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Androgen Deprivation Therapy (ADT) and other drugs

Treatment Class	Specific Treatment	Uses	Side Effects
Surgical Treatment	Orchiectomy	Castration within 6hrs	Cosmetic perception Less side effects than drugs
Androgen Receptor Antagonist	First Generation: Bicalutamide (Casodex, 50mg daily) Flutamide (Eulexin) Nilutamide (Nilandron)	Prevent T surge with initiation of GnRH agonists	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)	mCRPC	Both: rash, fatigue, diarrhea Enzalutamide: seizures (< 1%) Apalutamide: falls/fractures (12%), hypothyroid (8%)
GnRH Inhibition	Agonists: leuprolide (Lupron/Eligard), goserelin (Zoladex) Antagonists: degarelix (Firmagon), relugolix (Orgovyx)	Monotherapy or combination with other medications	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 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

When to Use Immediate ADT

Situation	Immediate ADT?
Low risk, localized disease	No benefit
Locally advanced	Improves cancer-specific survival No benefit in overall survival
Asymptomatic metastatic disease
Node-positive prior to primary therapy	May provide benefit
Node-positive after surgery	Improves overall survival
After biochemical recurrence, asymptomatic	Not required, okay for intermittent ADT (set threshold)

General complications of ADT

• Osteoporosis: risk of fracture 19% (vs 13%) at 5yrs and 40% (vs 19%) at 15yrs, recommend Ca 1000-1200 mg/d and Vitamin D 400-1000 IU/d, consider bisphosphonates, calculate 10yr risk with FRAX calculator
• Hot flashes: seen in 50-80%, treat with megestrol (Megace) 20mg BID (but increased risk for thrombotic events), venlafaxine 37.5mg/d, DES < 0.5mg/d
• Cardiovascular: 20% increased risk of morbidity at 1yr, 5.5% vs 2% at 5yrs, GnRH antagonists are less likely to have cardiovascular effects
• Sexual dysfunction: 10-17% maintain erectile function, 5% maintain libido, PDE5i are not effective
• Gynecomastia: can be painful, prophylactic (not treatment) XRT (12-15Gy single dose), tamoxifen 10-20mg/d, breast reduction surgery
• Cognitive function: Lonergan 2022 reported a 2.3% increase in dementia at 7yr, creater risk with longer use
• Weight gain: 2-4% at 1yr and loss of muscle mass
• Diabetes: increased insulin resistance occurs within 4mo initiating treatment then plateaus
• Lipids: increased LDL/triglycerides, occur within 3mo initiating treatment
• 3-16% with leuprolide, can treat with prophylactic XRT (10-15Gy single fraction) but has no benefit after development of symptoms
• Anemia: common (> 10%), reaches nadir by 6mo, treat by stopping ADT or giving ePO
• Monitoring: check BP, lipids, CBC, and glucose q3-6mo after starting treatment, DEXA scan at initiation and q2yr

Intermittent ADT

• Indications: castrate-sensitive prostate cancer, either metastatic or non-metastatic
• Compared to continuous ADT: no difference in overall survival, increased prostate-cancer specific mortality balanced by decreased all-cause mortality
• Not recommended if: having minimal ADT side effects (no benefit to iADT, just give continuous), M0 with GG 4-5 (better survival with continuous ADT), persistently elevated PSA despite ADT initiation (respond better to continuous ADT)

Survival on ADT

• PSA 8mo after castration for BCR w/ M0: mortality rates 2% for PSA ≤ 0.2 vs 49% for PSA ≥ 0.2 at 7yr
• PSA 8mo after castration for M1: overall survival 6.2yr if PSA ≤ 0.2, 3.7yr if PSA 0.2-4, 1-2yr if PSA > 4

Metastatic Prostate Cancer

Defining Metastatic Disease

• High Volume (CHAARTED definition): visceral metastases and/or greater than 4 bone metastases, with at least one outside the vertebral column and pelvis
• Low Volume: does not meet high-volume criteria
• High risk (LATITUDE definition): 2/3 features - Gleason ≥8, ≥ 3 bone lesions, or visceral metastases

Treatment Recommendations for Metastatic and/or Castrate Resistant Prostate Cancer

Metastatic?	Castrate Resistant?	Workup	Treatments	Monitoring
No	No	PSAdt CT/MR Bone scan Consider PET	Observation iADT (PSA cutoff 4-10) Clinical trials	PSA q3-6mo Consider repeat imaging q6-12mo
Yes	No	CT/MR Bone scan PET (57% positive if PSA > 1) Consider genetic testing	iADT/cADT XRT + ADT (if low volume) Abiraterone + ADT Apalutamide/Enzalutamide + ADT Docetaxel + ADT (if high volume)
No	Yes	Calculate PSAdt (cutoff ≤ 10mo) CT/MR Bone scan	observation or ADT (if PSAdt > 10mo) Apalutamide/Enzalutamide/Darolutamide + ADT (if PSAdt ≤ 10mo)
Yes	Yes	PSA, T, LDH, Hgb, AlkPhos CT/MR Bone scan Consider genetic testing	ADT + Abiraterone ADT + Docetaxel ADT + Enzalutamide Sipuleucel-T (if asymptomatic or minimally symptomatic) Radium-223 (if bony metastases only) Cabazitaxel (if prior docetaxel) Olaparib/Rucaparib (if germline mutation) Carboplatin (if no germline mutation) Pembrolizumab (if MMR mutations)	Annual imaging

Initial management of metastatic disease

• Imaging: obtain bone scan and CT A/P to assess degree of presumed metastatic prostate cancer
• Other tests: check baseline PSA and T, obtain biopsy (prostate may be easier than bone)
• Bicalutamide block: 50mg daily x1mo, controversial due to theoretical but low risk of T flare with up-front GnRH agonist, recommended in patients with T < 250 or spinal metastases (risk for cord compression)
• cN1M0: multimodal local therapy recommended, can perform XRT +/- RALP with lifelong ADT

Castrate resistant disease

• Definition: check testosterone levels with PSA, if PSA rising despite T < 50 then patient has castrate-resistant disease
• ADT: continue ADT, as some of the cancer will still be hormone-sensitive and respond to treatment
• Imaging: obtani bone scan and chest/abdominal imaging, metastatic risk is > 10% even with low PSA and long doubling time
• Bone met management: up to 50% will develop a "skeletal related event" within 2yrs, treat symptomatic lesions with XRT, start zoledronic acid (Zometa, 4mg IV q3-4wk) or denosumab (Xgeva, 120mg SC q4wk), give w/ calcium + Vit D, refer for dental exam, osteonecrosis seen in 1-2%

Acute cord compression management

• Imaging: complete spine MRI to identify lesions and potential other lesions
• Dexamethasone: give 100mg IV bolus, followed by 25mg PO QID x3d then taper
• Immediate castration: orchiectomy (castrate within 2-12hr), ketoconazole 400mg TID x3d (castrate within 8hr), GnRH antagonist
• GnRH agonist: do not give in acute setting, can worsen cord compression
• Surgical decompression indications: ADT/XRT failure, spinal instability, recurrent compression after XRT, bony protrusion into cord, neurologic compromise
• XRT indications: recommended if surgical therapy not indicated