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!`