What it is:Adenocarcinoma of the prostate (over 95% of cases are this histology), almost always diagnosed off an elevated PSA and confirmed by biopsy. Most cases are slow-growing and picked up while still confined to the gland, but a subset behaves aggressively and spreads to bone early.
The core problem:Prostate epithelium, normal or malignant, depends on androgen receptor (AR) signaling to grow. Dihydrotestosterone (DHT), not testosterone itself, is the ligand that actually drives the receptor in prostate tissue. Nearly every drug class in this chapter exists to interrupt that one axis somewhere along its length, from the hypothalamus down to the receptor itself.
What you do about it:Risk-stratify using Gleason grade, PSA, and clinical stage, then match intensity of therapy to that risk and the patient's life expectancy. Low-risk, long life expectancy patients are watched, not treated. Anything advanced or metastatic gets androgen deprivation therapy (ADT) as the backbone, with additional agents layered on as the disease becomes castration-resistant.
Organize the whole drug list by where on the hormonal axis each drug acts: hypothalamus/pituitary (LHRH agonists, GnRH antagonists), gonadal/adrenal synthesis (orchiectomy, abiraterone), or the androgen receptor itself (first- and second-generation antiandrogens). If you can place a drug on that axis, you already know its role, its main side effect pattern, and roughly where it fits in the treatment sequence.
Three numbers drive every treatment decision in this chapter: Gleason grade, PSA, and clinical stage (T-category). None of them alone tells you what to do; the combination does.
A pathologist scores the two most common architectural patterns seen on biopsy, each from 3 (well-differentiated) to 5 (poorly differentiated), and adds them for a Gleason score of 6-10. Because a "6" sounds reassuringly average to patients when it's actually the lowest possible score reported, modern reporting converts the sum into Grade Groups 1-5(Group 1 = Gleason 6, Group 5 = Gleason 9-10). Higher grade group means faster growth, more aggressive spread, and worse prognosis.
| Stage | What it means in practice |
|---|---|
| T1c | Not felt on exam at all. Found only because a PSA was elevated and a biopsy was done. |
| T2a-T2c | Palpable on digital rectal exam, but still confined inside the prostate capsule. |
| T3a-T3b | Has broken through the capsule and/or invaded the seminal vesicles. |
| T4 | Invading structures next to the prostate (bladder neck, rectum, pelvic wall). |
| N1 / M1 | Regional lymph nodes involved (N1) or distant spread present (M1), most often bone. |
| Risk group | Defining features (roughly) |
|---|---|
| Very low | T1c, Grade Group 1, PSA <10, <3 positive cores each ≤50% cancer, PSA density <0.15 |
| Low | T1-T2a, Grade Group 1, PSA <10, doesn't meet very-low criteria |
| Intermediate, favorable | Only 1 intermediate risk factor (T2b-T2c, Grade Group 2-3, or PSA 10-20), Grade Group 1-2, <50% cores positive |
| Intermediate, unfavorable | 2-3 intermediate risk factors, or Grade Group 3, or ≥50% cores positive |
| High | Exactly one of: T3a, Grade Group 4-5, or PSA >20 |
| Very high | T3b-T4, primary Gleason pattern 5, 2-3 high-risk features, or ≥4 cores Grade Group 4-5 |
| Locally advanced / metastatic | Any N1, or any M1 |
Gleason/Grade Group tells you how aggressive the cells look. T-stage tells you how far the tumor has physically spread. PSA is a blood marker that roughly tracks tumor burden but isn't diagnostic by itself.A patient can have a low Gleason score with a high PSA, or vice versa. Risk stratification requires all three together, not any single number.
Finasteride and dutasteride are not approved or recommended to prevent prostate cancer, despite trial data being studied for over a decade. The concern is that suppressing 5-alpha-reductase may select for more aggressive tumors without a clear survival benefit, on top of the drugs' own adverse effect burden. Don't confuse their well-established role in BPH with a cancer-prevention indication they don't have.
Nearly the entire pharmacologic arsenal in prostate cancer makes sense once you trace this pathway from the brain to the receptor.
The hypothalamus releases LHRH (also called GnRH)in pulses. That pulsatile signal tells the anterior pituitary to secrete LH and FSH. LH acts on Leydig cells in the testes to make testosterone(plus a small amount of estrogen); FSH acts on Sertoli cells to mature LH receptors. Circulating testosterone and estradiol then feed back negatively on the hypothalamus and pituitary to throttle further LHRH/LH/FSH release. The testes and adrenal glands are the two sources of circulating androgens, which is exactly why some drugs target the adrenal gland too, not just the testes.
Inside the prostate cell, testosterone is converted by 5-alpha-reductaseinto DHT, a much more potent ligand for the androgen receptor. DHT-AR binding drives transcription of genes that promote both normal prostatic growth and, when the cell has become malignant, tumor growth. This is true whether the "prostate problem" is BPH or cancer; the difference is which cells are proliferating, not the signaling pathway.
Map the drug classes onto this pathway and the whole chapter becomes logical instead of a memorization exercise. LHRH agonists and GnRH antagonistsact at the hypothalamic-pituitary level to shut down LH/testosterone production. Orchiectomyremoves the testicular source directly. Abirateroneblocks CYP17A1, an enzyme both the testes and the adrenal glands need to make androgens, so it hits both sources at once. Antiandrogens(first- and second-generation) don't touch hormone levels at all; they block DHT from binding the androgen receptor itself, which is why they're used on top of, not instead of, castration in most regimens.
GnRH/LHRH only suppresses the axis when it's delivered continuously and non-pulsatile, which is the opposite of how the body normally releases it. When an LHRH agonist is first given, it initially stimulatesthe receptor just like endogenous pulsatile LHRH would, causing a transient surgein LH, FSH, and testosterone before the receptors downregulate and internalize. Only after about a week of continuous exposure does testosterone fall, reaching castrate levels by 3-4 weeks. That early surge is the mechanistic reason for "tumor flare." GnRH antagonists skip this problem entirely because they block the receptor from the start rather than stimulating it first, so testosterone falls to castrate levels within about 7 days with no surge.
Local extension, lymphatic drainage, and hematogenous spread are all possible, but skeletal metastases from hematogenous spread are by far the most common site of distant disease.Visceral involvement (lung, liver, brain, adrenal glands) happens too, but usually later in the disease course, not at initial presentation.
| Stage | Typical findings |
|---|---|
| Localized | Usually completely asymptomatic. This is why almost all early diagnoses start with an incidental or screening PSA, not a complaint. |
| Locally invasive | Urinary frequency, hesitancy, dribbling (from ureteral/bladder neck impingement) and impotence. |
| Advanced / metastatic | Back pain and stiffness from osseous metastases, lower extremity edema from lymphatic obstruction, anemia, and unintentional weight loss. |
New back pain in a man with known or suspected prostate cancer is osseous metastasis until proven otherwise. Untreated spinal metastases can progress to cord compression, a true oncologic emergency (see Complications below).
Routine DRE and PSA screening in asymptomatic men is no longer a blanket recommendation; it now requires an informed discussion of risks and benefits. The American Urological Association does notrecommend routine screening for average-risk men age 40-54. For men 55-69, the risks and benefits should be discussed individually. If a patient elects screening, it should be done no more than every 2 years, and every 5 years may be adequatefor men who remain low risk.
PSA is a glycoprotein made by prostate epithelial cells, benign or malignant. A single elevated value does not diagnose cancer, it usually prompts a confirmatory repeat before biopsy is pursued. Values above roughly 4 ng/mL, or above 3 ng/mL in men who carry other risk factors for prostate cancer, generally prompt further workup, alongside an abnormal DRE finding (palpable nodule or induration) or a personal history that raises suspicion.
| Non-cancer causes of an elevated PSA |
|---|
| Acute urinary retention |
| Acute prostatitis |
| Prostatic ischemia or infarction |
| Benign prostatic hyperplasia (BPH) |
| Recent prostate biopsy or surgery |
Its weakness is specificity for diagnosis(too many benign things raise it), but its strength is trending response to therapy. Once a diagnosis is made and treatment started, serial PSA is one of the best tools you have to confirm the tumor is responding, and a rising PSA on therapy is usually the first sign of progression, often before imaging or symptoms change.
Biopsy with histologic grading (Gleason/Grade Group) confirms the diagnosis and establishes aggressiveness. Together with clinical stage and PSA, this is what places the patient into a recurrence-risk group and determines initial therapy.
Goals of treatment depend entirely on stage.In early-stage disease, the goal is to minimize morbidity and mortality, and cure is realistic. In advanced disease, treatment is no longer curative, so the goal shifts to symptom relief and preserving quality of life.
Initial treatment selection depends on disease stage, Gleason grade, presence of symptoms, and the patient's life expectancy. A very-low-risk tumor in a man with a 6-year life expectancy and a very-low-risk tumor in a man with a 25-year life expectancy get completely different initial plans, even with identical pathology.
| Option | When it's used |
|---|---|
| Observation | Shorter life expectancy plus lower-risk disease. Monitor with labs/imaging, treat palliatively only if progression occurs. No curative intent. |
| Active surveillance | Longer life expectancy, very-low to favorable-intermediate risk. Closer monitoring than observation, curative therapy still on the table if the disease reclassifies as higher risk. |
| Radical prostatectomy | Potentially curative. Complications: blood loss, stricture, incontinence, lymphocele, fistula, anesthetic risk, and impotence (nerve-sparing technique can preserve potency). |
| Radiation therapy | Potentially curative, external beam or brachytherapy. Acute: cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, impotence. Chronic: proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, incontinence. |
| Bilateral orchiectomy | Surgical castration; rapidly drops androgens to castrate levels. Many patients decline for psychological reasons or aren't surgical candidates, but it's the preferred initial treatment when spinal cord compression or ureteral obstruction is impending, because it works faster than a medication trial. |
Because radical prostatectomy and radiation carry real morbidity, many patients with lower-risk disease reasonably choose to delay definitive therapy until symptoms actually develop, which is the whole rationale behind observation and active surveillance.
Whenever a patient needs systemic hormonal therapy, there are three equally effective ways to get testosterone to castrate levels (defined as <50 ng/dL, 1.7 nmol/L). The choice usually comes down to cost, dosing schedule, and whether avoiding tumor flare matters for that patient.
Bilateral orchiectomy. Fastest onset, one-time procedure, no adherence issue, but irreversible and often psychologically unacceptable.
Reversible, as effective as orchiectomy. Causes an initial testosterone surgebefore suppression.
Blocks the receptor immediately, no surge, no flare-cover needed.
LHRH/GnRH agonists (leuprolide, goserelin, triptorelin) initially stimulate the receptor before downregulating it, causing a transient LH/FSH/testosterone surge in the first 1-2 weeks.In a patient with bulky metastatic disease, especially bone metastases or urinary obstruction, that surge can transiently worsen bone pain or urinary symptoms, a "flare." GnRH antagonists (degarelix, relugolix) block the receptor from the first dose with no agonist activity, so there is no surge and no flare, which is their single biggest practical advantage.
Give an antiandrogen (flutamide, bicalutamide, or nilutamide) starting a few days before the first LHRH agonist dose and continuing for 2-4 weeks, to block the receptor while testosterone is transiently surging. This matters most in patients with bulky or symptomatic metastatic disease where a flare could cause real harm (worsening cord compression risk, severe bone pain, acute urinary retention); it's less critical in men with minimal disease burden.
Castrate testosterone levels accelerate bone loss, raising the risk of osteoporosis, osteopenia, and fracture. Get a baseline bone mineral density, ensure adequate calcium and vitamin D, and start an antiresorptive agent (alendronate, denosumab, or zoledronic acid) to reduce skeletal-related events in patients at elevated fracture risk. ADT also carries increased cardiometabolic risk, so screen for cardiovascular disease and diabetes at baseline and periodically during therapy.
| Drug | Usual dose | Key admin/monitoring note |
|---|---|---|
| First-generation antiandrogens (add-on only, not monotherapy) | ||
| Bicalutamide | 50 mg/day PO (up to 150 mg/day unlabeled) | Discontinue if ALT >2x ULN or jaundice; LFTs baseline then monthly x4 months |
| Flutamide | 250 mg PO TID (750 mg/day) | Contraindicated in hepatic impairment; capsule may be opened into soft food |
| Nilutamide | 300 mg/day PO x1 month, then 150 mg/day | Contraindicated in hepatic impairment; baseline chest x-ray, consider PFTs |
| Second-generation antiandrogens | ||
| Apalutamide | 240 mg/day PO | No renal/hepatic adjustment; TSH at baseline and q4 months |
| Enzalutamide | 160 mg/day PO | No renal/hepatic adjustment; CBC and LFTs baseline then periodically |
| Darolutamide | 600 mg PO BID (1200 mg/day) | Take with food.Reduce to 600 mg/day for moderate hepatic or severe renal impairment |
| Androgen synthesis inhibitor | ||
| Abiraterone acetate | 1000 mg/day PO + prednisone 5 mg daily (castration-naive) or 5 mg BID (CRPC) | Empty stomach, 1 h before/2 h after food. LFTs baseline, q2wk x3mo, then monthly |
| Micronized abiraterone | 500 mg/day PO + methylprednisolone 4 mg BID (CRPC) | Can be taken regardless of food |
| LHRH/GnRH agonists | ||
| Leuprolide | 7.5 mg IM monthly / 22.5 mg q3mo / 30 mg q4mo / 45 mg q6mo | Vary injection site; testosterone ~4 weeks after start |
| Goserelin | 3.6 mg SQ implant monthly / 10.8 mg SQ implant q3mo | Monitor BMD, calcium, lipids |
| Triptorelin | 3.75 mg IM monthly / 11.25 mg q3mo / 22.5 mg q6mo | Monitor testosterone and PSA periodically |
| GnRH/LHRH receptor antagonists | ||
| Degarelix | 240 mg SQ loading dose, then 80 mg SQ q28 days | Caution CrCl <50; avoid in severe hepatic impairment |
| Relugolix | 360 mg PO x1, then 120 mg PO daily | Oral, adherence is critical; watch CYP3A4/P-gp and QTc-prolonging interactions |
| Drug | Usual dose | Key monitoring / note |
|---|---|---|
| Chemotherapy | ||
| Docetaxel | 75 mg/m² IV q3wk + prednisone 5 mg BID | CBC diff, LFTs, hypersensitivity monitoring; 3-day steroid premed |
| Cabazitaxel | 25 mg/m² IV q3wk + prednisone 10 mg daily | CBC weekly cycle 1, then pretreatment; watch neutropenia/febrile neutropenia |
| Immunotherapy | ||
| Sipuleucel-T | 3 IV infusions, 2 weeks apart, autologous cellular product | Premedicate with acetaminophen + antihistamine; observe 30 min post-infusion |
| Pembrolizumab | 200 mg IV q3wk or 400 mg IV q6wk | Reserved for MSI-H/dMMR tumors (~5-12% of metastatic CRPC); watch immune-mediated toxicity |
| Targeted (PARP inhibitors) | ||
| Olaparib | 300 mg PO BID | Requires BRCA1/2 or other HRR gene alteration; CBC baseline and monthly |
| Rucaparib | 600 mg PO BID | Same genetic prerequisite as olaparib; CBC baseline and monthly |
| Nuclear medicine | ||
| Radium-223 | 50 kBq/kg slow IV, q4wk x6 doses | Alpha emitter for symptomatic bone mets; CBC before every injection |
Both classes reliably drop testosterone to castrate levels and are considered equally effective; there are no head-to-head trials proving superiority of one over the other, so the choice usually comes down to cost, dosing interval preference, and whether flare avoidance matters for that particular patient.
LHRH agonists(leuprolide, goserelin, triptorelin) are older, generally cheaper, and available in dosing intervals from monthly out to every 6 months, which many patients prefer. Their tradeoff is the initial surge and need for flare coverage with an antiandrogen.
GnRH antagonists(degarelix, relugolix) suppress testosterone faster (within about 7 days) with no surge, so no flare-covering antiandrogen is needed. Degarelix is a subcutaneous injection every 28 days; relugolix is a once-daily oral tablet, which shifts the adherence burden onto the patient in a way injections don't. Relugolix notably does not carry the increased cardiovascular risk signal seen with other LHRH agonists/antagonists, but it does interact with CYP3A4 inhibitors, P-glycoprotein inhibitors, and other QT-prolonging drugs.
Common adverse effects across both classes: hot flashes, decreased libido, erectile dysfunction, and injection-site reactions (for the injectables). These are direct, predictable consequences of castrate testosterone, not idiosyncratic reactions, and patients should be told to expect them before starting.
First-generation antiandrogens(flutamide, bicalutamide, nilutamide) are never used as monotherapyin advanced disease; they're consistently less effective than LHRH agonist monotherapy when compared alone. Their role is strictly as an add-on: bicalutamide or flutamide with an LHRH agonist, or nilutamide with orchiectomy, mainly to blunt the flare and modestly add to castration's effect. Adverse effects include gynecomastia, hot flashes, GI upset, decreased libido, breast tenderness, and LFT abnormalities, all of which need baseline and monthly-for-4-months transaminase monitoring.
Second-generation antiandrogens(apalutamide, enzalutamide, darolutamide) bind the androgen receptor with much higher affinity and, unlike the first-generation drugs, also block AR nuclear translocation. They're used specifically in castration-resistant disease and in metastatic castration-naive disease as an add-on to ADT, not first-generation-style adjuncts. Apalutamide is approved for nonmetastatic CRPC and metastatic castration-naive disease. Enzalutamide has the broadest label: nonmetastatic CRPC, metastatic castration-naive, and metastatic CRPC, letting clinicians use it to delay starting chemotherapy. Darolutamide is approved specifically for nonmetastatic CRPC. Adverse effects to know: fatigue, GI disturbances, musculoskeletal complaints, and (notably) seizures, so use caution with a seizure history or other drugs that lower seizure threshold.
Don't confuse the mechanism: antiandrogens block the receptor(no effect on testosterone level), while LHRH agonists/GnRH antagonists lower the testosterone level itself. A patient can have castrate testosterone and still progress if the receptor pathway reactivates, which is exactly the scenario second-generation antiandrogens are built to address.
Abiraterone inhibits CYP17A1, an enzyme required for androgen synthesis in the testes, adrenal glands, andwithin the tumor itself. Because it hits adrenal synthesis too, it lowers androgen exposure further than castration of the testes alone can achieve, which is why it's added on top of ADT rather than used by itself.
Blocking CYP17A1 also shunts the adrenal steroid pathway toward excess mineralocorticoid production, causing hypertension, hypokalemia, and fluid retentionfrom abiraterone-induced hypoadrenalism. Co-administering low-dose prednisonereplaces the glucocorticoid the pathway can no longer make and largely prevents this. Withhold abiraterone if LFTs rise above 5x ULN or bilirubin above 3x ULN, and dose-reduce in Child-Pugh B hepatic impairment (avoid entirely in Child-Pugh C).
It's indicated in both metastatic castration-naive disease and metastatic CRPC. Abiraterone is also a CYP2D6 inhibitor, so always screen the med list for interacting drugs metabolized through that pathway.
Docetaxelplus prednisone was the first regimen shown to improve survival in CRPC, and it's still used in first-line CRPC or added earlier in high-risk metastatic castration-naive disease alongside ADT. Watch for nausea, alopecia, and myelosuppression.
Cabazitaxelplus prednisone is reserved for patients who've already progressed on docetaxel; it significantly improves progression-free and overall survival in that specific post-docetaxel setting. Its signature toxicities are neutropenia (including febrile neutropenia), neuropathy, and diarrhea.
Sipuleucel-Tis an autologous cellular immunotherapy (the patient's own leukapheresed cells are activated against a prostate tumor antigen and reinfused) for asymptomatic or minimally symptomatic metastatic CRPC. It hasn't been compared head-to-head with secondary hormonal therapies, so it's more of an option than a clearly sequenced step. Expect hypersensitivity reactions, chills, fatigue, and fever with the infusions.
Pembrolizumabonly has a role in the roughly 5-12% of metastatic CRPC patients whose tumor is MSI-H or dMMR on molecular testing. This is a testing-gated indication, not a general CRPC option.
Olaparib and rucaparib(PARP inhibitors) require a specific homologous-recombination-repair gene alteration, most notably BRCA1/BRCA2, somatic or germline, found on genetic testing. This is exactly why genetic testing is recommended for all metastatic CRPC patients, to identify who is even eligible for this class. Common toxicities: fatigue/asthenia, nausea, anemia, decreased appetite.
Up to 80% of men with advanced prostate cancer respond to initial hormonal therapy, but progression is typically seen within 2-4 years. Combined androgen blockade (CAB), pairing an antiandrogen with an LHRH agonist to attack the pathway at two points, was proposed to delay that progression. The antiandrogen should precede or start alongside the LHRH agonist. In practice, any survival advantage of long-term CAB over castration alone has been small.
CRPC is disease progression despite castrate testosterone levels, essentially the tumor has found a way to keep signaling through the androgen receptor pathway even without normal androgen levels (receptor mutation, amplification, or intratumoral androgen synthesis, among other mechanisms). Once a patient reaches metastatic CRPC, care should include best supportive care in addition tofurther systemic therapy, and genetic testing is recommendedto identify candidates for PARP inhibitors or pembrolizumab.
| Extent | Typical initial therapy |
|---|---|
| Any T, N1 (regional nodes only) | ADT +/- abiraterone and prednisone, or radiation + ADT +/- abiraterone and prednisone |
| Any T, any N, M1 (distant metastasis) | ADT plus one of: apalutamide, abiraterone + prednisone, docetaxel, or enzalutamide |
Radium-223 is an alpha-emitter that's chemically similar to calcium, so it's taken up preferentially at sites of bone turnover, i.e., bone metastases. It's used for metastatic CRPC with symptomaticbone metastases, in first-, second-, or third-line settings. It improves survival, pain-related outcomes, and quality of life, and reduces opioid need. It has notbeen approved for concurrent use with abiraterone, second-generation antiandrogens, chemotherapy, immunotherapy, or targeted therapy, an important sequencing/combination trap. Watch for nausea, diarrhea, vomiting, peripheral edema, and bone marrow suppression.
New back pain plus any neuro red flag (leg weakness, saddle numbness, bowel/bladder changes) in a man with known or suspected prostate cancer needs urgent imaging. Orchiectomy is preferred over an LHRH agonist here specifically because it lowers testosterone immediately, without the surge risk that could worsen cord compression while an antiandrogen cover is being arranged.
Starting an LHRH agonist without antiandrogen coverage in a patient with bulky metastatic or symptomatic disease risks a transient worsening of bone pain, urinary retention, or (rarely) cord compression during the first 1-2 weeks. This is preventable and predictable, always plan flare coverage before the first dose in these patients.
Hypertension, hypokalemia, and fluid retention from mineralocorticoid excess. Prednisone co-administration is not optional supportive care, it's part of how the regimen is designed to be tolerated. Monitor BP, potassium, and fluid status monthly.
Every patient on long-term ADT is functionally in a hypogonadal, high-fracture-risk state. Baseline DXA scan, calcium/vitamin D supplementation, and an antiresorptive agent (denosumab, zoledronic acid, or alendronate) for those at elevated fracture risk should be considered standard, not optional, parts of the ADT care plan.
| Parameter | When | Watching for |
|---|---|---|
| PSA | q6-12 months for the first 5 years after definitive therapy, then annually; more frequently while on active systemic therapy | Response to therapy or early biochemical recurrence, often the first sign of progression |
| Serum testosterone | ~4 weeks after starting ADT, then periodically | Confirm castrate level <50 ng/dL (1.7 nmol/L) |
| LFTs | Baseline, then per-drug schedule (monthly x4mo for first-gen antiandrogens; q2wk x3mo then monthly for abiraterone) | Hepatotoxicity, especially with antiandrogens and abiraterone |
| Blood pressure, potassium, fluid status | Monthly on abiraterone | Mineralocorticoid excess from CYP17A1 inhibition |
| Bone mineral density | Baseline, then periodically on long-term ADT | Osteoporosis/fracture risk from castrate testosterone |
| CBC | Baseline and per-cycle/monthly on chemo, PARP inhibitors, or radium-223 | Myelosuppression, neutropenia, anemia |
| Blood glucose / HbA1c, lipids | Baseline and periodically on ADT | Cardiometabolic risk from androgen deprivation |
| TSH | Baseline and q4 months on apalutamide | Thyroid dysfunction |
| Medication adherence | Every visit for oral agents (relugolix, enzalutamide, apalutamide, darolutamide, abiraterone) | Missed doses undo hormone suppression fast, unlike a missed depot injection |