Prostate Cancer
PSA levels between __ and ____ng/mL are suspicious for something going wrong
4 and 10
What is the 5 year survival for prostate cancer?
98.2
What common mutation for patients with prostate cancer indicates PARP inhibitors
BRCA2
CSPC/CRPC responds to ADT
CSPC
What molecule binds to it's receptor in the prostate to promote growth of the prostate?
DHT, which is converted by 5-alpha-reductase from testosterone
Where is testosterone produced?
Testes
progression of disease, either clinical or biomedical, in the presence of castrate levels of testosterone
castration resistant
symptoms of prostate cancer (5)
-frequency -hesitancy -discomfort when urinating -sexual dysfunction -pain in lower back upper thighs or hips
Gleason Score 1. scale ranges from ___ to _____ for each sample. Two samples are taken so the collective score ranges from ___ to ___ 2. The highest score on a sample means highly/poorly ________ cells 3. The lowest score on a sample means highly/poorly _______ cells 4. A high/low score indicates poor prognosis
1. 1-5, 2-10 2. poorly differentiated 3. highly differentiated 4. HIGH (undifferentiated cells)
Radium 223 Xofigo 1. mechanism of action 2. only used for castrate sensitive/resistant cancer with ________ metastases 3. cheap/expensive
1. Alpha-emitter calcium mimetic, induces double stranded DNA breaks 2.Treatment of mCRPC with bone only metastasis 3. expensive AF
What are the 5 components of diagnosing prostate cancer
1. Digital rectal exam 2. Prostate specific antigen 3. Transrectal ultrasound 4. Prostate tissue biopsy 5. Gleason score
PARP inhibitors mechanism of action
1. Disable PARP (a DNA repair enzyme) from healing single stranded break, which results in a double stranded break
Drug interactions with second generation antiandrogens enzalutamide, apalutamide, darolutamide 1. _____ and ______ are strong CYP _______ and ________ inhibitor/inducers 2. ________ has the fewest drug interactions, but does interact with _______astatin
1. Enzalutamide and Apalutamide are strong Cyp3a4 and CYP2C19 inducers 2. Darolutamide, rosuvastatin
Second generation anti-androgens enzalutamide, apalutamide, darolutamide 1. mechanism of action 2. one major risk with them
1. bind to AR receptor, inhibit translocation of AR receptor into the nucleus 2. penetrate BBB, can cause seizures (enzalutamide worst, darolutamide least)
Cabazitaxel 1. used for
1. castrate resistant metastatic prostate cancer
What, among the second generation antiandrogens, is unique about darolutamide
1. dose twice daily (with food) 2. FEWER drug interactions 3. lowest risk of seizures
Abiraterone adverse effects (3) What must be done to address one of the side effects What must be monitored for the first 3 months of therapy?
1. hypertension, hypokalemia, edema (from mineralocorticoid excess syndrome) 2. give prednisone 5mg daily 3. monitor LFTs for first 3 months
Sipulecucel -T (Provenge) 1. mechanism 2. cheap/expensive 3. setting when it's used
1. take WBC out of patient, reengineer them with prostate antigen 2. expensive AFFFFFF!! 3. castrate resistant, metastatic
How long does it for the negative feedback loop of LHRH agonists to work?
14-21 days
Which is NOT (currently) a treatment option for metastatic sensitive prostate cancer 1. ADT + Docetaxel 2. ADT + Darolutamide 3. ADT + Abiraterone 4. ADT + Enzalutamide 5. ADT + Apalutamide
2. darolutamide is not approved (yet)
How long does it take for LHRH antagonists to shut down testosterone production
3 days
Risk factors for prostate cancer (4)
Age (older) Family History (relatives) Genetics (BRCA1, BRCA2, ATM, CHEK2, PALB2) Race - African Americans have highest risk of getting it Scandanavian countries have greater risk of death
Which second generation antiandrogens would require the largest change in clopidogrel dose (theoretically)
Apalutamide (from CYP2C19 induction)
What is the least commonly used adjunct for metastatic, hormone sensitive prostate cancer?
Docetaxel
In a metastatic hormone sensitive setting, what options can you add on to your typical androgen deprivation therapy?
Docetaxel apalutamide enzalutamide abiraterone
T/F After getting LHRH agonists, we usually switch to an LHRH antagonist
False, other way. If we need to use the antagonist, once the patient is effectively castrated, we will switch to the agonist
Which would be a better choice for a patients with prostate cancer and previous MI
LHRH antagonists (Degarelix and Relugolix)
Name the LHRH agonists (4)
Leuprolide-most common histrelin goserelin tritorelin
Olaparib is a ________ inhibitor
PARP
What is the point of using Non-steroidal antiandrogens? What is their mechanism of action?
Prevent the initial testosterone surge with LRHR agonists Competitive inhibitors for androgen receptor
According to the HERO trial, which had a higher incidence of cardiovascular events, especially in a patient with previous history a. Leuprolide b. relugolix
a. Leuprolide
Non-steroidal antiandrogens are used in combination with a. LHRH agonists b. LHRH antagonists
a. agonists
Most types of prostate cancer at diagnosis are __________
adenocarcinoma
the point of ____ _____ ____ is to reduce testosterone to prevent prostate cancer cells from growin
androgen deprivation therapy
LHRH agonists/antagonists are associated with FEWER cardiovascular events
antagonists (makes sense if you think about it)
Most patients with metastatic disease have alk phos elevated... Why?
bone strengthening medications raise Alk phos
rice size pellets inserted directly below prostate as one time insertion procedure for low risk disease
brachytherapy
Which patients should get germline testing for prostate cancer. Select all that apply a. all elderly male patients b. no one c. patients with positive family history d. Ashkenazi Jewish ancestry e. african americans
c, d
CRPC
castration resistant prostate cancer
CSPC stands for
castration sensitive prostate cancer (also called hormone sensitive)
What are the main LHRH antagonists?(2) What dosage form
degarelix relugolix Subq injection for degarelix Relugolix is oral daily
What are the 3 most consequential toxicities of docetaxel
fluid retention myelosuppression peripheral neuropathy (destablilizes microtubules by depolymerization)
What are the three Non-steroidal antiandrogens? (3)
flutamide, bicalutamide, nilutamide
Most common site of cancers in prostate arise from the
glandular epithelium of the peripheral zone
3 main toxicities of PARP inhibitors The main toxicity of Parp inhibitors that we worry about
hematologic, gastrointestinal, constitutional (fatigue, headache) Hematological (anemia, thrombocytopenia, neutropenia
What is the most common site of the metastases
in bone
Mechanism of action of LHRH agonists
increases GNRH to anterior pituitary which increases FSH and LH, which increases testosterone, which leads to a negative feedback loop, causing a decrease in GNRH
What is the mechanism of action of abiraterone acetate? This mechanism results in increased _____ and _______ excess
inhibits steroid 17 hydroxylase (decreases androgens) increased ACTH production, and mineralocorticoid excess
What is one initial disadvantage of LHRH agonists
initial increase in testosterone which may promote prostate cancer cell growth
How often are the LHRH agonists given? What dosage form?
injections every 1,3,4 or 6 months depending on the drug
Cabazitaxel, Radium233, and Spiulecucel-T increase survival by more/less than 6 months
less
When chemical castration is elected for androgen deprivation therapy, what is the goal testosterone level? What is the ideal "deep castration"
less than 50 less than 20
KC is a 79 yo who presented to the ER with worsening back pain over the past 2-3 months. CT chest, abdomen, pelvis revealed diffuse spine metastasis and bi-lateral rib metastasis. Biopsy of bone metastasis shows prostate adenocarcinoma. PSA is 132 ng/mL. •PMH: HTN, Afib COPD, DM and mild peripheral neuropathy, recent DEXA scan T score -2.0 •Family History: Father died 57 MI, mother HTN, DM •Medications: apixaban 5 mg BID, metoprolol 50 mg BID, nifedipine ER 60 mg daily, simvastatin 40 mg qHS, fish oil 1000 mg daily •Vitals: BP 130/80, HR 81, Ht 176 cm, Wt 103.2 kg •Labs: •WBC 4.8, HGB 12.2, HCT 38.4, PLTs 265 •NA 140, K 3.7, Cl 98, CO2 25, BUN 20, Cr 1.01, Glu 98, Ca 9.0, Phos 4.3, Alb 3.6 •Bili 0.3, AST 21, ALT, 30, Alk Phos 270 •PSA 39 ng/mL, Testosterone 350 How would you classify this patients prostate cancer? What options are available? 1.docetaxel, apalutamide, enzalutamide, darolutamide 2.Abiraterone, apalutamide, enzalutamide, cabazitaxel 3.Docetaxel, apalutamide, abiraterone, enzalutamide 4.Abiraterone, darolutamide, apalutamide, cabazitaxel What's the best option, and why?
metastatic, castrate sensitive (if the testosterone is at 350, he has not been castrated yet) 3.Docetaxel, apalutamide, abiraterone, enzalutamide 4. abiraterone (fewest DDIs)
KC tolerates his therapy well with an undetectable PSA for 2 years. On routine monitoring his PSA increases on 3 separate clinic visits, he also reports increasing back pain. He has repeat MRI/CT scans to which show progressive metastatic disease in the spine and new metastatic disease ribs and pelvis. Molecular genetics were sent on his last biopsy which revealed an ATM mutation. His labs are as follows. WBC 4, HGB 11.8, HCT 37, PLTs 350 NA 135, K 3.9, Cl 98, CO2 20, BUN 18, Cr 1.07, Glu 115, Ca 9.5, Phos 4.7, Alb 3.4 Bili 0.3, AST 20, ALT 76, Alk Phos 275 PSA 7, Testosterone 10 How would you classify KC's prostate cancer now and why?
metastatic, castration/hormone resistant prostate cancer
Elevated PSA is sensitive/specific/neither for detecting prostate cancer
neither
What does the prostate do?
produces the fluid that makes up semen
what can be used for nonmetastatic, castrate resistant prostate cancer, 1 class 3 drugs
second generation antiandrogens enzalutamide, apalutamide, darolutamide Bind
Name some drugs that Enzalutamide and Apalutamide interact with (6)
statins, DOACs, CCBs, Opioids, PPI's, Losartan
Two ways you can do androgen deprivation therapy
surgical castration chemical castration with LHRH agonist or LHRH antagonist, or both
What is a good counseling point for abiraterone?
take without food. Fat increases AUC 10 fold!`