Prostate Cancer Flashcards
Androgens
- Normal growth and differentiation of the
prostate depends on the presence of
androgens - Prostate CANCER depends on androgens for
growth - LHRH is released from the hypothalamus
stimulating release of LH and FSH from
anterior pituitary gland - LH stimulates production of testosterone
in testes - Testosterone makes up 95% of circulating
androgens - Testicular androgens are the major driver of
prostate cancer growth
Steroidogenesis – Androgen creation
- Androgen biosynthesis pathway can
exist in any tissue but for men, it’s
primarily in testes (90-95%) and
adrenal gland (5-10%) - Cholesterol is the foundational
molecule for creating other hormones
including testosterone,
glucocorticoids, & mineralocorticoids - CYP17 is a critical enzyme for
conversion of pregnenolone/
progesterone to androgens or cortisol.
Androgens in Prostate Cancer
- Testosterone from testes is
converted to Dihydrotestosterone
(DHT) within the prostate cell - Activation of Androgen Receptor
(AR) by DHT in prostate cancer
cells: - Signals cell growth and proliferation
- Prevents apoptosis
- Drive an increase in Prostate Specific
Antigen (PSA)
Prostate Specific Antigen (PSA)
- PSA is a protein produced by cancerous and non-cancerous prostate
tissue - PSA can be measured through a blood test
- Normal 0-4 ng/mL
- Normal rising of PSA occurs with aging
- PSA of >10ng/mL can be suggestive of prostate cancer
Normal PSA can still have cancer
Using PSA for Prostate Cancer Screening
- Limitations:
- No PSA value completely excludes prostate cancer
- Low PSA thresholds for further investigations increases the probability of false positive
(overdiagnosis) - Low specificity – PSA can be elevated for several different reasons (not just in cancer)
- PSA can be used for screening but is controversial
- Men should discuss with their physician starting at age 50
- MyHealth.Alberta offers a patient discussion aid to facilitate shared decision making regarding PSA
- PSA screening is more likely to be considered in those at higher risk (but is still not
recommended by guidelines) - African ancestry
- Father or brother that had prostate cancer before age 65
- Genetic disposition (such as BRCA mutation)
Prostate Cancer Screening
pros and cons
Prostate cancer is more likely to be found with PSA testing than
without PSA testing (10% who are screened will be diagnosed
vs 7% who are not screened
help find some prostate cancers early
cons
High PSA level is not specific to cancer. It can be high due to
several reasons (BPH, infection).
Overdiagnosis (can identify a cancer that would not have
caused a problem) and lead to unnecessary treatment
(estimated about 27 out of 1,000 men may get treatment they
don’t need).
without PSA testing (10% who are screened will be diagnosed
vs 7% who are not screened
Only a small proportion of prostate cancer causes symptomatic
disease or death. Most prostate cancers progress slowly and
are not life threatening
Harms such as false positives, overdiagnosis, and complications
with follow up tests (bleeding, infection, urinary incontinence)
commonly occur with PSA screening
- Digital Rectal Examination (DRE)
- Palpation of the prostate through
the rectum - Canadian Task Force on
Preventative Health Care no
longer recommends as a method
of screening (as of 2014) - No evidence that DRE reduces
prostate cancer mortality - DRE can help support a suspected
diagnosis of Prostate Cancer
risk factors
Age
* Over 70% of cases are diagnosed in men over 65
years old
* Ethnicity:
* African decent have higher incidence and mortality rate
* Low rate in Japan and other Asian countries
Higher testosterone in African populations
Data is coming out to say it is due to social determinants of health, later access to health care for African population
Warning signs are ignored
- Family history (brother or father)
- Risk increases two fold
- Germline genetic mutations (about 12% of men
with metastatic prostate cancer have a germline
mutations known to increase cancer risk) - BRCA 1 or 2
- Lynch syndrome
- Various others
- Diet/Supplements
- Mediterranean diet reduces risk
- Increased risk with high meat or high fat diet
- Vitamin E (SELECT trial found Vitamin E increased
risk by 17%) Vitamin E supplementation actually has higher incidence of prostate cancer - Hormonal
- Not present in castrated men
- Up to 80% are hormone-dependent
- African decent have 15% increased testosterone
- Japanese decent have lower 5-alpha-reductase
activity - Smoking increases risk and mortality\
- Benign Prostatic Hypertrophy (BPH)
- Does not appear to increase prostate cancer risk
- Has similar symptoms and hence can complicate the
diagnosis of prostate cancer
Symptoms could be masked by thinking it is BPH
Prostate Cancer – Clinical Presentation
- Local Disease
- Asymptomatic
- Ureteral dysfunction
- Frequency, hesitancy, dribbling
- Impotence
- Advanced Disease
- Back pain, cord compression,
fractures (bone is the most
common site of metastases) - Anemia
- Weight Loss
Prostate Cancer Diagnosis and Workup
- Diagnosis:
- Diagnosis done via ultrasound guided needle biopsy
- Transrectal biopsy or transperineal biopsy
- Elevated PSA and/or abnormal DRE are NOT diagnostic for prostate cancer
although they do serve to risk stratify patients - Workup
- History & physical exam
- Laboratory tests (CBC, SCr, urinalysis)
- PSA – likely done before biopsy
- Bone scan or CT scan if high risk (assessment for mets)
- MRI
Factors to Consider for Developing Treatment Plan
- Disease Factors:
- Stage
- TNM
- Localized vs Regional vs Metastatic
- Risk Category
- Grading
- Pathology or Histologic Stage
- Gleason Score or Grade Group
- Prostate Specific Antigen (PSA)
- Patient Factors:
- Life expectancy:
- ≥ 20 years, 10-20 years, < 10 years
- Symptoms
- Is patient symptomatic??
staging?
slide 17
Prostate Cancer Grading (determining “risk”)
- Grading is based on histologic
appearance - Rated on a scale of 1 (well differentiated)
to 5 (poorly differentiated) - “Gleason score”
- Two score from two samples added
together (sum out of ten) - “Grade Group”
- Two scores written separately “3+4”
- Poorly differentiated tumours typically
grow more rapidly and carry a poorer
prognosis.
Look at 2 samples taken from biopsy
How far wawy from good looking prostate cells are we?
What is the most prominent cell and pattern seen?
PSA (determining “risk”)
based on PSA level
- PSA level in Prostate Cancer Patient
- <10 ng/mL – low risk indicator
- 10-20 ng/mL – intermediate risk indicator
- > 20 ng/mL – high risk indicator
- How fast a PSA is rising can also be a clue to disease
aggression (PSA doubling time)
Treatment Modalities
- Active Surveillance
- Ongoing close monitoring (symptom monitoring & scheduled monitoring of PSA and DRE, with repeat biopsies if clinically indicated)
- Surgery
- Radical prostatectomy (RP)
- Surgical removal of prostate gland and surrounding tissues (including seminal vesicles)
- Adverse effects include urinary incontinence and/or erectile dysfunction
- If “nerve sparing”, then 50-80% regain sexual potency within the first year
- Pelvic Lymph Node Biopsy (PLNB)
- Done with RP if patient is deemed high risk of developing lymph node metastases
- Orchiectomy (surgical castration)
- Rarely done
- Radiation
- External beam radiation therapy (EBRT) and/or Brachytherapy - Refer to Radiotherapy lecture (Dr Debenham)
- Pharmacotherapy
- Androgen Deprivation Therapy (“Medical Castration”)
- “Novel” hormonal manipulation therapies (enzalutamide/apalutamide or abiraterone)
- Chemotherapy
Active Surveillance
- Careful monitoring and regular testing (PSA, DRE, symptoms etc)
- Rebiopsy at regular intervals (example every 3 years or when clinically
indicated) - Appropriate for:
- Low risk localized disease
- Short life expectancy
Androgen Deprivation Therapy (ADT)
- Rationale: to deplete testosterone levels thus inhibiting further
cancer growth - Depleting testosterone with pharmacotherapy simulates castration
(medical castration) - ADT Therapies include:
- Luteinizing hormone releasing hormone (LHRH) Agonists
- Gonadotropin –releasing hormone (GnRH) antagonist (AKA: LHRH Antagonist)
- Anti-androgens (androgen receptor antagonists)
ADT: LHRH Analogs (Agonists)
* MOA
- LHRH analogs initially stimulate an increase in
LH hormone resulting in a transient elevation
in serum androgen. But with chronic
administration, there is a down regulation of
LHRH receptors in the pituitary gland with
leads to decreased production of LH and
ultimately testosterone. - Options:
- Leuprolide (most common in practice)
- Buserelin
- Goserelin
If we give LHRH agonist, pt and disease gwt a flare
Neg feedback leads to down-reuglation
Leuprolide is covered 100% from the cancer program of AB, will get it at tom baker pharmacy, not often at comm pharm
ADT: Leuprolide
- Synthetic analog of LHRH
- Brands:
- Lupron Depot® (IM)
- Eligard® (SC) more common
- Dosing options:
- 7.5 mg q4wk, 22.5mg q12wk, 30mg q16wk, 45 mg q24wk
- Adverse Effects/Monitoring:
- Osteoporosis/Fractures
- Hypogonadic state produced by leuprolide can result in decreased bone mineral density
- Monitor BMD, supplement with calcium + Vitamin D (unless hypercalcemic) Bone metastases –> at risk for hypercalcemia, need to watch out for that
- Drug Induced Disease Flare
- The transient increase in androgens at the start of therapy (first month) can temporarily worsen cancer symptoms (examples: urinary symptoms or bone pain)
- Decreased libido (100%), impotence (90%) improves
- Hot Flashes (40-77%)
- Depression
- Elevation in cholestero
ADT: Gonadotropin-Releasing Hormone Antagonist
(aka LHRH antagonist)
- Degarelix
- Binds to GnRH receptors in pituitary gland
- Reduces release of LH/FSH leading to a reduction in
testosterone production. - Subcutaneous injection every 4 weeks
- Not currently funded in Alberta
- Degaralix Adverse Effects
- Hot flashes
- Injection site reactions
- QTc interval prolongation (20%)
- Reduced libido, erectile dysfunction
Tumour flare does not usually occur with Degaralix
Not as accessibe in AB
High incidence of QT prolongation
“Older” Antiandrogens
(androgen receptor antagonists)
- MOA
- Competes with androgens for binding at
androgen receptors - Options:
- Nonsteroidal
- Bicalutamide 50 mg po daily
- Nilutamide 300 mg po daily X 1 month,
then 150 mg daily - Flutamide 150 mg po TID
Steroidal
* Cyproterone 100 mg po BID
Place in therapy:
* Rarely used as monotherapy as feedback
loops will overcome the suppressive effects
* As monotherapy, antiandrogen efficacy is
inferior to LHRH agonist therapy
* Most commonly, these agents are started
just prior to first LHRH analog injection and
continued for 4 weeks to reduce symptoms
of flare response
Feedback loops will work for a while but then body will overcome suppressive effects
Wen we use leuprlodie there is flare of disease, this will bridge us for during the flare
Couple wks before leuoprolide, falre wont be as bad with hot flashes, surge of pain for metastaes
“Older” Antiandrogens
(androgen receptor antagonists
AE
- Gynecomastia, breast tenderness
- Hot flashes
- Fatigue
- Diarrhea
Natural History of Prostate Cancer
* What if PR’s PSA starts to progress despite ADT?
After a while of depleting testosterone, cancer overcomes
Make it’s own testosterone
After 2-3 yrs, PSA rises again
If it respnds well to test depletion/castration = castrate sensitive prostate cancer
Other way around is resistant
- If the cancer is well controlled with ADT, then this is considered “Castrate
SENSITIVE Prostate Cancer (CSPC)” - The progression of prostate cancer can be thought of as a series of phases. Eventually, the cancer will overcome the deprivation of testosterone.
- Despite castrate levels of testosterone, PSA will eventually begin to rise and the tumour will progress (usually in about 2-3 years)
- When the cancer is no longer controlled with ADT, this is referred to as “Castrate RESISTANT Prostate Cancer” (CRPC)
Novel Antiandrogens
(androgen receptor signaling inhibitors)
name 3
- Enzalutamide, Apalutamide,
Darolutamide - Used in combination with ADT
(LHRH analog or orchiectomy)!! - MoA: Acts at several steps in the
androgen receptor signaling
pathway: - competitively inhibits binding of
androgens to androgen receptors
with more affinity than older
antiandrogen agents (like
bicalutamide) - inhibits nuclear translocation of the
androgen receptors, DNA binding,
and coactivator recruitment
Inhibit going into the nucleus
Inhibit DNA inding the nucleus
which nvoel antiandrogen needs to be given w food
which are indicated for rnon-metastatic castrationresistant prostate cancer (nm-CRPC)?
Indicated for metastatic castrationresistant prostate cancer (m-CRPC)?
Indicated for metastatic castrationsensitive prostate cancer (m-CSPC)?
Enzalutamide
160 mg po once daily
NOTE: Available as 40 mg liquid filled caps
(Patients take 4 caps daily)
Administer with food or on an empty stomach.
inidcated for nm-CRPC, m-CRPC, m-CSPC
Apalutamide
240 mg PO once daily
NOTE: Available as 60 mg tablets (Patients ake 4 tabs daily)
Administer with food or on an empty stomach.
inidcated for nm-CRPC, m-CSPC
Darolutamide
600 mg po TWICE daily.
NOTE: Available as 300 mg tablets (patients take 2 tabs twice daily)
Administer WITH FOOD
inidcated for nm-CRPC
Enzualutamide Apalutamide Darolutamide
all increase HTN, apalutamide has high chance of htn and high elevation of lipids
hot flushes for all and diarrhea, fatiuge
FRACTURE RISK – remember, still on ADT and hence high risk for osteoporosis
* Risk exacerbated by falls, seizures, fatigue, etc.
enza and apa cross BBB , darolutaminde min penetration thru bbb
blackbox warning for seizures
but daro only as data in the setting for non-metastatic CRPC, but not the other 2 settings
see slide 36 for other AE
Enzalutamide & Apalutamide Drug Interactions
- Enzyme Inducer:
- STRONG inducer of CYP 3A4
- Moderate to strong inducer of CYP
2C9 &2C19 - VERY LONG t1/2 (6 days for enzalutamide or
3 days for apalutamide), hence effects on
enzymes may persist for several weeks or
longer after discontinuation - Substrate of CYP 2C8 & 3A4
- QT prolongation
- Chronic therapy so be aware of risk
with multiple agents
Daralutamide Drug Interactions
- Enzyme Induction
- WEAK inducer of 3A4
- T1/2 is only 20 hours
- Substrate of 3A4 and PGP
- Concern if a drug is an 3A4 and PGP inducer
- Seems to have minimal impact on QT interval
Get basleine and intermittent ECG
Steroidogenesis – Revisited
- Following castration (surgical or
medical), androgen synthesis
can persist in other tissues - Adrenals
- Prostate cancer cells themselves
- Tumour cells can eventually
overcome ADT and proliferate
