtubule disassembly
Neutropenia, peripheral
neuropathy, edema,
alopecia, hepatotoxicity
75 mg/m2 IV over 1 hr
every 3 weeks with 5
mg prednisone BID
Cabazitaxel Similar to docetaxel Neutropenia, nausea,
vomiting, diarrhea
25 mg/m2 IV over 1 hr
every 3 weeks with 10
mg prednisone qd
Abiraterone21 Selective CYP17 inhibitor;
prevents androgen
synthesis
Hypertension, edema,
electrolyte disturbances,
hepatotoxicity
1000 mg orally QD with
5 mg prednisone BID
Mitoxanthrone20 Type II topoisomerase
inhibitor; prevents DNA
synthesis
Nausea, vomiting,
alopecia,
myelosuppression
12 mg/m2 IV over 30
minutes on day 1 with 5
mg prednisone BID
57

Chemotherapy for Asymptomatic CRPC
 If asymptomatic cases, sipuleucel-T is first line
 Class: autologous immunotherapy
 Mechanism of action:
 Uses patient’s own immune cells; white blood cells are
exposed to PAP – GM-CSF fusion protein (PAP is an
antigen expressed in prostate cancers; granulocyte-
macrophage colony-stimulating factor [GM-CSF] is a
growth factor)
 Primed immune cells are injected back into patient
 Adverse effects: chills, fatigue, fever, acute infusion
reactions
 Administration: three doses, every two weeks
 Give acetaminophen and diphenhydramine 30 minutes prior
58

Review
 Be able to describe the pathogenesis and risk
factors, signs and symptoms for prostate cancer
 Know how it is diagnosed, and when to screen
 Choose treatment options for each recurrence
risk and what to do for relapses
 Know the drugs
59

Thank You!
 Questions?
 Ask (don’t be shy) or email me:
hyunik@eden.rutgers.edu
60

Overview and Pharmacotherapy of Prostate Cancer (based on NCCN 2012 guidelines for prostate cancer)

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