Hillis: Prostate Cancer

What 4 factors are associated with the highest risk of developing prostate cancer?

1. Age 

   1. Lifetime exposure to testosterone 

   2. >70% diagnosed in men over age 65

2. Ethnicity 

   1. African: higher incidence

   2. Asian: lower incidence

   3. Ashkenazi Jew: carriers of BRCA1 and BRCA2 mutations have increased risk 

3. Family History 

   1. First degree relative w/ prostate cancer → doubles risk 

   2. Family history of breast cancer 

   3. Genetic mutations

4. Supplements + Medications 

   1. Hormone therapies (testosterone and estrogenic supplementation) 

   2. Vitamin E & Folate → higher amounts can increase risk 

Explain why observation or active surveillance would be reasonable options for an elderly man with prostate cancer.

1. Observation is preferred in low-risk prostate cancer with life expectancy < 10 years

   1. Goal: palliative tx if needed

Why does ‘tumor flare’ occur with GnRH agonist therapy, and how is it prevented/minimized?

1. “Tumor flare” seen in GnRH agonists only due to temporary surge in LH/FSH and testosterone level before negative feedback loop on GnRH receptors

   1. Flares can increase symptoms of known sites of disease and concern for patients who have metastasis in weight bearing bones who would at risk of serious fracture 

2. Prevention/minimization

   1. 1st generation AntiAndrogens (inhibits binding of testosterone and dihydrotesterone to androgen receptor and interrupts the androgen-dependent cellular cascade)

   2. Bicalutamide 50mg daily, Flutamide 250 mg TID, Nilutamide 300mg daily x1month then 150 mg daily 

Why are androgen receptor antagonists started before GNRH agonists?  Why are the second generation androgen receptor antagonists preferred over the first-generation drugs?

1. Androgen receptor antagonists started before GNRH agonist to prevent testosterone surge/tumor flare from GnRH agonist 

2. 2nd generation androgen receptor antagonist preferred over 1st because unlike 1st gen agents, will not develop agonist activity with long-term use 

Explain why a drug such as leuprolide after the flare DECREASES testosterone despite it being a GnRH agonist.

GnRH agonists increase FSH and LH which signals to testes to initial increase secretion of testosterone → stimulating a Negative feedback loop to DECREASE the production of testosterone 

Explain how the mechanism of action of leuprolide differs from that of degarelix, and what some of the advantages of degarelix are promoted to be.

1. Degarelix is a GnRH antagonist- it has an immediate onset of action preventing gonadotropin release through receptor blockade leading to rapid suppression of LH and testosterone. 

2. Leuprolide- Indirect suppression of testosterone 

3. Degarelix- direct suppression of testosterone

4. Advantages no tumor flare

Explain how the mechanism of action of leuprolide differs from that of relugolix, and what some of the advantages of relugolix are promoted to be.

• Relugolix is a GnRH antagonist- it has an immediate onset of action preventing gonadotropin release through receptor blockade leading to rapid suppression of LH and testosterone.

• Leuprolide (indirect testosterone suppression) vs Relugolix (direct testosterone suppression)

• Advantages- no tumor flare

What are the roles of androgen deprivation therapy, and how is this achieved?

1st Generation Antiandrogens - What is the mechanism of action of the various oral antiandrogens and what side effects should be expected? What is their role or place in therapy? (eg, at what point in the natural history of prostate cancer?)

1st Generation Antiandrogens (Bicalutamide, Nilutamide, Flutamide)

→ MOA: inhibits the binding of testosterone and dihydrotestosterone to androgen receptors and interrupts the androgen-dependent cellular cascade Eventually develop agonist vs antagonist activity due to stimulation of the androgen receptor  MUST be given w/ GnRH agonist ~1 week to reduce the risk of tumor flare  → Place in therapy: used to lap with GnRH agonist to reduce the risk of tumor flare  → Class Effects: hot flashes, diarrhea,  Flutamide: nausea, hepatotoxicity  Bicalutamide (Preferred agent): hepatotoxicity Nilutamide: nausea, disulfiram-like reactions, decreased visual, hepatotoxicity

2nd Generation Antiandrogens - What is the mechanism of action of the various oral antiandrogens and what side effects should be expected? What is their role or place in therapy? (eg, at what point in the natural history of prostate cancer?)

2nd Generation Antiandrogens (Apalutamide, Darolutamide, Enzalutamide)

→ MOA: inhibit the binding of testosterone and dihydrotestosterone to androgen receptor and interrupts the androgen-dependent cellular cascade Unlike 1st gen will not develop agonist activity with long-term use  → Place in therapy: nmCRPC, mCSPC → Adverse Effects:  Apalutamide: fatigue, rash, fractures, hypothyroidism, HTN, seizures Darolutamide: fatigue, HTN, rash Enzalutamide: Fatigue, falls, fractures, HTN, seizures

Abiraterone Acetate - What is the mechanism of action of the various oral antiandrogens and what side effects should be expected? What is their role or place in therapy? (eg, at what point in the natural history of prostate cancer?)

Abiraterone Acetate

→ MOA: CYP17A1 Inhibitor- blocks the synthesis of androgens (DHEA and androstenedione) Also reduces cortisol and causes a compensatory increase in ACTH  → Abiraterone Acetate (most common) → Abiraterone Acetate-Micronized  → Place in therapy: mCSPC, mCRPC, or if 2nd gen agents contraindicated in non metastatic disease  → Adverse effects: mineralocorticoid excess (given with prednisone), use safety in patients with LVEF < 50% or NYHA class III or IV HF Monitor LFTs q2 weeks x 3 months

What clinical presentation or medical history of a patient with prostate cancer would suggest the use of abiraterone INSTEAD of enzalutamide?

1. Metastatic disease (CRPC or CSPC)

2. In a patient with non metastatic castration resistant disease with PSADT< 10 months and 2nd gen hormonal therapy is CI (i.e. Patients with a hx of seizures/epilepsy, falls, fractures)

Why is prednisone administered with abiraterone?

1. Due to mineralocorticoid excess due to the effects on cortisol/ACTH-prednisone is used as glucocorticoid replacement 

What other drug therapy is assumed to continue with abiraterone or enzalutamide?

ADT (GnRH Agonist or Antagonist)

At what point in the natural history of prostate cancer is cytotoxic chemotherapy such as docetaxel likely to be employed?

Symptomatic mCRPC

What issues of bone health arise in men treated for prostate cancer, and how should they be minimized?

1. Hormonal tx for prostate cancer can cause→ osteoporosis , fractures, decreased muscle mass 

2. Screen and treat patients per osteoporosis guidelines 

   1. Supplement 1000-1200 mg Calcium, Vitamin D3 level 30-50 ng/mL 

3. Skeletal-related events (SRE)- pathological fractures, spinal cord compression, bone pain secondary to metastasis

   1. Reclast 4 mg IV q28 days or q12 weeks

   2. Denosumab 120 mg SQ q28 days