Treatment of Prostate Cancer

Question 1

What two almost equivalent sources of androgen must you take into account when targeting prostate cancer?

Answer 1

1. Testicular and Local Testosterone and DHT
2. Adrenal DHEA (dehydroepiandrosterone)

Question 2

What is the 1st line of treatment in patients with prostate cancer?

Answer 2

1^st line: Medical or Surgical Castration + Anti-androgen therapy

Radiation and Iodine coated titanium seeds can also be used

Question 3

What GnRH analogs are used in chemical castration for prostate cancer?

Answer 3

GnRH agonists

Goserelin, Histrelin, Leuprolide, Triptorelin (the “relins”)

Question 4

GnRH agonists

• Administration
• MOA
• Name Them

Answer 4

**GnRH agonists

Goserelin, Histrelin, Leuprolide, Triptorelin**

ADMINISTRATION
SC injection; monthly

_MOA_
Persistent Agonism (\> 2-4 weeks) of the GnRH receptor leads to increased FSH and LH levels (disease flare) followed by DOWNREGULATION of the receptor

Question 5

What should Goserelin, Histrelin, Leuprolide, and Triptorelin be administered with to reduce side effects when initiating treatment?

Answer 5

**AR blockers can be used to block the initial flare

Question 6

GnRH Agonists

• Name Them
• Adverse Effects

Answer 6

GnRH agonists

Goserelin, Histrelin, Leuprolide, Triptorelin

ADVERSE EFFECTS
All the effects of castration: Low Testosterone => Hot Flashes, Decreased Libido, ED, Gynecomastic, Osteoporosis

Question 7

GnRH Agonists
Goserelin, Histrelin, Leuprolide, Triptorelin
- Indications
- Contraindications

Answer 7

INDICATION
Prostate cancer, Breast cancer (goserelin)

CONTRAINDICATION
Category X

Question 8

What drug has an action opposite to that of Goserelin, Leuprolide, Histrelin, and Triptorelin?

Answer 8

Degarelix

Question 9

GnRH Antagonist

• Name it.
• Administration
• MOA

Answer 9

Degarelix

ADMINISTRATION
SC injections

MOA
Reversible agent, blocks GnRH, clearly no surge with this drug

Question 10

Degarelix
- Adverse Effects

Answer 10

ADVERSE EFFECTS
All the effects of castration: Low Testosterone => Hot Flashes, Decreased Libido, ED, Gynecomastic, Osteoporosis

Question 11

Degarelix

• Indication
• Contraindication

Answer 11

INDICATION
Prostate cancer, Breast cancer (goserelin)

CONTRAINDICATION
Category X

Question 12

Estramustine

• Administration
• MOA

Answer 12

Estramustine

ADMINISTRATION
Oral

MOA
Steroidal drug that targets Estramustine Binding Protein (EMBP) on prostate cancer, in doing so it brings an alkylator that functions as a microtubule inhibitor => G2/M arrest and DNA strand Breakage

**ALSO this produces circulating levels of estrodiol comparable to those seen in women’s estrogen therapy. Estrogen feedback on HPG axis further reduces testosterone**

Question 13

Estramustine
- Adverse Effects

Answer 13

Estramustine

ADVERSE EFFECTS
Similar Stucture to Estogen leads to “feedback-like” inhibition of the HPG axis

Estrogen-like effects: Gynecomastia, ED, Thromboembolism (similar to estrogen therapy), Stroke, Edema

Hepatic Effects: Elevated Hepatic Enzyme, Hyperbilirubinemia

Question 14

Estramustine

• Indication
• Contraindication

Answer 14

Estramustine

INDICATION
Prostate Cancer

CONTRAINDICATION
None stated, but probably watch out giving this to people with prior-existing CV risk factors

Question 15

What Androgen Receptor Blockers are used in the treatment of Prostate cancer?

Answer 15

Androgen Receptor Blockers

Bicalutamide, Enzalutamide, Flutamide, Nilutamide – the “lutamides”

Question 16

Androgen Receptor Blockers

• Name them
• Administration
• Adverse Effects

Answer 16

Androgen Receptor Blockers
Bicalutamide, Enzalutamide, Flutamide, Nilutamide – the “lutamides”

ADMINISTRATION
Oral - daily

MOA
Blockage of androgen receptors to prevent receptor stimulation on cancer cells. Administered concurrently with GnRH agonist

Question 17

Bicalutamide, Enzalutamide, Flutamide, Nilutamide
- Adverse Effects

Answer 17

Androgen Receptor Blockers
Bicalutamide, Enzalutamide, Flutamide, Nilutamide – the “lutamides”

ADVERSE EFFECTS
Castration Effects: Hot flashes, decreased libido, ED, gynecomastia, osteoporosis
Teratogens

Question 18

Bcalutamide, Enzalutamide, Flutamide, Nilutamide

• Indications
• Contraindications (exceptions?)

Answer 18

Androgen Receptor Blockers
Bicalutamide, Enzalutamide, Flutamide, Nilutamide – the “lutamides”

INDICATION
Prostate Cancer
FLUTAMIDE ALSO USED TO TREAT HIRSUTISM OR POLYCYSTIC OVARIAN SYNDROME

CONTRAINDICATION
Category X, exceptor nilutamide – Category C

Question 19

What anti-hypertensive drug can also be used in the treatment of prostate cancer?
- how so?

Answer 19

Spironolactone - works as an androgen receptor blocker

Question 20

What drug is used as immunotherapy against prostate cancer?

Answer 20

Sipuleucel - T

Question 21

Sipuleucel-T

• Administration
• MOA

Answer 21

Sipuleucel-T

ADMINISTRATION
IV

MOA
Patients WBC’s including APCs are removed and cultured with GM-CSF + PAP (prostate acid phosphatase) => The APCs take up the antigen and express it on their surface to T, B, and NK cells. These products are then reinfused into the patient.

Question 22

Sipuleucel-T

• Adverse Effects
• Indication

Answer 22

Sipuleucel-T

ADVERSE EFFECTS
Mild infusion reactions; fever/chills/dyspnea; GI effects
Paresthesias, Citrate Toxicity, and fatigue

INDICATION
Prostate Cancer

Question 23

A previously normotensive man comes in for a check up on his prostate cancer therapy and his blood pressure is now 150/95. What drug is he likely recieving?

Answer 23

Abiraterone - blocks 17-alpha hydroxylase and shunts all pregnenolone to become aldosterone leading to a hypermineralocorticoid state

Question 24

Abiraterone
- MOA

Answer 24

CYP17 (17-alpha-hydroxylase) inhibitor, prevents Cholesterol from getting turned into adrogen

Question 25

Abiraterone - Adverse Effects - Problems with quick withdrawal?

Answer 25

**Abiraterone AEs: - HTN, Hypokalemia, Fluid Retention =\> may exacerbate previously existing CV issues IF WITHDRAWN too quickly adrenal insufficiency (hypotension, tachycardria, hyperkalemia) may occur Check LFTs, because they become elevated TERATOGEN**

Question 26

Why should males taking Abiraterone wear condoms? - what other precautions should be taken?

Answer 26

\*\*Because this drug is pregnancy category X males should wear condoms and women shouldn’t handle the drug

Question 27

What are the risks and benefits of using estrogens to inhibit estrogen and testosterone release in Prostate Cancer?

Answer 27

**Estrogens** Advantages: **Osteoprotectiv**e Disadvantages: **None really**, because transdermal estrogen administration *prevents CV effects (DVT, thromboembolism)*

Question 28

If estrogen is used in the treatment of prostate cancer, what is the best way to administer it?

Answer 28

**Estrogens** Transdermal estrogens can be given to men to **prevent LH (and FSH) release**.

Question 29

What is the use of Finasteride and Dutasteride in prostate cancer?

Answer 29

**Finasteride, Dutasteride** _ADMINISTRATION_ PO _MOA_ **Inhibition of 5 alpha reductase** prevents DHT formation (androgen believed to be implicated in proliferation of prostate cancer). HOWEVER, the *location and expression level of the enzyme cannot predict the degree of testosterone metabolism to DHT* (variation could be polymorphisms). Effects of DHT are believed to be related to off-target effects.

Question 30

What class of chemotherapeutics is used in Conventional prostate chemotherapy?

Answer 30

Taxanes: Docetaxel, Carbaitaxel

Question 31

What do you need to administer before infusing taxanes?

Answer 31

\*\*Patients must be pre-medicated with Corticosteriods and anti-histamines to prevent infusion reactions associated with these drugs given that they often contain surfactant in their preparation\*\*

Question 32

How does Carazitaxel differ from other taxanes?

Answer 32

* *Carbazitaxel** * *Differs from other taxanes** in that it is **not a good substrate for Pgp**. This makes it **good for tx of multidrug resistant tumors.** It can also **penetrate the BBB** (given its ability to not get effluxed by Pgp that is heavily expressed at the BBB).