Chapter 20 · Associated Medical Professionals of New York · New York
Localized disease is covered in Chapter 8. This chapter is the detailed reference for advanced disease — the biology, the disease states, the drugs, and the treatment algorithms.
Saved privately in this browser and shared across state tabs.
Localized disease is covered in Chapter 8. This chapter is the detailed reference for advanced disease — the biology, the disease states, the drugs, and the treatment algorithms. The field moves quickly; treat this as a framework and confirm regimens against the current NCCN guideline and your treating oncologist/urologic-oncologist. Molecular imaging that drives many of these decisions (PSMA PET) is in Chapter 21, and bone-directed care in Chapter 23.
Prostate cancer is androgen-driven. Testosterone is converted to dihydrotestosterone, which binds the androgen receptor (AR) and drives proliferation. Remove the androgen and the cancer regresses — this is why castration works, and it is why it has been the backbone of treatment for 80 years. But the cancer adapts: it amplifies the AR, mutates it, produces AR splice variants that are constitutively active, and synthesizes its own androgens intratumorally. That adaptation is what we call CASTRATION RESISTANCE — and understanding it explains the entire modern drug armamentarium, which is largely about hitting the AR axis harder and from more angles.
Advanced prostate cancer is best understood as a sequence of clinical states defined by two axes: whether the cancer still responds to testosterone suppression (castration-sensitive vs. castration-resistant) and whether metastases are visible on imaging (non-metastatic vs. metastatic). Naming the state dictates the treatment menu.
State |
Definition |
Core principle |
Biochemical recurrence (BCR) |
Rising PSA after surgery or radiation, no visible metastases |
Restage (PSMA PET); consider salvage therapy vs. monitoring. PSA doubling time drives urgency |
mCSPC (metastatic castration-sensitive) |
Metastases present, still responds to ADT |
ADT + intensification — NEVER ADT alone |
nmCRPC (non-metastatic castration-resistant) |
Rising PSA on ADT with castrate testosterone, no mets on conventional imaging |
Add an ARPI if the PSA doubling time is short |
mCRPC (metastatic castration-resistant) |
Progression despite castrate testosterone |
Sequence ARPI, chemo, radioligand, PARP, immunotherapy per biomarkers |
Androgen deprivation therapy (ADT) — usually medical castration and only rarely surgical castration — underlies all advanced-disease treatment. The castrate target is a serum testosterone < 50 ng/dL (many aim for < 20). Check the testosterone, not just the PSA — a “rising PSA on ADT” in a patient whose testosterone is 90 is not castration resistance, it is inadequate castration.
Agent |
Mechanism / dosing |
Notes |
Leuprolide, goserelin, triptorelin |
LHRH AGONIST; depot injections q1–6 months |
Causes an initial testosterone FLARE (a paradoxical surge before downregulation). Cover with a short course of an antiandrogen (bicalutamide) started before or with the first dose in patients with significant metastatic burden — flare can cause cord compression, bladder-outlet obstruction, or pain |
Degarelix |
LHRH ANTAGONIST; injectable, monthly loading |
No flare; rapid castration. Useful when you need testosterone down NOW (impending cord compression) |
Relugolix (Orgovyx) |
ORAL LHRH antagonist, daily |
No flare; rapid castration and rapid recovery on stopping; a favorable cardiovascular profile in trial data. Dispensed in-house at our practice |
Bilateral orchiectomy |
Surgical castration |
Rarely used. Reserve primarily for patients who are uninsured or unlikely to remain compliant with ongoing medical ADT. Rapid, durable, and low-cost with no injections, but irreversible; for most patients it does not make sense when medical ADT is feasible |
ADT toxicity — the APP owns this — hot flashes, loss of libido and ED, fatigue, muscle loss and sarcopenia, weight gain and metabolic syndrome, insulin resistance, dyslipidemia, cardiovascular risk, anemia, gynecomastia, mood changes and depression, cognitive complaints, and accelerated bone loss. Screen and manage each of these actively. Every patient starting or receiving ADT gets a baseline DEXA and denosumab: 60 mg every 6 months when there are no bone metastases, or 120 mg every 12 weeks when bone metastases are present. Use the bone-metastasis dose instead of the ADT dose — not both. Continue bone health per Chapter 23, cardiometabolic risk in partnership with primary care, and exercise (resistance training) which is genuinely disease-modifying for these toxicities.
The single most important change in advanced prostate cancer over the last decade: metastatic castration-sensitive disease should almost NEVER be treated with ADT alone. Adding an androgen-receptor pathway inhibitor (ARPI), and in fit patients docetaxel, substantially improves survival. Yet ADT monotherapy remains common in the community — do not let that happen to our patients.
Volume matters — high-volume disease (CHAARTED criteria) means visceral metastases, or ≥ 4 bone lesions with at least one beyond the vertebral column and pelvis. High volume drives the decision to add chemotherapy.
Regimen |
What it is |
Best fit |
Doublet: ADT + ARPI |
ADT plus abiraterone, apalutamide, enzalutamide, or darolutamide |
The MINIMUM standard for essentially all mCSPC patients |
Triplet: ADT + docetaxel + ARPI |
Add 6 cycles of docetaxel; ARPI = darolutamide (ARASENS) or abiraterone (PEACE-1) |
High-volume, fit patients — Category 1 preferred for high-volume disease |
ADT alone |
Testosterone suppression only |
Rarely appropriate — only if the patient truly cannot take any intensification |
mCSPC pearls
|
Non-metastatic castration-resistant disease is a rising PSA on ADT with a castrate testosterone and no metastases on CONVENTIONAL imaging. Risk is driven by the PSA doubling time — under about 10 months is high-risk for rapid metastasis and warrants treatment.
Add a second-generation ARPI: apalutamide (SPARTAN), enzalutamide (PROSPER), or darolutamide (ARAMIS). Each improves metastasis-free AND overall survival. Darolutamide is notable for a favorable side-effect and CNS profile (it does not cross the blood-brain barrier appreciably — less fatigue, fewer falls, fewer seizures), which matters in older men.
The reality check: many patients labeled “non-metastatic” by CT and bone scan already have PSMA-avid disease. Modern imaging reclassifies a large share of them as metastatic (Chapter 21) — which changes the label, though the treatment principle (intensify) is the same.
Metastatic castration-resistant prostate cancer is where the modern toolkit is largest. CONTINUE ADT (keep testosterone castrate) throughout — never stop it — and layer therapy chosen by prior treatment, symptoms, sites of disease, and, critically, biomarkers.
Class / agent |
Notes & selection |
ARPI — abiraterone + prednisone |
A CYP17 inhibitor that blocks androgen synthesis everywhere (adrenal, tumor). REQUIRES prednisone. Monitor LFTs, potassium, and blood pressure (mineralocorticoid excess). Dispensed in-house |
ARPI — enzalutamide, apalutamide, darolutamide |
Direct AR antagonists. Fatigue, falls, hypertension; rare seizure (enzalutamide); rash (apalutamide). Darolutamide has the cleanest CNS profile |
Taxane chemotherapy — docetaxel, then cabazitaxel |
Docetaxel for symptomatic, visceral, or rapidly progressive disease, or after ARPI progression; cabazitaxel after docetaxel. Monitor for neutropenia (fever = emergency), neuropathy, fatigue, and alopecia |
PSMA radioligand therapy — Lu-177 PSMA-617 (Pluvicto) |
A targeted radioligand that delivers beta radiation directly to PSMA-expressing cells. For PSMA-POSITIVE mCRPC after an ARPI (now usable pre- OR post-taxane). REQUIRES a PSMA PET to confirm the target first. Monitor marrow (cytopenias), renal function, and dry mouth (salivary uptake) |
PARP inhibitors — olaparib, rucaparib; combinations (talazoparib + enzalutamide; niraparib + abiraterone; olaparib + abiraterone) |
Exploit synthetic lethality in HRR/BRCA-mutated disease — a defective repair pathway plus PARP inhibition is lethal to the cell. Requires genomic testing to select. Monitor cytopenias and fatigue |
Capivasertib + abiraterone |
AKT inhibitor combination for PTEN-deficient / PI3K-pathway-altered disease. Monitor hyperglycemia, diarrhea, rash |
Immunotherapy — pembrolizumab |
For MSI-high/dMMR or high tumor mutational burden tumors. Uncommon in prostate (~3–5%) but transformative when present — which is exactly why you must test. Infused in-house |
Sipuleucel-T (Provenge) |
Autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC. Improves survival WITHOUT lowering PSA — do not judge it by the PSA and do not stop it because the PSA rises |
Radium-223 |
An alpha-emitter that targets areas of high bone turnover. For bone-predominant SYMPTOMATIC disease WITHOUT visceral metastases. Prolongs survival and reduces skeletal events. Do not combine with abiraterone/prednisone up front (fracture risk) |
Germline genetic testing: for ALL metastatic patients (and high-risk/strong-family-history patients) — BRCA1/2, ATM, PALB2, CHEK2, and the mismatch-repair genes. It drives PARP-inhibitor and immunotherapy eligibility, and it triggers cascade screening that can save a patient's children and siblings. BRCA2 carriers have more aggressive disease and need earlier, more intensive treatment.
Somatic (tumor) testing: HRR alterations, MSI/dMMR, and PTEN status — to match PARP inhibitors, pembrolizumab, and capivasertib combinations. Use tissue when available; liquid biopsy (circulating tumor DNA) is a reasonable alternative when tissue is old or scarce.
The testing failure to avoid Do not wait until the patient has exhausted three lines of therapy to send genomic testing. Send it at the time of metastatic diagnosis. A BRCA2-mutant patient who never got a PARP inhibitor because nobody tested is a preventable tragedy. |
Bone health: every patient on ADT and every patient with bone metastases gets a baseline DEXA plus denosumab. Use 60 mg every 6 months for ADT without bone metastases; use 120 mg every 12 weeks for bone metastases to prevent skeletal-related events (see Chapter 23). Do not give both regimens. Before any denosumab, obtain dental clearance, check calcium and vitamin D levels, correct abnormalities, and start OTC calcium citrate + vitamin D3 gummies providing 1,200 mg calcium daily. Monitor calcium. If denosumab is stopped, transition the patient to zoledronic acid (Zometa).
ADT side-effect management: bone density, cardiometabolic risk, hot flashes (venlafaxine or gabapentin help), sexual health, mood; coordinate with primary care and cardiology. Prescribe exercise.
Watch for emergencies: SPINAL CORD COMPRESSION (back pain with any neurologic symptom — urgent MRI of the whole spine and high-dose steroids; do not wait for the morning) and obstructive uropathy from local progression or nodal disease (which can present as silent renal failure).
Track response: PSA trend plus imaging. Remember that PSA is not a perfect surrogate — some agents (sipuleucel-T) work without lowering it, and some aggressive/neuroendocrine variants progress WITHOUT a rising PSA. If the patient is clinically worse and the PSA is flat, image them.
Palliative care is not giving up: early palliative-care involvement improves both quality of life and survival in advanced cancer. Introduce it as an added layer of support, not as an endpoint.
Simplified treatment algorithm
|
A major advantage for our patients is that advanced cancer care happens under our roof. Associated Medical Professionals of New York provides the latest in cancer-care infusion therapy and in-house pharmacy dispensing, so patients start treatment faster and stay within the practice rather than being sent elsewhere.
Dispensed in-house (oral agents): Orgovyx (relugolix), Xtandi (enzalutamide), Erleada (apalutamide), Nubeqa (darolutamide), and more — our pharmacy gets patients on therapy quickly and supports adherence.
Infused in-house (immunotherapy): Keytruda (pembrolizumab), Opdivo (nivolumab), and ipilimumab (Yervoy) — delivered in our infusion suites.
Newest option: we also offer the new subcutaneous pembrolizumab (Keytruda Qlex), a faster, injection-based alternative to standard IV infusion for eligible patients.
Why in-house infusion + pharmacy matters
|
We run a lot of immunotherapy at Associated Medical Professionals of New York — Keytruda (pembrolizumab), Opdivo (nivolumab), and Yervoy (ipilimumab) — across kidney cancer, bladder cancer, and selected prostate cancer. If you are going to give these drugs, you must own their toxicity, because it is unlike chemotherapy toxicity in a way that catches people out.
Tumors survive by pressing the immune system's brakes. Checkpoint inhibitors release those brakes: PD-1 inhibitors (pembrolizumab, nivolumab) and CTLA-4 inhibitors (ipilimumab) block the receptors that would otherwise switch T-cells off. The T-cells then attack the cancer — but the SAME released brakes let T-cells attack normal tissue. That is the entire story of immune-related adverse events (irAEs): they are autoimmunity, deliberately induced. It follows that (a) an irAE can occur in ANY organ, (b) it is treated by SUPPRESSING the immune system with steroids — not with symptomatic remedies — and (c) toxicity does not track with the infusion the way chemo does; it can appear weeks to months after starting, and even AFTER the drug has been stopped.
Agent |
Target |
Common urologic use |
Pembrolizumab (Keytruda) |
PD-1 |
Bladder/urothelial cancer (including BCG-unresponsive NMIBC and advanced disease); MSI-high/dMMR tumors of any site, including prostate. Also available as subcutaneous Keytruda Qlex |
Nivolumab (Opdivo) |
PD-1 |
Advanced kidney cancer (often with ipilimumab); adjuvant and advanced urothelial cancer |
Ipilimumab (Yervoy) |
CTLA-4 |
Advanced kidney cancer, in combination with nivolumab. CTLA-4 blockade causes MORE frequent and MORE severe irAEs than PD-1 blockade — combination ipi/nivo is the highest-toxicity regimen we give |
The mental model that will serve you best: take any organ, add “-itis,” and that is a potential immune-related adverse event. Learn this table.
irAE (the “-itis”) |
How it presents |
What to do |
Colitis / enteritis |
DIARRHEA (increased stools over baseline), abdominal pain, blood or mucus in the stool. One of the MOST COMMON and most dangerous — it can progress to bowel perforation |
Do NOT just give loperamide. Grade the diarrhea, hold the drug, and start corticosteroids for anything beyond mild. Escalate early — this is the classic irAE that gets mismanaged as “gastroenteritis” |
Thyroiditis → hypo/hyperthyroidism |
Often a painless, biphasic course: a transient THYROTOXIC phase (palpitations, anxiety, weight loss) followed by permanent HYPOthyroidism (fatigue, cold intolerance, weight gain, constipation). Very common |
Monitor TSH/free T4 with every cycle. Usually does NOT require stopping the drug or steroids — just replace with levothyroxine. This is the most common irAE and the easiest to manage |
Hepatitis |
Usually ASYMPTOMATIC — detected as a rise in AST/ALT on routine labs. Occasionally jaundice or right-upper-quadrant pain |
Check LFTs before every cycle. Hold the drug and start steroids for significant transaminase elevation. Exclude viral hepatitis and biliary obstruction |
Pneumonitis |
New or worsening cough, DYSPNEA, chest tightness, hypoxia. Can be fatal |
Any new shortness of breath in a patient on immunotherapy is pneumonitis until proven otherwise. Get a CT chest, hold the drug, and start steroids. Do not write it off as deconditioning or a chest infection |
Hypophysitis (pituitary) and adrenalitis |
Vague but dangerous: profound FATIGUE, headache, nausea, anorexia, hypotension, hyponatremia. Most common with ipilimumab |
Check a morning cortisol and ACTH, plus TSH. This causes secondary ADRENAL INSUFFICIENCY, which can present as adrenal crisis and death. If you suspect it, give stress-dose steroids FIRST and ask questions after. Most need lifelong hormone replacement |
Nephritis |
Rising creatinine, usually asymptomatic |
Check renal function every cycle. Hold and give steroids; exclude other causes (dehydration, obstruction, contrast, NSAIDs) |
Dermatitis |
Rash and pruritus — the most common irAE overall and usually mild. But watch for blistering, mucosal involvement, or skin sloughing (Stevens-Johnson/TEN) |
Topical steroids and antihistamines for mild disease. Any blistering or mucosal involvement is a dermatologic emergency |
Myocarditis |
RARE but frequently FATAL — chest pain, dyspnea, palpitations, arrhythmia, heart failure, elevated troponin |
The one that kills. Any cardiac symptom in a patient on immunotherapy: check troponin and ECG immediately, stop the drug, and admit. High-dose steroids urgently |
Pancreatitis |
Abdominal pain radiating to the back; often an asymptomatic lipase/amylase rise |
Hold and evaluate; steroids for symptomatic disease. An isolated asymptomatic enzyme rise does not always require treatment |
Arthritis / myositis / neuritis |
Joint pain and swelling; muscle weakness and pain (check CK); neuropathy, and rarely myasthenia-like weakness or Guillain-Barré |
Myositis can overlap with myocarditis — if CK is up, check troponin too. Neurologic irAEs need urgent evaluation |
Uveitis / episcleritis |
Eye pain, redness, blurred vision, photophobia |
Urgent ophthalmology referral; topical or systemic steroids |
SUSPECT IT. Any new symptom in a patient on a checkpoint inhibitor is an irAE until proven otherwise. This is the single most important habit. Do not attribute new fatigue, diarrhea, or breathlessness to “the cancer” or “a bug.”
GRADE IT. Severity (CTCAE grade 1–4) drives everything: grade 1 usually continue with close monitoring; grade 2 hold the drug and start steroids (e.g., prednisone 0.5–1 mg/kg/day); grade 3–4 hold or permanently discontinue, give high-dose steroids (1–2 mg/kg/day), and admit.
STEROIDS ARE THE TREATMENT. Corticosteroids, promptly and at an adequate dose, then a SLOW taper over at least 4–6 weeks — tapering too fast is a common cause of rebound. For steroid-refractory disease, escalate to infliximab (colitis), mycophenolate (hepatitis), or other immunosuppressants — with oncology.
ENDOCRINE irAEs ARE THE EXCEPTION. Thyroiditis, hypophysitis, and adrenalitis are usually managed by REPLACING the hormone (levothyroxine, hydrocortisone), not by suppressing the immune system — and the patient can often continue the drug.
MONITOR PROACTIVELY. Baseline and pre-cycle labs: CBC, CMP (LFTs and creatinine), TSH/free T4, and glucose. Add troponin/ECG and cortisol when clinically indicated.
DO NOT RESTART without discussion. Rechallenge after a serious irAE is a physician-level decision, and after a grade 3–4 event (especially myocarditis or pneumonitis) it is usually permanent discontinuation.
Immunotherapy — the rules that save lives
|
Advanced prostate cancer is best understood as a sequence of clinical states — biochemical recurrence, mCSPC, nmCRPC, and mCRPC. Naming the state dictates the treatment menu. Localized disease is Chapter 8, PSMA PET is Chapter 21, and bone-directed care is Chapter 23. The field moves quickly — treat this as a framework and confirm regimens against the current NCCN guideline and your treating oncologist or urologic oncologist.
Castration underlies everything else — and the toxicity that comes with it is APP-owned work.
Select a box to open its teaching details.
Prostate cancer is androgen-driven; remove the androgen and it regresses. Castration resistance is the cancer adapting — amplifying and mutating the AR, producing constitutively active splice variants, and synthesizing its own androgens intratumorally.
Choose the castration agent
Early palliative-care involvement improves both quality of life and survival in advanced cancer.
The first of the chapter's four disease states: rising PSA after definitive local therapy with no visible metastases.
Select a box to open its teaching details.
Per the chapter's disease-state table: rising PSA after surgery or radiation, with no visible metastases.
Per the chapter: PSA doubling time drives urgency. A slowly rising PSA and a rapidly rising PSA are different clinical problems even at the same absolute value.
Salvage therapy vs. monitoring
Metastatic castration-sensitive disease should almost never be treated with ADT alone.
Select a box to open its teaching details.
The single most important change in advanced prostate cancer over the last decade: adding an ARPI, and in fit patients docetaxel, substantially improves survival.
High volume drives the decision to add chemotherapy.
Choose the regimen
See the biomarker track (Section 20.7).
Rising PSA on ADT with castrate testosterone and no metastases on conventional imaging.
Select a box to open its teaching details.
Add a second-generation ARPI
Many patients labeled non-metastatic by CT and bone scan already have PSMA-avid disease. Modern imaging reclassifies a large share of them as metastatic (Chapter 21).
Progression despite castrate testosterone. Continue ADT and layer therapy chosen by prior treatment, symptoms, sites of disease, and biomarkers.
Select a box to open its teaching details.
The backbone sequence: ARPI, then taxane
Biomarker- and target-selected options
Synthetic lethality — a defective repair pathway plus PARP inhibition is lethal to the cell.
Immunotherapy and bone-directed options
Uncommon in prostate — roughly 3–5% — but transformative when present, which is exactly why you must test.
Do it early, do it on everyone — at the time of metastatic diagnosis, not at the third line.
Select a box to open its teaching details.
Germline testing triggers cascade screening that can save a patient's children and siblings — this is part of the value of testing, not an afterthought.
Advanced cancer care happens under our roof — which means the APP owns immune-related adverse events.
Select a box to open its teaching details.
The dangerous three — recognize by symptom
The quieter ones — found on labs or exam