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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) Antagonists: 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	See section below table
Hot Flashes	50-80%	Venlafaxine 37.5mg/d (preferred option) Megestrol (Megace) 20mg BID (increased risk for thrombotic events) DES < 0.5mg/d
Cardiovascular	16-20% increased risk of morbidity at 1yr 5.5% (vs baseline 2%) at 5yrs	Consider PCP/cardiology evaluation 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	40% risk, 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	Discuss statin initiaion with PCP
Anemia	> 10% prevalence Plateaus by 6mo	Consider giving ePO
Monitoring
check blood pressure	check CBC, Lipids, glucose q3-6mo	DEXA at initiation and q2yr

Bone health

• Screening: DXA scan before or within 6mo of starting ADT (repeat q1-3yr), can also use FRAX 10yr risk calculator
• Supplements: recommend calcium 1000-1200mg/d, Vitamin D 1000-2000 IU/d
• Bisphosphonate indications: indicated if T-score ≤ -2.5, FRAX > 20% for major fractures or > 3% for hip fractures, or vertebral fragility fractures - need dental screening prior to initiation
• Bisphosphonate options: alendronate 35-70mg PO weekly, risedronate 35mg PO weekly or 150mg PO monthly, zolderonic acid 5mg IV annually, denosumab 60mg subQ q6mo

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)

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

Initial management of metastatic disease

• PET/CT: metastatic disease detection 21-72% when PSA < 1, node threshold 4-9mm increases with rising PSA, best initial test if available
• Conventional imaging: bone scan and CT A/P have poor sensitivities at low PSA
• Other tests: check baseline PSA and T
• Biopsy: obtain tissue to confirm diagnosis and for targeted therapies, prostate biopsy may be more helpful than bone
• PSA > 50 per 2023 AUA early detection guidelines, can proceed with urgent treatment prior to biopsy (98.5% chance of high-risk prostate cancer)
• Antiandrogen blockade: theoretical but low risk of T flare with up-front GnRH agonist (10% risk bone pain or urinary retention), recommended in patients with T < 250 or spinal metastases (risk for cord compression), bicalutamide 50mg daily or flutamide 250mg TID for one month
• Genetics: recommended for all patients with metastatic disease
• PSA nadir: after 6 months ADT, patients with PSA >4, 0.2-4, and <0.2 have median survivals of 13 months, 44 months, and 75 months, respectively (SWOG 9346, AUA guidelines)
• Bone protection: anyone with metastatic disease to bone should be on a protective agent (denosumab, zoledronic acid) to prevent skeletal-related events

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

• 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