Metastatic Prostate Cancer

Androgen Deprivation Therapy (ADT) and other drugs

Available treatment options

Treatment Class Specific Treatment Mechanism/Use Side Effects
Surgical Treatment Orchiectomy Removes T source quickly
(castration within 6hrs)
Cosmetic perception
Less side effects than drugs
Androgen Receptor Antagonist First Generation:
Bicalutamide (Casodex, 50mg daily)
Flutamide (Eulexin)
Nilutamide (Nilandron)
Used for bridging to GnRH agonist Inadequate as monotherapy
T converted to E, gynecomastia
Impotency (80%)
Hepatitis (monitor LFTs)
Withdrawal can decrease PSA due to mutation causing drug to act as an agonist
Second Generation
Enzalutamide (Xtandi, 160mg daily)
Apalutamide (Erleada, 240mg daily)
Darolutamide (Nubeqa, 600mg BID)
Used with ADT for primary treatment
Per PROSPER, enzalutamide PSA nadir predicts predicts risk of metastasis and death
Both: rash, fatigue, diarrhea
Enzalutamide: seizures (< 1%)
Apalutamide: falls/fractures (12%), hypothyroid (8%)
GnRH Inhibition Agonists:
Leuprolide (Lupron/Eligard), Goserelin (Zoladex)
Degarelix (Firmagon), Relugolix (Orgovyx, 120mg PO QD)
Stop T production via HPA axis T surge: occurs within 10-20 days, can cause symptom exacerbation if bone mets
Androgen Synthesis Inhibitors Abiraterone (Zytiga, 1000mg daily) CYP17 inhibitor Treat with prednisone (5mg QD for CS, BID for CR) to prevent hypocortisolism
Ketoconazole (400mg TID) Blocks 17,20 desmolase
castration within 4hrs
Treat with hydrocortisone (5-20mg BID)
Gynecomastia, hepatitis
Non-ADT Treatments Docetaxel (Taxotere, q3wk) Microtubule assembly inhibitor Febrile neutropenia (15%)
Systemic symptoms (7%)
GI symptoms (8%)
Cabazitaxel (q3wk) Used for mCRPC after docetaxel Neutropenia
Sipuleucel-T (Provenge) Immunotherapy Improves survival but without clinical/serologic/radiographic response
Radium-223 (Xofigo) a-emitting particle causing dsDNA breaks
Bone metastases without visceral metastases
Neutropenia (2%)
Thrombocytopenia (6%)
Do not give with abiraterone
PSA monitoring is not accurate
Olaparib (Lynparza, 300mg BID)
Rucaparib (Rubraca, 600mg BID)
PARP inhibitor Anemia, nausea, DVT (7%), MDS/AML (< 1.5%)
Pembrolizumab anti-PD1 monoclonal antibody Immunosuppresion side effects

Should I give ADT?

Situation Immediate ADT?
Localized disease No benefit, don't give
Locally advanced disease Improves cancer-specific survival
No benefit in overall survival
Asymptomatic metastatic disease
Node-positive prior to primary therapy May provide benefit, can consider
Node-positive after surgery Improves overall survival
After biochemical recurrence, asymptomatic Not recommended, but can offer intermittent ADT (set threshold)

Complications of ADT

Complication Prevalence/Risk Management
Osteoporosis Fracture risk:
19% (vs 13%) at 5yr
40% (vs 19%) at 15yr
Calcium 1000-1200mg/d
Vitamin D 1000 IU/d
Can offer bisphosphonates
FRAX 10yr risk calculator
Hot Flashes 50-80% Venlafaxine 37.5mg/d (preferred option)
Megestrol (Megace) 20mg BID (increased risk for thrombotic events)
DES < 0.5mg/d
Cardiovascular 20% increased risk of morbidity at 1yr
5.5% (vs baseline 2%) at 5yrs
GnRH antagonists have less risk
Sexual dysfunction Erectile dysfunction: 80-90%
Decreased libido: 95%
PDE5i usually not effective
Gynecomastia 3-16%, can be painful XRT: prophylactic (not treatment) 12-15Gy single dose
Tamoxifen 10-20mg/d
Breast reduction surgery
Cognitive decline 2.3% absolute increase at 7yr (Lonergan, 2022) Risk increases with long-term use
Diabetes Insulin resistance occurs within 4mo treatment, then plateaus
Weight gain 2-4% at 1yr
Muscle mass loss
Lipids Occurs within 3mo initiating treatment
Increased LDL/TG
Anemia > 10% prevalence
Plateaus by 6mo
Consider giving ePO
check blood pressure check CBC, Lipids, glucose q3-6mo DEXA at initiation and q2yr

Intermittent ADT

Metastatic Prostate Cancer

Defining Metastatic Disease

Initial management of metastatic disease

Treatment Recommendations for Metastatic and/or Castrate Resistant Prostate Cancer

Metastatic? Castrate Resistant? Treatments Monitoring
No No Observation
Clinical trials
Consider iADT (PSA cutoff 4-10)
PSA q3-6mo
Consider repeat imaging q6-12mo
Yes No iADT/cADT
XRT + ADT (if low volume)
ADT + Abiraterone
ADT + Apalutamide/Enzalutamide
ADT + Docetaxel (if high volume)
ADT + docetaxel + abiraterone/darolutamide
No Yes observation or ADT (if PSAdt > 10mo)
Apalutamide/Enzalutamide/Darolutamide + ADT (if PSAdt ≤ 10mo)
Yes Yes ADT + Abiraterone
ADT + Docetaxel
ADT + Enzalutamide
Sipuleucel-T (if asymptomatic or minimally symptomatic)
Radium-223 (if bony metastases only)
177Lu-PSMA-617 (if prior docetaxel and strongly positive PSMA)
Cabazitaxel (if prior docetaxel)
Olaparib/Rucaparib (if germline mutation)
Carboplatin (if no germline mutation)
Pembrolizumab (if MMR mutations)

Castrate resistant disease

Acute cord compression management