Prostate Cancer

Epidemiology and Pathogenesis

Prostate cancer is the most common male malignancy in North America but follows an indolent course in most men — only ~16% of those diagnosed ultimately die of it, and the most common cause of death in men with prostate cancer is cardiac disease. Its incidence has been driven heavily by PSA screening, and a substantial minority of cases are hereditary.

Epidemiology

Incidence:

• Worldwide — the 2nd most common visceral malignancy in men; highest in countries with the most screening (estimated 1,414,259 cases in 2020).
• US — the most common male malignancy (lung/bronchus second); estimated 299,010 in 2024 (288,300 in 2023; 268,490 in 2022). About 1 in 8 males is diagnosed in his lifetime. (A projected 2040 incidence of 66,000 is cited in the source — see Corrections; this appears inconsistent with the rising trend.)
• Canada — the most common male malignancy, followed by lung/bronchus (13.2%) and colorectal (12.9%); estimated 23,300 in 2020. (In Canadian females the most common cancers are breast 25%, lung 13.5%, colorectal 10.9%.)

Trends: PSA was discovered in 1979 and FDA-licensed as a test in 1986; incidence then rose sharply, peaking in 1992 (~5 years after PSA), declined until 1995 (screen-detection depleting the source population), then rose again at a pre-PSA rate, fluctuating since 2001 until the 2011 draft USPSTF recommendation against PSA screening (grade D). Median age at diagnosis is 67; men <50 account for 2% of cases.

Mortality (US): estimated 34,700 in 2023 — the 2nd most common cause of cancer death (lung first); cause of death in ~3% of men. Mortality has been decreasing since 2001; the average age at death is 77, and mortality in African-Americans is ~2.4× that of Caucasians.

Stage at diagnosis (SEER): ~80% localized, ~12% regional, ~5% metastatic.

Pathogenesis and Risk Factors

Inherited (germline): the frequency of germline DNA-repair-gene mutations rises with disease burden — metastatic 12%, localized 5%, general population 2.7%. True hereditary disease is defined as >3 cases in one family, prostate cancer in 3 successive generations, or >2 men diagnosed <55 years; it has earlier onset (by 6–7 years) but is not more aggressive.

• BRCA1/BRCA2 — a 2–6× lifetime risk, with higher-grade, locally advanced, and metastatic disease and worse cancer-specific and metastasis-free survival after prostatectomy; BRCA2 is more strongly associated than BRCA1; systematic PSA screening is indicated. Part of hereditary breast and ovarian cancer (HBOC) syndrome — associated cancers: breast (male and female), ovarian, prostate, pancreatic, melanoma.
• Lynch syndrome (HNPCC) — from mismatch-repair gene mutations (MLH1, MSH2, MSH6, PMS2, EPCAM); associated cancers: colorectal, gastric, ovarian, small bowel, urologic (upper-tract urothelial, bladder, prostate), biliary tract, pancreatic, brain (glioblastoma), sebaceous adenomas, keratoacanthomas.
• Other mutations (require further study): ATM, MLH1, MSH2, MSH6, PMS2, HOXB13, NBS1, CHEK2.

Family history — ~15% of patients have the familial/hereditary form (defined as >2 first- or second-degree relatives on the same side). Relative risk by affected relative:

Affected relative	Relative risk
Father	2.2×
Brother	3.4×
First-degree relative, age <65 at diagnosis	3.3×
>2 first-degree relatives	5.1×
Second-degree relative	1.7×

A "strong" family history = ≥1 brother/father or ≥2 male relatives diagnosed <60, who died of prostate cancer, or who had metastatic disease; or ≥2 HBOC/Lynch-spectrum cancers in the family. Patients with a strong family history should ideally be genotyped (BRCA1/2, Lynch, ATM, CHEK2, and other DNA-repair mutations).

Ethnicity: incidence is Blacks > Whites > Hispanics > Asian-Americans (Blacks ~1.7× Whites and ~2× Hispanics); Asian-Americans have higher risk than Asians in Asia, suggesting dietary/lifestyle/environmental factors.

Age (autopsy prevalence): <30 years 5%; 70–79 years 36% (Caucasians) and 51% (African-Americans); >79 years 59%.

External factors: inflammation (triggered by dietary carcinogens from cooked meats, estrogens, and infections — STI/prostatitis data are mixed); polymorphisms in the androgen receptor, 5-alpha reductase type 2, and testosterone-biosynthesis genes; the insulin-like growth factor axis; low-activity vitamin-D-receptor polymorphisms; and smoking (worse biochemical recurrence, metastasis, and cancer-specific mortality). Alcohol data are mixed.

Molecular Genetics

Known susceptibility genes control the inflammatory response, homeobox functions, DNA repair, and infection susceptibility. The most common gene fusion in localized disease is TMPRSS2:ERG (~50% of cancers) — TMPRSS2 is prostate-specific, androgen-induced, and present in prostate stem cells (it may also fuse to SLC45A3, HERPUD1, or NDRG promoters). The most common point mutation is in SPOP (a ubiquitin-ligase subunit). Prostate cancer is largely polygenic (GWAS has identified >70 risk alleles), with epigenetic mechanisms including chromatin remodeling, promoter hyper-/hypomethylation, histone modification, microRNAs, and long non-coding RNAs.

Prevention

No agent is recommended for prostate-cancer chemoprevention. The 5-alpha reductase inhibitors reduce overall cancer detection but raise concern about high-grade disease, and antioxidant supplements have shown no benefit (vitamin E may be harmful).

5-Alpha Reductase Inhibitors

Randomized trials (PCPT and REDUCE) showed 5-ARIs give a ~5% reduced risk of cancer detection but a slight increase in high-grade cancer — thought to reflect easier detection of a high-grade focus in a drug-shrunken gland. The FDA concluded 5-ARIs do not have a favourable risk-benefit profile for chemoprevention (for every 150–200 men treated, 1 additional high-grade cancer would be diagnosed to avert 3–4 low-grade cancers).

• PCPT (Thompson 2003) — n=18,882, age ≥55, normal DRE, PSA ≤3.0; finasteride 5 mg vs placebo, with end-of-study (7-year) or for-cause biopsy. Finasteride gave a 6% absolute risk reduction in incident cancer (18.4% vs 24.4%) but a 15% absolute increase in biopsy Gleason 7–10 among those biopsied (37% vs 22%). Long-term follow-up showed no effect on cancer-specific survival (Goodman 2019).
• REDUCE (Andriole 2010) — n=8,231, age 50–75, negative prior biopsy, PSA 2.5–10, prostate ≤80 cc; dutasteride vs placebo with mandated biopsies at 2 and 4 years. Dutasteride gave a 5% absolute risk reduction (19.9% vs 25.1%); no overall difference in Gleason 7–10, but an increased risk of Gleason 8–10 in years 3–4.

Selenium and Vitamin E (SELECT, Lippman 2009)

n=35,533 with normal DRE, PSA ≤4, and normal blood pressure, randomized to selenium, vitamin E, both, or placebo. The trial was stopped early for no effect; follow-up showed dietary vitamin E supplementation increased prostate-cancer risk.

Lycopene and Others

• Lycopene — a carotenoid in tomatoes; an animal model showed a protective effect for calorie restriction and tomato powder but not pure lycopene, and a meta-analysis of 3 RCTs found no association with prostate-cancer risk.
• HGPIN trials: selenium + vitamin E + soy did not reduce risk; green tea catechin reduced risk (n=60); toremifene did not reduce risk at 3 years (n=1,467).

Diagnosis, Staging and Evaluation

Working up prostate cancer runs in sequence: screen asymptomatic men, pursue diagnosis with PSA and imaging, confirm with biopsy, then grade and stage the tumour and evaluate for inherited risk. The sections below follow that order.

Screening

Screening tests asymptomatic men to detect prostate cancer earlier; three landmark randomized trials (ERSPC and Göteborg positive, PLCO negative) and successive guideline revisions define when and how to screen. The primary outcome in every screening trial is cancer-specific mortality.

Evidence — Key Trials

Of seven randomized trials, the three most informative (per CUA/AUA) are PLCO (no net benefit), ERSPC (net benefit), and Göteborg (net benefit).

• PLCO (Andriole 2009; Pinsky 2019) — n=76,685 US men aged 55–74; annual PSA ×6 + DRE ×4 vs usual care (biopsy if PSA >4 or suspicious DRE). No difference in cancer-specific mortality (RR 0.93) and slightly increased incidence (RR 1.05). Heavily criticized for high contamination (~77%), extensive pre-screening, poor biopsy adherence, and being underpowered.
• ERSPC (Schröder 2009; Hugosson 2019) — n=162,243 men aged 55–69 across 8 countries; PSA every 4 years vs usual care. Cancer-specific mortality RR 0.80; number needed to invite (NNI) 570, number needed to diagnose (NND) 18 (in those actually screened, ~37% reduction, number needed to screen ~98, NND ~5); incidence RR 1.41; contamination ~20–25%. A subgroup of men who discontinued screening at 70–74 (de Vos 2024) had a cumulative cancer-specific mortality by age 85 of only 0.54%.
• Göteborg (Hugosson 2010/2018) — n=20,000 men aged 50–64; PSA every 2 years (thresholds lowered over time to 2.5 ng/mL). Cancer-specific mortality RR 0.65; NNI 231, NND 10; incidence RR 1.51; 41% fewer advanced cases at diagnosis.
• CAP (Martin 2018/2024) — n=415,357 UK men aged 50–69; a single PSA invitation vs usual care (cancers offered the ProtecT trial). Cancer-specific mortality RR 0.92 at 15 years (absolute difference 0.09%; 0.69% vs 0.78%) with no overall-survival difference; increased low-risk detection.

Number needed to invite to screening (for context): colorectal FOBT 900, flexible sigmoidoscopy 450; mammography 1904 (age 39–49), 1339 (50–59), 377 (60–69); prostate — ERSPC 570, Göteborg 231, CAP 1111.

USPSTF Recommendations

Grade I (insufficient evidence) in 1996, 2002, and 2008 (<75); grade D (against) for ≥75 in 2008 and for all men in 2012. Current (2018): grade C (selectively offer after shared decision-making) for men 55–69, and grade D (against) for men ≥70.

When to Start Screening

Guideline	Not recommended	Offer if increased risk	Routine start
CUA 2022	Age <45	45–50 if increased risk (e.g. first-/second-degree family history)	≥50
AUA 2023	Age <40	40–45 if Black ancestry, germline mutation (BRCA, Lynch), or strong family history	45–50 (baseline PSA)
NCCN 2024	Age <40	40–45 if risk factors (as AUA)	45–75

The 2023 AUA earlier-start change is supported by the prognostic value of a baseline midlife PSA; the positive trials (Göteborg-1, ERSPC) began at 50 and 55, and there is no randomized evidence supporting routine screening before 45. A "strong" family history = ≥1 brother/father or ≥2 male relatives diagnosed <60, who died of prostate cancer, or who had metastatic disease; or ≥2 HBOC/Lynch-spectrum cancers (genotype these patients).

Frequency and Discontinuing Screening

• CUA 2022: PSA <1 ng/mL every 4 years, 1–3 every 2 years, >3 more frequent/adjunctive testing. Discontinue if age >70, age >60 with PSA <1, or life expectancy <10 years.
• AUA 2023: screen every 2–4 years for ages 50–69 (PSA 1–3 → every 1–4 years; PSA <1 → prolong). At age 60 with PSA <1, or age ≥75 with PSA <3, reasonable to lengthen the interval or stop (shared decision-making); screen more frequently if higher-risk; continue (every 2–4 years) only with life expectancy ≥10 years.
• NCCN 2024: PSA <1 every 2–4 years, 1–3 every 1–2 years (high-risk ≤3 every 1–2 years). Discontinue if life expectancy <10 years or age >75 (beyond 75 only in very healthy men).
• Use life-expectancy calculators (e.g. SSA, MSKCC, Cambridge Prognostic Groups), which are more reliable than clinician judgment.

Diagnosis

Prostate cancer is the only genitourinary malignancy diagnosed by screening. Localized disease is usually asymptomatic, so evaluation centers on PSA, increasingly multiparametric MRI, and ultimately biopsy when clinically significant cancer is suspected and the diagnosis will change management.

Clinical Presentation

At diagnosis, ~80% present with localized, ~12% regional, and ~5% metastatic disease (the metastatic proportion has fallen with PSA screening). Regional symptoms (advanced disease): lower-urinary-tract symptoms, hematuria, hematospermia, obstruction/renal failure, reduced ejaculate volume. Metastatic symptoms: bone pain, lethargy, anemia, weight loss, pathologic fractures, lower-extremity edema; rarely malignant retroperitoneal fibrosis, paraneoplastic syndromes, DIC, or paralysis.

History and Physical Exam

• History — symptoms, risk factors, eligibility/competing risk (will the patient benefit, given age/comorbidity?), and patient preference. A strong family history (≥1 brother/father or ≥2 male relatives diagnosed <60, who died of, or who had metastatic prostate cancer; or ≥2 HBOC/Lynch-spectrum cancers) should prompt genotyping (see the Epidemiology tab).
• Digital rectal exam (DRE) — a palpable tumor reflects local extent (cT stage) but DRE has poor sensitivity/reproducibility (useful to detect, not to stage); an abnormal DRE raises the risk of high-grade (Gleason 8–10) cancer. Per 2023 AUA, PSA is the primary screening test and DRE should not be used alone, but if PSA ≥2 ng/mL, strongly consider a supplementary DRE.

PSA

PSA liquefies semen, has a half-life of 2–3 days, becomes detectable at puberty, and circulates free (20–30%) or bound (70–80%) (to α1-antichymotrypsin, α2-macroglobulin, α1-protease inhibitor). It is the single test with the highest positive predictive value, though 70–80% of men with an elevated PSA do not have cancer — repeat a newly elevated value (25–40% normalize). PSA inversely correlates with organ-confined disease:

PSA	Organ-confined (pT2)		Nodal involvement
<4 ng/mL	80%	PSA >20	20%
4–10	66%	PSA >50	75%
>10	<50%

• Causes of elevation: prostate disease (BPH, prostatitis, cancer) and manipulation — biopsy and TURP cause large rises (median +6–8 and +6–13 ng/mL, returning to baseline in 2–3 weeks); cystoscopy, catheterization, DRE, and TRUS cause minimal change; long bike rides and ejaculation raise it ~10%.
• Clinical factors: PSA rises with age and prostate volume (~4%/mL), is higher in African-American men, and falls with increasing BMI.
• Derivatives (improve specificity): PSA density (≥0.15 supports biopsy in PSA 4–10 with normal DRE); PSA velocity (>0.75 ng/mL/yr; do not use as a sole biopsy trigger); % free PSA (low %fPSA → higher risk; Catalona 1998 — AUC 0.72 vs 0.53 for total PSA; ≤25% gives 95% sensitivity/20% specificity; FDA-approved for PSA 4–10 with negative DRE); and complexed PSA. 5-ARIs halve total PSA by 12 months (double the measured value to interpret; %fPSA is unchanged).

Blood, Urine and Tissue-Based Markers

Beyond PSA, a range of blood, urine, and tissue biomarkers refine the decision to biopsy (especially with a mildly elevated PSA or a prior negative biopsy) and help estimate the risk of aggressive disease.

PSA Biology

PSA is a 33-kD serine protease of the kallikrein family that liquefies semen, produced mainly by prostatic luminal epithelial cells (synthesized as preproPSA → proPSA → active PSA after hK2 cleavage). Its expression is androgen-driven (detectable at puberty) — so in hypogonadal men a low PSA may not reflect true prostate disease. It is also found in female ejaculate, breast milk, and amniotic fluid, with ectopic expression in some non-prostatic tumors. Half-life is 2–3 days; it circulates bound/complexed (70–80%) and free (20–30%).

• Bound forms: α1-antichymotrypsin (binds most PSA irreversibly; detectable), α2-macroglobulin (binds 5–10%; undetectable by most assays), α1-protease inhibitor (1–2%; detectable).
• Free forms (inactive isoforms): intact PSA, BPSA (transition-zone, high in BPH), and proPSA (−2/−4/−7; high in prostate cancer).

Landmark studies: Stamey 1987 established PSA as a marker of disease progression/treatment response; Catalona 1991 established its screening role (no "normal" value — cancer occurs at low PSA, and risk is a continuum); Catalona 1994 showed detection is highest with PSA and DRE together (PSA alone > DRE alone).

Adjunctive Biomarkers

• Blood: Prostate Health Index (PHI) = fPSA + tPSA + −2proPSA (FDA-approved for age ≥50, PSA 4–10, negative DRE); 4Kscore = fPSA + tPSA + intact PSA + hK2 (for elevated PSA considering biopsy).
• Urine: PCA3 — a prostate-specific long non-coding RNA (9q21–22); a post-DRE urine test reported as the PCA3:PSA mRNA ratio ×1000 (common cutoffs 10/25/35; FDA-approved after a negative biopsy and for initial screening). TMPRSS2:ERG — ~100% specific but only ~50% sensitive; best used in a urine multiplex with PCA3. Also ExoDx, MiPS, SelectMDx.
• Tissue: epigenetic changes — hypermethylation silences genes (GSTP1, APC, RARβ2, RASSF1A) and hypomethylation activates oncogenes (ConfirmMDx assays methylation in negative-biopsy tissue; NPV 0.90, sensitivity 0.68). Gene-expression panels: Prolaris (31 cell-cycle genes; progression/death risk), Oncotype DX (post-biopsy: predicts adverse pathology — T3 or Gleason 4 — at prostatectomy), and Decipher (metastasis risk in high-risk and biochemical-recurrence disease).

Imaging

• TRUS does not improve staging over DRE, tends to understage, and poorly detects transition-zone lesions.
• Multiparametric MRI (mpMRI) — key sequences: T2WI (zonal anatomy and transition-zone lesions; cancer is low-intensity, with a benign DDx of hemorrhage, atrophy, prostatitis, post-treatment change, scars, and BPH stromal hyperplasia); DWI/ADC (best for peripheral-zone lesions; cancer restricts diffusion — low ADC, and lower ADC = higher grade); T1WI (hemorrhage); DCE (vascularity — focal early enhancement suggests malignancy). Biparametric MRI (T2 + DWI, no contrast/coil) has equivalent sensitivity/specificity to mpMRI (Woo 2018). Post-biopsy MRI should wait 6–8 weeks (hemorrhage mimics cancer).
• PI-RADS scores each lesion 1–5 for the likelihood of clinically significant cancer (defined as Gleason ≥7, volume ≥0.5 cc, and/or EPE):

PI-RADS	Detection (any cancer)	PPV for GG≥2
1–2	15%	7%
3	25%	12–15%
4	58%	39–48%
5	85% (~66% GS ≥3+4; 37% GS 4+3)	72%

PI-RADS ≥4 → biopsy should be considered; ≤3 → depends on other factors.

• MRI-and-biopsy evidence (condensed): PROMIS (Ahmed 2017) — mpMRI as a triage test had sensitivity 88%, NPV 76%, specificity 45%, and could avoid ~25% of biopsies. PRECISION (Kasivisvanathan 2018) — MRI ± targeted biopsy was non-inferior and superior to standard TRUS for significant cancer (38% vs 26%) with less insignificant cancer. STHLM3-MRI (Eklund 2021) and GÖTEBORG-2 (Hugosson 2022/2024) — in screening, MRI with targeted-only biopsy detects significant cancer non-inferiorly while markedly reducing insignificant-cancer detection. MRI-FIRST (Rouvière 2019) and Ahdoot 2020 — combining targeted and systematic biopsy maximizes detection (don't omit systematic). About 10% (up to 20%) of negative MRIs still harbor significant cancer; predictors include PSA density >0.15, prior negative biopsy, abnormal DRE, and family history.
• PSMA-PET — PSMA (glutamate carboxypeptidase II) is overexpressed in >90% of prostate cancers (more with higher grade and castration resistance). Tracers: 18F-DCFPyL (Pylarify) and 68Ga-PSMA-11. Physiologic uptake (lacrimal/salivary glands, kidneys; celiac/stellate ganglia can mimic nodes); false negatives with small-volume disease, neuroendocrine differentiation, or prolonged ADT. proPSMA (Hofman 2020) — in high-risk disease, PSMA-PET-CT beat conventional imaging for nodal/distant metastasis (accuracy 92% vs 65%; sensitivity 85% vs 38%) and changed management more often with less radiation. Roles: primary staging of high-risk disease, staging biochemical recurrence (most common indication), and selecting patients for PSMA radioligand therapy; FDA-approved to detect metastases not seen on conventional imaging and to evaluate biochemical recurrence. It is far more sensitive than conventional imaging at low PSA (<0.5–2.0 ng/mL).
• Metastatic staging: CT/MRI for regional nodes; radionuclide bone scan is the most common test for skeletal metastases (PSMA-PET is more sensitive at low PSA).

Transrectal Ultrasound (TRUS)

Transrectal ultrasound (TRUS) is the workhorse for prostate volume measurement and biopsy/brachytherapy guidance; it is insensitive and non-specific for cancer detection itself.

Uses and Technique

Uses (5): assess prostate volume, locate focal abnormalities, assess for an obstructive cause of infertility (dilated seminal vesicles from ejaculatory-duct obstruction), guide biopsy, and guide brachytherapy seed placement.

Increasing probe frequency increases resolution but decreases penetration; the common 7-MHz transducer images the peripheral zone (where most cancers arise) well. On axial view the right prostate appears on the left of the screen (like CT). Zonal anatomy: anterior fibromuscular stroma, transition zone, central zone, peripheral zone, periurethral zone — the PZ and CZ cannot be distinguished on TRUS (collectively "PZ", the isoechoic reference); the TZ is hyperechoic, and corpora amylacea mark the PZ–TZ plane.

Lesions and Post-Treatment Appearance

• Cancer echogenicity: hypoechoic 60%, isoechoic 39%, hyperechoic 1%; a hypoechoic lesion contains cancer ~57% of the time (biopsy it, but it's neither pathognomonic nor grade-correlated). DDx of a hypoechoic lesion (6): prostate cancer, granulomatous prostatitis, prostatic infarct, lymphoma, BPH nodules, normal urethra.
• Post-treatment volume change: external-beam radiation decreases volume by 6 months; brachytherapy reduces it ~37% at 1 year and >50% at 8 years; 5-ARIs ~21% at 6 months; ADT ~30%. Irradiated prostates appear diffusely hypoechoic.

Prostatic Cysts

Anechoic; classified congenital vs acquired. Congenital cysts arise from Müllerian (prostatic utricle, Müllerian-duct cysts) or Wolffian (ejaculatory-duct, seminal-vesicle cysts) structures. An enlarged prostatic utricle (midline, at the verumontanum) is associated with genital anomalies (hypospadias most common, ambiguous genitalia, undescended testes, urethral polyps). Müllerian-duct and SV cysts should prompt renal ultrasound for unilateral renal agenesis. Zinner syndrome = ipsilateral SV cyst + ejaculatory-duct obstruction + unilateral renal agenesis.

Estimating Volume

Most formulas assume an ideal shape — ellipsoid (π/6 × transverse × AP × longitudinal), sphere, or prolate spheroid — and correlate well with specimen weight (1 cc ≈ 1 g). Planimetry (summing areas across cross-sections) is the most accurate ultrasound method.

Proceeding to Biopsy

Biopsy is offered when clinically significant cancer is suspected and the diagnosis will influence management. The PSA threshold is controversial (the PCPT showed ~15% cancer detection even with PSA <4, including Gleason ≥7) — for BRCA carriers, the referral threshold is 3 ng/mL. Validated risk calculators (ERSPC, PCPT, PBCG) and adjunctive blood/urine markers (detailed in the Blood, Urine and Tissue-Based Markers section earlier in this tab) refine the decision, especially for PSA 2.5–10 with a prior negative biopsy. With PSA >50 ng/mL (and no benign explanation), biopsy may be omitted when it poses significant risk and treatment is urgent (e.g. impending cord compression).

• Technique: a systematic biopsy samples ≥12 cores; for an MRI-visible lesion, perform targeted plus systematic biopsy; with a negative MRI but elevated risk, proceed with systematic biopsy (negative-MRI NPV ~91% for GG2+).
• Repeat biopsy by prior finding: focal HGPIN — no immediate repeat (~20–30% subsequent cancer, same as after a benign biopsy); multifocal HGPIN — risk-based (~30% cancer risk; repeat biopsy in 1–3 years); ASAP — additional testing (30–50% cancer, 10–20% GG2+); atypical intraductal proliferation — additional testing; negative biopsy — reassess risk with a calculator that incorporates the prior negative biopsy and obtain MRI before re-biopsy (don't repeat on PSA alone).

Prostate Biopsy

Prostate biopsy confirms the diagnosis when clinically significant cancer is suspected. The transrectal and transperineal routes have similar cancer-detection rates, but differ in infectious risk and access to anterior/apical tumors.

Indications and Contraindications

Indications: detection (raised PSA without UTI/retention/acute prostatitis, or an abnormal DRE), restaging (rising PSA after non-surgical treatment), active-surveillance protocols, and suspicious-but-not-diagnostic histology. Contraindications: significant coagulopathy, severe immunosuppression, acute prostatitis.

Approach

	Transrectal	Transperineal
Trajectory	Through the rectum	Through perineal skin (avoids rectum)
Advantages	Patient comfort/preference; familiarity	Fewer infections; better anterior/apical detection; feasible without a rectum
Drawbacks	Higher infection risk	May need more anesthesia (but can be done under local)

Preparation

• Anticoagulation: low-dose aspirin can be continued; warfarin and clopidogrel are stopped 7–10 days before; NOACs (apixaban, dabigatran, rivaroxaban) 2–5 days before; biopsy when INR <1.5, with heparin bridging for high thromboembolic risk.
• Antibiotic prophylaxis — transrectal: recommended for all patients (2019 AUA: a fluoroquinolone, or a cephalosporin + aminoglycoside; rectal-swab-targeted prophylaxis has utility where fluoroquinolone resistance is a concern). A Cochrane review (Zani 2011) found prophylaxis reduces bacteriuria, UTI, bacteremia, fever, and hospitalization. Transperineal: the NORAPP trial (2022) found antibiotics do not significantly reduce infection. A cleansing enema improves the acoustic window (infection benefit debatable).

Cores and Technique

• Transrectal: the extended 12-core systematic biopsy (apical and far-lateral cores) is standard — increasing from 6 to 12 cores improved detection, but going to 18–21 (saturation) is reserved for repeat biopsy. Transperineal: ~20 cores (5 sites per side). ≥2 cores per MRI target (incremental value diminishes beyond 3); the transition zone and seminal vesicles are not routinely sampled (isolated TZ tumors occur <5%); submit sextant cores in separate containers. Seminal vesicle biopsy is indicated only when SV invasion is suspected or when planning salvage cryotherapy after radiation.
• Technique (condensed): a biplanar probe (side- or end-fire — equivalent detection), an 18-gauge biopsy device, and a periprostatic nerve block (1% lidocaine, max 3 mg/kg, or 7 mg/kg with epinephrine; ~5 mL per side at the base/neurovascular bundle). Transrectal is usually done in the left-lateral decubitus position; transperineal in lithotomy (often with a pudendal block — the pudendal nerve lies ~2 cm lateral to the anal verge and ~3 cm deep). After a DRE, scan base-to-apex, measure volume, perform the nerve block, and biopsy per template. Targeted biopsy of an MRI lesion uses software-based or cognitive fusion (comparable in expert hands).

Complications

• Bleeding: hematuria ~50% (intervention <1%), hematospermia ~50% (persists >4 weeks in ~30%), rectal bleeding ~30% (intervention ~2.5%; avoided by the transperineal route).
• Infection (prostatitis/fever/epididymitis): transrectal ~5–7% (> transperineal); hospitalization for infection ~1–3%. An Ontario cohort showed 30-day admission rising from 1% (1996) to 4% (2005), mostly infectious, with 30-day mortality 0.09%. Risk factors (6): non-White race, more comorbidities, diabetes, prostate enlargement, foreign travel, recent antibiotic use.
• Other: transient LUTS 6–25%, urinary retention <1%, transient erectile dysfunction <1%, and false negatives. About ~75% of TRUS biopsies are negative; the false-negative rate is ~20–30% (initial detection ~22% for PSA 4–10, then 10% / 5% / 4% on second/third/fourth biopsy).

Pathology

Most prostate cancers are peripheral-zone adenocarcinomas, graded by the Gleason system (now reported as Grade Groups 1–5) and staged by the AJCC 8th-edition TNM system. Precursor and atypical biopsy findings (HGPIN, ASAP) drive repeat-biopsy decisions, and the radical-prostatectomy specimen yields the strongest prognostic factors.

Precursor and Atypical Lesions

• Adenosis — characteristically in the transition zone; not associated with increased risk of harboring or developing adenocarcinoma.
• Prostatic intraepithelial neoplasia (PIN): low-grade PIN should not be reported (not reproducibly distinguishable from benign tissue). High-grade PIN (HGPIN) is a precursor to many peripheral intermediate/high-grade cancers (though not necessary for cancer); ~20% harbor the TMPRSS2:ERG fusion; PSA is not elevated. Cancer on subsequent biopsy within a year is ~26.4% — not significantly higher than the 10–25% after a benign biopsy. Management by number of cores: 1 core → repeat biopsy at 3 years; ≥2 cores → repeat within 1 year.
• Atypia / atypical small acinar proliferation (ASAP) — suggestive but not diagnostic of cancer (~5% of biopsies). Cancer risk is ~40–50% (much higher than HGPIN). ASAP retains basal cells and is HMWCK-positive, whereas prostate cancer lacks basal cells and is HMWCK-negative — HMWCK staining is the key discriminator. Seek expert review first; all patients should have a repeat biopsy, typically within 6 months, regardless of PSA.

Adenocarcinoma

• Location: ~85% arise in the peripheral zone; most cT1c tumors are posterior/posterolateral; multifocal in >85%.
• Spread: because the prostate lacks a discrete capsule, extraprostatic extension (EPE) is the preferred term; it occurs preferentially posteriorly/posterolaterally. Transition-zone tumors need larger volumes than peripheral-zone tumors for comparable EPE/metastasis. Most frequent metastatic sites (descending): lymph nodes > bone > lung > bladder > liver > adrenal.
• Histology: malignant glands lack basal cells (basal cells label with high-molecular-weight cytokeratin and TP63).

Gleason Grading and Grade Groups

Gleason pattern	Description
1	Circumscribed nodule of closely packed, uniform, medium-sized acini
2	Like pattern 1 but with minimal edge infiltration; more loosely arranged
3	Discrete, smaller, infiltrative glands with marked size/shape variation
4	Fused microacinar, ill-defined, or cribriform glands; hypernephromatoid
5	No glandular differentiation (sheets/cords/single cells); comedocarcinoma with necrosis

On biopsy the Gleason score is the most common pattern + the highest grade (ISUP 2005; the high grade is included because biopsy underestimates burden). Gleason 2–4 should not be assigned on needle biopsy. The 2014 ISUP Grade Group system:

Grade Group	Gleason	Description
1	≤6	Only well-formed glands
2	3+4=7	Predominantly well-formed + lesser poorly-formed/fused/cribriform
3	4+3=7	Predominantly poorly-formed/fused/cribriform + lesser well-formed
4	8 (4+4, 3+5, 5+3)	Only poorly-formed/fused/cribriform glands (or combinations lacking glands)
5	9–10	Lacks gland formation (± necrosis)

Advantages: reassures Grade Group 1 patients (lowest possible grade), separates Gleason 3+4 from 4+3 (prognostically distinct), and unifies biopsy and prostatectomy reporting.

Specimen Assessment

Biopsy — grade and tumor extent generally predict adverse RP findings, but favorable biopsy findings don't guarantee favorable RP findings (sampling error). Upgrading from biopsy to RP is associated with increased cancer extent, increased PSA, fewer cores sampled, and a smaller prostate. Intraductal carcinoma (high-grade, poor prognosis — treat definitively) and perineural invasion (~75% EPE; prognostic for external-beam radiotherapy, less so brachytherapy) are notable.

Radical prostatectomy — prognostic factors (7): lymph-node involvement (15-yr BCR-free/metastasis-free/cancer-specific survival 7.1%/41.5%/57.5%), grade group, tertiary high-grade pattern, vascular invasion, extent of EPE (focal vs non-focal), seminal-vesicle invasion (5-yr progression ~65%), and positive margins (~15% after RALP; only ~50% progress; margin length usually doesn't affect risk, but extent and grade at the margin are prognostic for adjuvant-radiation decisions). 5-year biochemical-relapse-free survival by grade group: GG1 97%, GG2 88%, GG3 70%, GG4 64%, GG5 34%. Non-prognostic at RP: tumor volume and perineural invasion (common; do not include in the report).

Treatment effect: endocrine therapy causes atrophy/squamous metaplasia and artifactually higher grade; neither hormonal nor radiation-treated cancers should be assigned a Gleason score.

Other Histologic Subtypes

• Neuroendocrine / small cell (<0.5–1%) — suspect with brain metastasis, pelvic masses, visceral involvement, or osteolytic metastasis with hypercalcemia (PTHrP). PSA is low/undetectable; chromogranin A and urine serotonin metabolites may be present; not Gleason-graded. Hormone-unresponsive — treat with chemotherapy (cisplatin/etoposide or docetaxel/carboplatin) + radiation; survival generally <12 months.
• Prostatic duct adenocarcinoma (0.4–0.8%) — periurethral, exophytic; hematuria/obstruction; low PSA (often normal PSA and DRE); aggressive (regarded as Grade Group 4).
• Pure squamous carcinoma (rare, aggressive); mucinous (not more aggressive; treated by prostatectomy); urothelial carcinoma of the prostate (see that tab); sarcomas (0.1–0.2%); leukemia/lymphoma.

Staging

TNM Staging (AJCC 8th Edition)

Clinical stage uses DRE, PSA, biopsy, and imaging (MRI is recognized for cT categorization); pathologic stage follows prostatectomy.

T stage	Definition
cT1a / cT1b	Incidental finding in ≤5% / >5% of resected tissue
cT1c	Identified by needle biopsy (e.g. for elevated PSA)
cT2a / cT2b / cT2c	≤½ of one lobe / >½ of one lobe / both lobes
pT2	Organ-confined (subdivision has no prognostic significance)
cT3a / pT3a	Extraprostatic extension (pT3a also includes microscopic bladder-neck invasion)
cT3b / pT3b	Seminal vesicle invasion (pT3b = muscle wall of the SV)
T4	Invades external sphincter, rectum, bladder, levators, or pelvic wall

pT1 does not exist — cT1a–c convert to pT2 (organ-confined) or pT3 (EPE) after prostatectomy. Microscopic bladder-neck invasion (pT3a) has not been associated with independent increased recurrence risk. N: N0 / N1 (regional node metastasis). M: M1a (non-regional nodes) / M1b (bone) / M1c (other distant sites — liver, lung, brain).

Evaluation

Germline mutations are inherited; somatic mutations are acquired. Indications (AUA 2022 / NCCN): Ashkenazi Jewish ancestry, a known familial cancer-risk mutation, a strong personal/family history of related cancers (breast, colorectal, ovarian, pancreatic, upper-tract urothelial), a strong family history of prostate cancer, adverse tumor features (high-risk disease, or intermediate-risk with intraductal/cribriform morphology), and metastatic or high-/very-high-risk localized disease. Multiplex tests (STHLM-3 — clinical variables + blood biomarkers + polygenic risk score; AUC 0.74 vs 0.56 for PSA, reducing biopsies ~32%) and polygenic risk scores (SNP-based) are emerging but cannot yet distinguish aggressive from indolent disease.

Management of Localized Prostate Cancer

Management is driven by risk stratification and life expectancy. Most localized cancers are indolent, so options range from active surveillance through radical prostatectomy and radiation (± androgen deprivation), balancing cure against the morbidity of treatment.

Pre-Treatment Evaluation

• Metastatic staging — not for asymptomatic low/intermediate-risk disease; performed for high-risk disease (and considered for unfavorable-intermediate). Use cross-sectional imaging (CT or mpMRI, moderate sensitivity/high specificity for nodes) plus bone scan; PSMA-PET (Ga-68 PSMA-11 or 18F-DCFPyL) is FDA-approved for high-risk staging and outperforms conventional imaging (proPSMA: 27% greater accuracy), though the survival benefit of acting on molecular-imaging findings is unproven.
• Life expectancy — treatment generally requires a minimum 8–10-year life expectancy to reduce death risk; use validated calculators (clinician estimates are unreliable).

Risk stratification (2022 AUA — PSA, clinical stage, grade group):

Risk	Criteria
Low	PSA <10 and Grade Group 1 and cT1–T2a
Intermediate	PSA 10–<20, or GG2–3, or cT2b–c. Favorable: <50% cores positive and (GG1 with 1 IR factor, or GG2 with no other IR factor) — i.e. GG1 + PSA <20 OR GG2 + PSA <10. Unfavorable: GG3, or GG2 with ≥1 other IR factor or ≥50% cores, or GG1 with 2 IR factors — i.e. GG2 + PSA 10–20 OR GG3 + PSA <20
High	PSA ≥20, or GG4–5, or cT3

Older models include D'Amico (predicts biochemical recurrence), Epstein criteria (identify insignificant cancer for AS), and the Cambridge Prognostic Groups (cancer-specific survival). Intraductal/cribriform morphology and high PSA density worsen prognosis; tissue genomic tests (Prolaris, Oncotype DX, Decipher) are used selectively.

Treatment by Risk Stratum (2022 AUA)

Situation	Recommended options
Life expectancy ≤5 years	Watchful waiting
Low-risk	Active surveillance preferred (select patients may elect definitive therapy)
Favorable intermediate-risk	Active surveillance, radical prostatectomy, or radiation without ADT
Unfavorable intermediate- or high-risk (LE >10 y)	Radical prostatectomy, or radiation + ADT (4–6 months for unfavorable intermediate; 18–36 months for high-risk)

For sufficiently high-risk disease (node-positive, or ≥2 of: cT3, PSA ≥40, Gleason ≥8), radiation + ADT may add 2 years of abiraterone + prednisone.

Conservative Management

• Watchful waiting — palliative intent, no routine cancer surveillance; for asymptomatic men with limited life expectancy (AUA <5 years; NCCN <5–10). At 10 years, the risk of cancer-specific death is ~15% and metastasis ~20%. Intervene (with palliative ADT) for symptomatic progression, upper-tract obstruction, or metastasis.
• Active surveillance — defers definitive treatment while retaining curative potential; the preferred option for low-risk disease (and selected favorable-intermediate disease with low PSA density, low volume, and low % Gleason 4). It reduces overdiagnosis/overtreatment (cancer-specific mortality/metastasis <1% at 10 years) at the cost of repeat biopsies and a small risk of missing the window for cure. Selection uses the Epstein criteria. Disease reclassification (often initial misclassification rather than true progression) occurs in ~25–50% within 5 years; risk factors include African-American race, BRCA2 (9× risk), and high PSA density.
  • Follow-up: PSA no more than every 6 months, DRE every 2 years, and surveillance biopsy every 1–4 years, with a confirmatory biopsy at 3–6 (or within 12) months; obtain mpMRI if the diagnostic biopsy lacked it (ASIST: MRI-targeted biopsy reduced later AS failures). Triggers for intervention: grade progression, increased cancer volume, rapidly rising PSA, or patient anxiety.

Observation vs treatment RCTs: PIVOT (Wilt) — no early survival difference, but an overall-survival benefit for radical prostatectomy emerged at 18.6 years (less so in low-risk/elderly men); SPCG-4 (Bill-Axelson) — prostatectomy improved overall, cancer-specific, and metastasis-free survival; ProtecT (Hamdy, 15 years) — no cancer-specific or overall survival difference between monitoring, surgery, and radiotherapy, but monitoring had more metastasis and ADT use.

Radical Prostatectomy

Offers possible cure with accurate pathologic staging and readily identified failure (allowing salvage radiation); disadvantages are recovery, possible incomplete resection, and morbidity (erectile dysfunction, incontinence). See the Radical Prostatectomy procedure page for surgical anatomy and operative technique.

• Approaches: open (perineal — less blood loss/shorter time but no access for lymphadenectomy and higher rectal-injury/fecal-incontinence risk; vs retropubic), laparoscopic, and robot-assisted (Coughlin 2018 RCT: no urinary/sexual difference vs open; minimally-invasive benefit). Generally offered up to ~76 years.
• Nerve-sparing — preserve neurovascular bundles when oncologically appropriate (lowers ED risk without increasing positive margins); questionable with extensive/high-grade disease, palpable EPE, PSA >10, or poor baseline erections.
• Pelvic lymphadenectomy — provides staging but no consistent survival benefit; if done, perform an extended dissection (obturator, external iliac, internal iliac); select by nomogram (NCCN thresholds 2–7%); complete the prostatectomy if positive nodes are found.
• Complications: incontinence (pads at 7–12 years ~18–24% vs ~3–8% radiotherapy), erectile dysfunction, vesicourethral anastomotic stenosis (1.3–4.8%; less with robotic; up to 22–40% after salvage RP), and (robotic) incisional hernia.
• Cancer control: PSA should be undetectable by ~2 months. Adverse features: non-organ-confined disease, lymphovascular invasion, EPE, positive margins, seminal-vesicle invasion, nodal metastasis. Nomograms: Partin tables (pathologic stage), Kattan (biochemical recurrence), CAPRA (age, PSA, stage, Gleason, % positive cores). Neoadjuvant ADT lowers positive margins but does not improve survival; neoadjuvant chemotherapy rarely gives complete responses.

Radiation Therapy

Pre-RT prognostic factors: PSA/velocity, grade group, % positive cores, cT stage, MRI. Contraindications — ST-LIAR: prostate Size >60 cc (brachytherapy) and prior TURP (brachytherapy) — relative; significant LUTS, IBD, Ataxia telangiectasia (absolute — severe radiation response), and prior pelvic Radiation.

• Modalities: EBRT has advanced from 3DCRT → IMRT (less rectal/bladder dose) → IGRT → SBRT/CyberKnife (hypofractionation). Dose escalation is standard (76–80+ Gy; ~70–72 low-risk, 75–76 intermediate, ≥80 high-risk). Brachytherapy delivers higher prostate doses (LDR: ~145 Gy iodine-125, ~125 Gy palladium-103; or temporary HDR), with rectal toxicity the limiting factor.
• EBRT + ADT: short-term (~6 months) for intermediate-risk; long-term (18–36 months) for high-risk. Supporting trials: EORTC 22863 (Bolla — long-term ADT improved OS), RTOG 86-10 and 92-02 (longer ADT benefit), EORTC 22961 (3 years > 6 months), and PR3/PR07 + SPCG-7 (adding radiation to ADT improves survival in locally advanced disease). PACE-B: SBRT non-inferior to conventional radiotherapy for low/intermediate-risk disease.
• Toxicity: GU (more with brachytherapy; acute urinary retention 12–35% after brachytherapy), GI (more with EBRT; 5–10% chronic proctitis), erectile dysfunction (~50%, more with EBRT than brachytherapy), and secondary malignancy (~1/70 living >10 years).
• PSA after RT: the nadir is reached over 2–3 years (not undetectable — residual benign epithelium persists). Failure definitions: ASTRO (3 consecutive rises) and the Phoenix definition (nadir + 2 ng/mL, not backdated). A PSA bounce (a transient rise of ~0.1–0.5 ng/mL above nadir, then decline) occurs in ~20%, more often after brachytherapy, usually within 2 years. Post-RT biopsy (to assess local control) is best at 30–36 months.

RP vs radiotherapy: no randomized comparison; surgery tends to fail at the margins and radiotherapy in the tumor center.

Other Treatments

• ADT monotherapy is never curative and is reserved for palliation in high-risk patients with local symptoms and limited life expectancy (the bicalutamide Early Prostate Cancer Programme showed benefit in locally advanced but not localized disease).
• Whole-gland or focal ablation — per AUA, considered only in selected, informed intermediate-risk patients (prioritize trials); not for low-risk (use AS) or high-risk (insufficient data). The index-lesion hypothesis underpins focal therapy (the largest focus drives behavior). Modalities: cryoablation, HIFU (AUR ~20%; prostate ≤40 mL), focal laser, irreversible electroporation, and photodynamic therapy; follow-up uses PSA, MRI, and targeted ± systematic biopsy.

High-Risk and Follow-Up

About 15% of localized disease is high-risk; options are radical prostatectomy or radiation + ADT (and clinical trials), with neoadjuvant/adjuvant intensification under study (PROTEUS, ATLAS, ENZARAD). Follow-up after treatment (2022 AUA): provide an individualized recurrence estimate; PSA every 3–6 months for 2 years, every 6 months through year 5, then annually, with validated QoL instruments for urinary/bowel/sexual function.

Radiotherapy for Prostate Cancer

This tab covers radiation delivery concepts (fractionation, particle therapy) and palliative radiation. The EBRT/brachytherapy modalities, dose escalation, EBRT + ADT trials, and toxicity/PSA-failure definitions are detailed in the Management of Localized Prostate Cancer tab.

Hypofractionation

The total dose is divided into fractions; hypofractionation delivers fewer, higher-dose fractions over a shorter course. Prostate cancer is thought to be especially sensitive to the dose delivered per fraction (low α/β ratio), so a few high-dose treatments may produce more cell kill than many 2-Gy fractions — potentially allowing a lower total dose with similar control and less normal-tissue injury. Phase III trials have delivered 2.6–3.1 Gy per fraction with low morbidity; extreme fractionation (6.7–10 Gy) shows good early biochemical control but limited follow-up. Safe delivery requires accurate setup and conformal planning.

Heavy-Particle Therapy

A form of 3D conformal radiation using neutrons or protons, which are harder to produce and control. Particles travel differently in tissue and exhibit a Bragg peak — a sharp dose cutoff at the end of the particle's range (sparing tissue beyond it). Neutrons may cause more normal-tissue damage than photons. Protons are expensive and have not demonstrated a clinical benefit over modern IMRT — planning studies show reduced low-to-medium (but not high) doses to nearby organs, with no head-to-head outcome comparison; control and morbidity are likely similar to IMRT.

Palliative Radiotherapy

• Bone metastases: a single-fraction regimen (800 cGy × 1) is preferred for uncomplicated non-spinal bone metastases — as effective as protracted regimens, more cost-effective, and less time-consuming. Pathologic fracture is infrequent (prostate metastases are primarily blastic). Consider prophylactic surgical fixation (orthopedic referral) for an intramedullary lytic lesion ≥50% of the bone's cross-sectional diameter, a cortical lytic lesion ≥ the bone diameter, or a lytic lesion >2.5 cm in axial length; give post-operative radiation after fixation.
• Spinal cord compression — the most serious complication of bone metastasis and a medical emergency, usually epidural from a vertebral body. Presentation: back pain (~95%), focal neurologic deficit, and bladder/bowel changes. MRI is the diagnostic modality of choice. Give corticosteroids immediately (dexamethasone load 4–10 mg, then 4–24 mg every 6 h); definitive treatment is radiation, surgery, or both. Favor surgery before radiation when the tissue diagnosis is unknown, the area was previously irradiated, or there is a pathologic fracture with instability/bony cord compression.

Molecular Therapies and Radiation

Inhibiting DNA-repair proteins (e.g. DNA-PK, ATM) with chemical or short-interfering RNA (siRNA) sensitizes cells to radiation; the main challenge for RNA-interference therapy is selective, cell-type-specific delivery to avoid sensitizing surrounding normal tissue.

Management of Locally Advanced Prostate Cancer

Locally advanced prostate cancer is stage ≥T3NX/+M0. Untreated, these men are at significant risk of disease progression and cancer-specific death; fewer now present at this stage because of screening. Two options carry a proven overall-survival benefit: radiation with long-term ADT, and radical prostatectomy with extended pelvic lymphadenectomy.

Radical Prostatectomy

Surgery is generally reserved for high-risk, low-volume tumours that can be completely excised. Prostatectomy alone is often insufficient, but some men with high-risk features are cured by surgery alone, and adjuvant or combined therapy may further improve outcomes. Non-surgical modalities are increasingly used for high-risk disease.

Prognosis — 15-year outcomes in men found to have positive nodes (pN1) after radical prostatectomy:

Outcome	15-year rate
Biochemical-recurrence-free survival	7.1%
Metastasis-free survival	41.5%
Cancer-specific survival	57.5%

Neoadjuvant and adjuvant ADT are addressed under Management of Localized Prostate Cancer; outside of N+ disease (see pN1 management below), evidence for adjuvant ADT in locally advanced tumours is limited.

Radiation After Prostatectomy

Men with extraprostatic extension (pT3a), seminal vesicle invasion (pT3b), or positive surgical margins may harbour residual cancer cells in the prostatic bed that postoperative radiotherapy can eradicate.

Adjuvant vs Salvage Timing

• Adjuvant radiotherapy is given proactively shortly after surgery while the PSA is undetectable.
• Salvage radiotherapy is given once the postoperative PSA is detectable; radiation for a persistent post-prostatectomy PSA is salvage, not adjuvant, and men with adverse pathology and a persistent PSA should be offered salvage RT.
• Arguments for adjuvant: most effective when tumour burden is smallest, requires a lower radiation dose, and needs less ADT.
• Arguments for early salvage: avoids overtreating men who would never recur (most focally positive margins ± extraprostatic extension are cured by surgery), and PSA is sensitive enough that little is lost by monitoring PSA velocity — particularly with limited life expectancy or Gleason 6–7 disease.
• Adjuvant toxicity: 5–10% risk of radiation proctitis or cystitis and a 50% risk of erectile dysfunction.

Adjuvant Radiation vs Observation

Three RCTs showed improved biochemical-recurrence-free and cancer-specific survival with adjuvant radiation versus observation for locally advanced / positive-margin disease:

Trial	Population	Key result
SWOG 8794 (Thompson 2009)	431 men, pT3 ± positive margins	Improved metastasis-free survival (14.7 vs 12.9 yr) and overall survival (15.2 vs 13.3 yr); NNT 9.1 to prevent one death at ~12.6 yr
EORTC 22911 (Bolla 2012)	1,005 men, pT3 ± positive margins	Biochemical PFS improved 21% at 5 yr (74% vs 53%); lower locoregional failure (5.4% vs 15.4%); no OS difference; benefit driven by the positive-margin subset (HR 0.38)
ARO 96-02 (Wiegel 2014)	368 men, pT3/pT4, N0, all undetectable PSA	Biochemical PFS improved 21% at 10 yr (56% vs 35%); no metastasis-free or overall survival benefit

A systematic review of these three trials found immediate RT reduces recurrence in aggressive disease at the cost of increased acute (15–35%) and late (2–8%) toxicity.

Adjuvant vs Early Salvage Radiation

Early salvage radiation means monitoring PSA and treating only on convincing progression. It works best at low PSA — salvage RT started at PSA ≤0.5 ng/mL gives better 5-year biochemical PFS than starting above 0.5 — and the benefit is strongest in men with the shortest PSA doubling times (<6 months).

• The ARTISTIC meta-analysis (Vale 2020) pooled RADICALS, GETUG-17, and RAVES (2,153 men) and found no difference in event-free survival between adjuvant RT and surveillance with early salvage (HR 0.95, 95% CI 0.75–1.21), with more genitourinary toxicity in the adjuvant arm — though few men had high-risk features.
• RADICALS-RT (Parker 2020) — 1,396 men with ≥1 risk factor (pT ≥3, grade group ≥2, positive margins, or preoperative PSA ≥10) showed no significant difference in 5-year biochemical PFS (85% adjuvant vs 88% salvage).
• GETUG-17 is comparing immediate adjuvant RT with salvage RT at PSA 0.2 ng/mL; RAVES (pT3 ± positive margins) was terminated for poor accrual.

Guideline Recommendations

Body	Recommendation
NCCN 2023	Life expectancy ≤5 yr → observe; >5 yr → adjuvant RT for pT3a, positive margins, or seminal vesicle involvement (positive margins benefit most). Salvage RT for a PSA that becomes detectable and rises on two measurements, or a persistently detectable PSA. More effective when pre-treatment PSA is low and PSADT long.
AUA 2023 (localized)	Adjuvant RT not routinely recommended; manage initially with PSA surveillance; possible role with high-risk features (Gleason 8–10 with extraprostatic extension, positive nodes).
AUA 2019	Offer adjuvant RT for pT3a, positive margins, or seminal vesicle involvement; offer salvage RT for PSA or local recurrence without distant metastases.
EAU 2022	Adjuvant IMRT/VMAT + IGRT only for high-risk pN0 men with ≥2 of 3 features (ISUP grade 4–5, pT3, positive margins). For PSA persistence >0.2 ng/mL, obtain a PSMA-PET if it will change management and treat non-metastatic disease with salvage RT + hormonal therapy. For BCR, offer early salvage RT at two consecutive PSA rises without waiting for a threshold; give ≥64 Gy as soon as possible.

Management of pN1 Disease

The natural history is heterogeneous — up to 30% of men remain free of disease long term without further therapy (one cohort of 369 pN1 men found 28% biochemical-recurrence-free at 10 years). Three options exist: observation, ADT, and EBRT + ADT.

• ADT — ECOG 7887/3886 (Messing; 98 men with nodal metastases after prostatectomy + lymph node dissection) showed immediate ADT improved disease-free, cancer-specific, and overall survival; the trial was underpowered (100 of a planned 240 enrolled) and the effect size has not been reproduced in larger cohorts. The EORTC trial (Schröder; 302 pN1–3M0 men without local treatment) found no significant OS difference (7.6 vs 6.1 yr; NNT 20.8 at 5 years).
• EBRT + ADT — National Cancer Database studies found EBRT + ADT improved biochemical-recurrence-free, cancer-specific, and overall survival versus ADT alone. Risk-stratify by number of positive nodes and postoperative PSA: with an undetectable PSA consider surveillance with early salvage (adjuvant ADT/RT are alternatives); with a detectable PSA, salvage ADT is recommended. Optimal timing remains unknown.

Radiation With Long-Term ADT

EBRT, or EBRT plus brachytherapy, with concurrent long-term ADT (18–36 months) is recommended (NCCN). The localized-disease trials (EORTC 22863, RTOG 86-10, PR3/PR07, SPCG-7/SFUO-3 — see Management of Localized Prostate Cancer) established that ADT alone is inferior to ADT plus radiation, and the method of ADT does not affect the combined-treatment outcome. Chemotherapy with radiation is less well studied than chemotherapy with surgery.

Primary ADT

ADT monotherapy has not been conclusively shown to improve overall survival in locally advanced disease. In the Bicalutamide Early Prostate Cancer Programme (Iversen 2010; 3,292 men T1b–4 N0/Nx M0 after prostatectomy or radiotherapy, including 657 with locally advanced disease), bicalutamide 150 mg daily improved progression-free survival in the locally advanced subgroup (HR 0.67) without an OS difference, while in the localized subgroup it gave no PFS benefit and an almost significant reduction in OS (HR 1.15).

The ideal PSA threshold for starting ADT is unknown. Both the MRC trial (934 men) and EORTC 30891 (986 men unsuitable for local treatment) found immediate ADT improved overall survival versus delayed ADT, though the EORTC benefit was small and did not extend to cancer-specific mortality. Bicalutamide 150 mg preserved sexual interest and physical capacity better than castration.

Focal Ablative Therapy

Cryotherapy or HIFU may have a role even in locally advanced disease, most likely combined with ADT or other systemic therapy (see Management of Localized Prostate Cancer).

Biochemical Recurrence

A detectable, rising PSA is usually the earliest sign of recurrence after definitive treatment, and it typically precedes clinical events by years. Management hinges on distinguishing local failure (salvageable) from distant failure (treated as metastatic castrate-sensitive disease), using PSA kinetics, the interval to recurrence, and Gleason grade.

After Radical Prostatectomy

After a successful prostatectomy the PSA should fall to undetectable (PSA half-life is 2–3 days; the fraction remaining after n half-lives is 1/2ⁿ). Biochemical recurrence (AUA/ASTRO) is a PSA ≥0.2 ng/mL confirmed by a second value; a prior period of undetectable PSA is not required.

Epidemiology and Natural History

• Roughly 25–41% of men develop PSA recurrence within 10 years of prostatectomy; of these, ~50% recur within 3 years, ~80% within 5 years, and ~99% within 10 years. Recurrence beyond 15 years is rare, so PSA follow-up beyond 10 years has limited utility, especially in older men.
• Not every detectable PSA progresses — some plateau, explained by residual benign prostatic tissue, non-prostatic PSA (urethral and salivary glands), or indolent residual cancer.
• The MSKCC postoperative nomogram predicts BCR and cancer-specific survival from PSA, Gleason score, extraprostatic extension, seminal vesicle invasion, lymph node involvement, margin status, and adjuvant radiation; positive-margin length is also predictive.
• Pound et al. (1999) — in 1,997 men followed after prostatectomy without neoadjuvant or adjuvant therapy, 304 (≈15%) developed BCR; the median time from BCR to metastasis was 8 years (metastasis-free survival 10 years in a later update), and from metastasis to death 5 years — a median of more than 13 years from BCR to death. The survival impact of BCR is limited to a subgroup: a short PSA doubling time with a high final Gleason score (after prostatectomy), or a short interval to failure with a high biopsy Gleason score (after radiotherapy), carries the worst prognosis.

EAU risk-stratification:

Risk	After prostatectomy	After radiotherapy
Low	PSA doubling time >1 yr and prostatectomy Gleason <8	Interval to BCR >18 mo and biopsy Gleason <8
High	PSA doubling time ≤1 yr or prostatectomy Gleason 8–10 (ISUP 4–5)	Interval to BCR ≤18 mo or biopsy Gleason 8–10 (ISUP 4–5)

Restaging Imaging

The goal is to separate local from distant failure. MRI identifies local recurrence with high accuracy even at low PSA (sensitivity/specificity/accuracy ≈98%/94%/93%, up to 100%/97%/91% when confirmed by biopsy). For distant disease, conventional CT and bone scan have a yield that depends heavily on PSA — the median PSA at a newly detected bone metastasis is 32 ng/mL, and ~25% occur at PSA <10 ng/mL:

Modality	Detection by PSA
CT (lymph nodes)	<20 ng/mL: 0%; >20 ng/mL: 1.1% (Abuzallouf 2004)
Bone scan	<10 ng/mL: 2.3%; 10–20: 5.3%; 20–49.9: 16.2% (Abuzallouf 2004)
PSMA / novel PET-CT	Higher sensitivity at low PSA (<2.0 ng/mL); FDA-approved after BCR to assess locoregional salvage; endorsed by the 2021 CUA Best Practice Report

Management — Local Failure (Salvage Radiation)

Of all salvage options (including ADT), radiation gives the best long-term progression-free survival, improving biochemical-recurrence-free, progression-free, cancer-specific, and overall survival.

• Timing and dose — outcomes improve at lower PSA (some treat at ≤0.5 ng/mL); at least 64 Gy is delivered to the prostatic bed, with emerging evidence favouring higher doses (cf. 76–80 Gy EBRT and ~145 Gy iodine / 125 Gy palladium brachytherapy for localized disease).
• Whole-pelvis vs prostatic-bed — no mature RCT shows added benefit of whole-pelvis radiation; RTOG 0534 is testing prostatic-bed RT alone vs + 6 months ADT vs + pelvic-node RT + 6 months ADT.
• Concurrent ADT — the 2017 AUA guideline recommends offering hormone therapy with salvage RT (Grade A). GETUG-AFU 16 (Carrie 2019) showed adding short-course ADT improved progression-free survival by 15% at 10 years (65% vs 49%), and RTOG 96-01 (Shipley 2017) showed 2 years of bicalutamide improved overall, cancer-specific, and metastasis-free survival (benefit greatest with PSA >0.60).
• Prognosis — favourable salvage responses occur with late, slowly rising PSA, low-grade tumour, and no seminal vesicle or nodal involvement; a post-salvage PSA nadir >0.05 ng/mL predicts distant metastasis and reduced cancer-specific survival.

Management — ADT After Prostatectomy

ADT is non-curative for post-prostatectomy biochemical failure and has no proven survival benefit, yet ~60% of men receive it as second-line therapy. The 2020 AUA guideline advises against routine ADT for BCR after prostatectomy; two large observational studies found no mortality difference between immediate and deferred ADT. If used without metastases, intermittent ADT may be offered. High-dose bicalutamide (150 mg daily) can delay progression with survival equivalent to orchiectomy and less sexual dysfunction and osteoporosis, but possibly more cardiovascular risk (Wirth 2001).

After Radiation Therapy

Definitions of failure — the 1996 ASTRO definition (three consecutive PSA rises 6 months apart, backdated) has been largely replaced by the 2005 Phoenix definition (PSA nadir + 2 ng/mL, not backdated), which has fewer false positives. Because the two modalities are defined differently, metastasis-free or cancer-specific survival are better measures for comparing prostatectomy and radiotherapy. Biochemical and histologic failure are best confirmed at least 2 years out to account for the PSA bounce.

Natural History

PSA-only recurrence after definitive radiation still leads to local and distant failure and cancer death. Four features predict clinical progression: time from RT to BCR <3 years, PSA doubling time <3 months (the most consistent predictor), pretreatment biopsy grade group ≥4, and pretreatment stage ≥cT3b.

Diagnosis and Evaluation

Men are at risk of both local and distant failure, so differentiate local (prostate biopsy) from distant (imaging) disease.

• Imaging — post-radiation fibrosis makes imaging difficult; MRI is the most promising for local recurrence, while PET/CT (11C-choline, PSMA) is under study. On bone scan, the chance of a lesion at PSA <10 ng/mL is <1% if PSADT >6 months and 10% if <6 months. CT is reasonable when advanced imaging is unavailable, though PSMA-PET is more sensitive for nodal disease.
• Biopsy after radiotherapy — strongly recommended to document local recurrence before salvage, but reserved for men in whom salvage local therapy is being considered (radiation changes cause a high false-positive rate in the first year). Use mpMRI-directed biopsy: standard systematic biopsy if PI-RADS 1, or a 12-core systematic biopsy plus ≥1 targeted core per MRI lesion otherwise. Seminal vesicle invasion was historically reported in up to 42% of cases.

Management — Local Failure (No Metastases)

Aggressive local therapy outside a trial is not recommended; options are active surveillance, local salvage therapy (salvage prostatectomy, cryosurgery, brachytherapy, or HIFU), or ADT.

• Active surveillance — reasonable for lower-risk men (BCR >3 years from RT, PSADT ≥16 months, pre-RT grade group 1) or life expectancy <10 years.
• Local salvage therapy — may improve metastasis-free survival, delay ADT, and eradicate disease in selected men (T1c–T2, PSA <10 ng/mL at recurrence, no metastases), although the survival benefit is unproven and biopsy-proven recurrence should be confirmed first.

Salvage radical prostatectomy is a technically demanding operation for highly selected men, performed only by experienced surgeons. The EAU restricts it to men with low comorbidity, life expectancy >10 years, initial stage T1–T2, initial biopsy ISUP grade <2/3, pre-salvage PSA <10 ng/mL, and no nodal or distant metastases.

• Outcomes — positive-margin rate ≈20%; biochemical-recurrence-free survival 47–82% (5 yr) and 28–53% (10 yr); cancer-specific survival 89–100% (5 yr) and 70–83% (10 yr); overall survival 54–90% at 10 years. Pre-salvage PSA is the strongest prognostic factor.
• Complications — significant perioperative morbidity and worse function than primary surgery: bladder-neck contracture 0–55%, erectile function sufficient for intercourse in only 0–20%, and rectal injury 0–28% (managed by two-layer closure, omentoplasty, or colostomy). Contemporary radiation techniques have reduced rectal injury (0–28% before 2000 vs 2–10% after), though incontinence and erectile dysfunction remain problematic.
• Approach — a multi-institutional series of 395 salvage prostatectomies found the robotic approach reduced blood loss, hospital stay, anastomotic stricture (8% vs 17% open), and incontinence at 12 months (32% open vs 22% robotic — see Corrections note), with no difference in overall or major complications (Gontero 2019). Adding pelvic lymphadenectomy improved overall and cancer-specific survival in SEER data, with marginal benefit beyond the 7th node.

Other salvage options — cryotherapy is a less morbid, outpatient alternative with durable progression-free and overall survival (erectile dysfunction is very common; other risks include urinary obstruction, urethrorectal fistula, urethral sloughing/stricture, and rectal pain). Salvage brachytherapy and HIFU are described but rest on weaker evidence.

Management — ADT and Systemic Therapy

ADT is the most common treatment for BCR after radiation but is generally not curative; the exact timing is unknown, and it is most reasonable to start in men at highest risk of distant failure (PSADT <12 months). Intermittent ADT is noninferior to continuous ADT in men with PSA >3 ng/mL without metastases, with better physical function, fatigue, libido, and erectile function (Crook 2012).

The EMBARK trial (Freedland 2023; 1,068 men with high-risk BCR — PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir after RT or ≥1 ng/mL after prostatectomy) randomized enzalutamide + leuprolide vs enzalutamide alone vs leuprolide alone: combination therapy improved 5-year metastasis-free survival to 87% vs 71% for leuprolide alone (absolute reduction 16%, NNT 6), with a non-significant 5-year OS difference (92% vs 87%). It was the first evidence that second-generation androgen-receptor monotherapy (enzalutamide) outperforms first-generation monotherapy for progression-free survival.

After Cryotherapy or HIFU

Definitions of failure after primary cryotherapy vary widely, and management strategies (repeat cryotherapy, salvage radiation, salvage prostatectomy) are not well established. After primary HIFU, PSA nadir + 1.2 ng/mL best predicts clinical failure; salvage radiotherapy and prostatectomy have been described.

Hormonal Therapy

Androgen deprivation therapy (ADT) is the backbone of systemic treatment for advanced prostate cancer. Because prostate cancer growth is androgen-driven, blocking the androgen axis — surgically or medically — produces a clinical response in the great majority of men, although the disease eventually becomes castrate-resistant.

Androgen Physiology and the Androgen Receptor

The principal androgen of the prostate is dihydrotestosterone (DHT), converted from testosterone by 5α-reductase. Type 1 is found mainly in non-genital skin and liver (and, to a lesser degree, prostate, testis, and brain); type 2 predominates in the prostate epithelium and other genital tissues, and is also present in liver, breast, hair follicles, and placenta. Functional type 2 enzyme is a prerequisite for normal prostate and external-genital development, and men with inherited 5α-reductase deficiency have minuscule prostatic tissue. DHT binds the androgen receptor (AR) with much higher affinity than testosterone, promoting nuclear translocation of the steroid–receptor complex and activation of androgen response elements. (5α-reductase inhibitors raise serum testosterone — usually within the normal range — and increase intraprostatic testosterone.)

Lack of testosterone is protective, but even hypogonadal men can develop prostate cancer through androgen-independent pathways, and the AR remains central to castrate-resistant progression. The AR is a ligand-inducible transcription factor, and five mechanisms drive castration resistance:

• Hypersensitivity — AR amplification lets even low androgen levels activate the pathway.
• Promiscuity — the AR is activated by non-androgen ligands.
• Outlaw — growth factors (EGF, IGF-1) raise AR activity in the absence of androgen.
• Bypass — parallel survival pathways keep cells alive without androgen.
• Lurker cell — pre-existing epithelial stem cells are selected out by androgen deprivation.

ADT is continued through CRPC because the disease is rarely truly resistant to androgen action — exogenous androgen causes symptomatic tumour flare in 87% of CRPC patients. (The term castrate-resistant is preferred over hormone-refractory.)

Approaches to Androgen-Axis Blockade

Charles Huggins first demonstrated hormonal control of prostate cancer in 1946 (orchiectomy and estrogen lowered serum acid phosphatase in 8 men with metastatic disease; PSA was not discovered until 1979), work that earned the 1966 Nobel Prize. The axis can be blocked at four points:

Target	Agents
Ablate the source	Bilateral orchiectomy
Inhibit stimulation (LHRH/LH)	Estrogen, LHRH agonists, LHRH antagonists
Inhibit synthesis	Ketoconazole, abiraterone
Block the receptor	Cyproterone acetate, flutamide, bicalutamide, enzalutamide, apalutamide, darolutamide

Surgical Castration and Estrogens

Bilateral orchiectomy reduces testosterone to castrate levels (<50 ng/dL) within 24 hours (>90% reduction) but has largely been replaced by LHRH analogues; subcapsular orchiectomy removes only glandular tissue to avoid an empty scrotum. Estrogen was the first central inhibitor — estradiol is 1,000× more potent than testosterone at suppressing LH/FSH — and diethylstilbestrol (DES) is as effective as surgical castration but limited by cardiovascular toxicity (though it remains the cheapest form of ADT).

LHRH Agonists

As effective as orchiectomy and now the dominant therapy thanks to long-acting depot preparations (e.g. goserelin 10.8 mg SC every 3 months, leuprolide 22.5 mg SC every 3 months, triptorelin). Their drawback is an initial testosterone flare: LH surges up to 10-fold, and the resulting testosterone rise can cause a life-threatening symptom exacerbation. Cover the flare with an anti-androgen (bicalutamide 50 mg daily) for 21–28 days (the flare itself lasts 10–20 days); simultaneous and pre-emptive dosing give similar PSA results. After the surge, phasic pituitary stimulation is lost and testosterone falls to castrate levels.

LHRH Antagonists

These bind LHRH receptors immediately and competitively, dropping LH by 84% within 24 hours and avoiding any surge — so no anti-androgen cover is needed and testosterone falls within 3 days (castrate in 34.5%, 60.5%, and 98.1% of men at days 2, 4, and 28). They are preferred when urgent castration is needed (impending cord compression, severe bone pain) or surgical castration is unsuitable. Agents are the "-lix" drugs (abarelix, cetrorelix, degarelix, relugolix); degarelix is dosed as a 280 mg induction then 80 mg every 28 days, was non-inferior to leuprolide at 1 year (Klotz 2008), and, unlike abarelix, causes no systemic allergic reaction.

The oral antagonist relugolix was tested in HERO (Shore 2020; 930 men with relapse after curative treatment, newly diagnosed metastatic hormone-sensitive disease, or advanced localized disease): relugolix 120 mg orally daily was superior to leuprolide for sustained castration at 48 weeks (96.7% vs 88.8%) and halved major cardiovascular events (HR 0.46).

By method, LHRH agonists reduce LH and only partially suppress FSH, LHRH antagonists reduce both LH and FSH, and surgical castration leaves LH and FSH significantly elevated.

Androgen Synthesis Inhibitors

Ketoconazole (historical) is a non-specific CYP450 inhibitor that abolishes adrenal and Leydig-cell steroid synthesis within hours; its effect is immediately reversible, requiring continuous 8-hourly dosing, and it is given with hydrocortisone (20 mg BID). Aminoglutethimide (historical) blocked an early steroidogenic step, acting as a medical adrenalectomy that required cortisone and fludrocortisone replacement.

Abiraterone acetate is an orally active, irreversible inhibitor of CYP17 (both 17,20-lyase and 17α-hydroxylase), blocking androgen synthesis in the testis, adrenals, and tumour itself — more potent than ketoconazole. Blocking 17α-hydroxylase raises mineralocorticoids (deoxycorticosterone, corticosterone) and suppresses cortisol with a compensatory ACTH rise, so it is co-administered with prednisone. Key adverse effects are hypertension, hypokalaemia, and fluid overload (mineralocorticoid excess), plus fatigue, raised lipids, myopathy, and — most seriously — hepatotoxicity (the commonest reason for dose reduction; check LFTs and electrolytes frequently). It is used in CRPC (COU-AA-301 post-docetaxel, COU-AA-302 pre-docetaxel) and hormone-sensitive disease (LATITUDE, STAMPEDE — see Metastatic Hormone-Sensitive Prostate Cancer).

Androgen-Receptor Antagonists

Anti-androgens are steroidal or non-steroidal:

• Steroidal (cyproterone acetate) also suppresses the hypothalamic-pituitary axis, lowering LH and testosterone (by 70–80%); adverse effects are fluid retention, thromboembolism, and hypogonadism.
• Non-steroidal ("-lutamides") block the AR at target tissues and the hypothalamus, raising LH and testosterone (to ~1.5× normal). They cause less hypogonadism and osteoporosis but more cardiovascular risk, and share class toxicities of hepatotoxicity (reversible hepatitis to fulminant failure — monitor LFTs), diarrhoea (worst with flutamide), and gynaecomastia/breast pain (from aromatization of testosterone to estradiol).

Generation	Agent	Notes
First	Flutamide	Short half-life, three-times-daily dosing
	Bicalutamide	Once daily; PK unaffected by age, renal, or moderate hepatic impairment; 150 mg/day monotherapy ≈ castration in metastatic/locally advanced disease, with better sexual interest and physical capacity but more gynaecomastia (66.2%) and breast pain (72.8%)
	Nilutamide	~25% report delayed dark adaptation after bright light
Second	Enzalutamide	Irreversibly binds the AR, blocking androgen binding, nuclear translocation, and DNA binding; contraindicated with a seizure history
	Apalutamide	Binds the AR ligand-binding domain; contraindicated with a seizure history; adds hypothyroidism and rash
	Darolutamide	Low blood–brain-barrier penetration → fewer and less severe toxic effects than the other two

Shared second-generation toxicities include hypertension, diarrhoea, fatigue, seizures (<1%), falls, and fractures. Their trial programmes:

Agent	Disease-state trials
Enzalutamide	AFFIRM (post-docetaxel mCRPC), PREVAIL (pre-docetaxel mCRPC), PROSPER (M0 CRPC), ENZAMET & ARCHES (M1 CSPC)
Apalutamide	SPARTAN (M0 CRPC), TITAN (M1 CSPC)
Darolutamide	ARAMIS (M0 CRPC)

A clinical response to ADT is almost universal; the magnitude and rapidity of the PSA fall are the best predictors of how durable that response will be, and a sluggish response signals a large androgen-refractory population.

Combined Androgen Blockade

Combined androgen blockade (CAB) adds an anti-androgen to castration to also block residual adrenal androgens. In a meta-analysis of 27 trials there was no overall 5-year survival difference (CAB 25.4% vs ADT 23.6%); cyproterone-containing arms did slightly worse (15.4% vs 18.1%, suggesting excess non-cancer deaths), whereas with the non-steroidal anti-androgens flutamide or nilutamide CAB gave a small but significant 3% absolute 5-year survival gain (27.6% vs 24.7%).

Indications and Timing

• Low-risk localized disease — no benefit, and worse overall survival, from primary ADT.
• Locally advanced / asymptomatic metastatic — the role is controversial; in community practice with limited monitoring, immediate ADT improves cancer-specific but not overall survival, while in men unsuitable for local treatment it improves overall but not cancer-specific survival.
• Node-positive — no advantage to immediate ADT in untreated cN+ disease, but a significant survival advantage (2.6-year median OS gain) for immediate ADT in pN+ disease after prostatectomy (ECOG 3886, Messing).
• Symptomatic metastatic disease — ADT is indicated.

The AUA recommends palliative ADT monotherapy only for high-risk localized disease with local symptoms and limited life expectancy, supports ADT for metastatic hormone-sensitive and castrate-resistant disease, and advises against routinely starting ADT for biochemical recurrence without metastases.

Intermittent vs Continuous ADT

Intermittent ADT lengthened the time to androgen-refractory growth in animal models and is intended to improve quality of life. Two trials defined its role:

Trial	Population	Result
PR7 (Crook 2012)	Rising PSA after radiotherapy	Intermittent ADT non-inferior for OS (8.8 vs 9.1 yr); better hot flashes, sexual desire, and urinary symptoms (95% CI upper limit 1.22, below the 1.25 non-inferiority margin)
SWOG 9346 (Hussain 2013)	Newly diagnosed metastatic	Statistically inconclusive, but median OS numerically worse with intermittent (5.1 vs 5.8 yr); intermittent "may compromise survival"

Both used an induction period (8 and 7 months) and stopped ADT once PSA fell below 4 ng/mL, managing CRPC continuously; they differed in population and restart thresholds (PSA 10 after radiotherapy vs 20 for metastatic disease). There is no consensus on the ideal schedule, but non-metastatic patients generally tolerate intermittent ADT without compromising oncologic outcomes, whereas metastatic patients should be offered it with caution.

Complications of ADT

The toxicities are broad — a useful mnemonic is "COACH Wants BDSM From Montreal": Cardiovascular disease, Osteoporosis, Anaemia, Cognitive dysfunction, Hot flashes, Weight gain, Breast events, Diabetes, Sexual dysfunction, Muscle-mass loss, Fatigue, and Metabolic effects.

Complication	Key facts
Cardiovascular	Pre-existing heart disease is the key risk factor for MACE; GnRH antagonists carry lower CV risk than agonists (HR 0.44; HERO MACE 3% vs 6%) — consider an antagonist after prior MI/stroke. Nanda (2009): excess mortality only in men with CAD-induced CHF or prior MI
Osteoporosis	BMD falls fastest in year 1; ~4 years of ADT pushes the average man into osteopenia (T-score <−1). Shahinian (2005): 5-year fracture risk 19% vs 13%, hospitalization for fracture 5.2% vs 2.4%
Anaemia	Normochromic, normocytic; Hb falls 1–2 g/dL (see Corrections note); ~90% on CAB drop ≥10%
Cognitive	Possible depression (HR 1.51), dementia (HR 1.21), and Alzheimer's (HR 1.16); causality remains weak
Hot flashes	Affect 50–80%; decrease over time
Weight / fat	Weight +2.1%, fat mass +8% (subcutaneous), as early as 1 month; may persist 2 years after stopping
Breast events	Gynaecomastia (aromatization to estradiol) — most common with anti-androgen monotherapy, rare with LHRH monotherapy or CAB
Diabetes	Alibhai (2009): incident diabetes HR 1.16
Sexual	Loss of libido up to 90%; stretched penile length fell 10.76 → 8.05 cm over 15 months; only ~20% maintain any sexual activity
Muscle / fatigue	Reduced grip strength, gait speed, and aerobic fitness; fatigue is multifactorial
Metabolic	Insulin resistance, glucose intolerance, raised triglycerides/LDL/total cholesterol, and metabolic syndrome (Braga-Basaria 2006)

The cardiovascular evidence is mixed — observational studies and randomized-trial meta-analyses agree on increased non-fatal cardiovascular disease but disagree on cardiovascular mortality, MI, and stroke. Among the agents, enzalutamide raises hypertension (but not cardiac events), while abiraterone is associated with more cardiac events, atrial tachyarrhythmia, and heart failure. (PRONOUNCE and RADICAL-PC are addressing cardiac outcomes prospectively.)

Monitoring and Prevention on ADT

Before starting ADT (2021 CUA guidance), assess cardiometabolic and bone risk:

• Cardiometabolic — history of MACE, cardiac risk factors, and prior VTE/stroke; measure BP, weight, waist circumference, and BMI; screen for diabetes (fasting glucose, OGTT, or HbA1c) and check a lipid profile; refer to cardiology after prior MI or stroke.
• Bone — falls-risk and height; check calcium and 25-hydroxyvitamin D; obtain a DXA and calculate the 10-year fracture risk (FRAX).

On treatment:

• Cardiometabolic — supervised resistance plus aerobic exercise (superior to self-directed programmes and beneficial across physical, functional, endocrine, and quality-of-life domains); target BP <130/80; repeat diabetes and lipid screening every 6–12 months.
• Bone — calcium 1,200 mg/day total and vitamin D 800–2,000 IU/day; bisphosphonates (zoledronic acid, alendronate, pamidronate) for osteoporosis, prior fragility fracture, or moderate/high fracture risk. The 2020 CUA CSPC guideline recommends vitamin D and calcium for all men on ADT, with bone-targeted therapy (zoledronic acid 5 mg yearly, alendronate 70 mg weekly, or denosumab 60 mg every 6 months) for those at high fracture risk; in CRPC with bone metastases, denosumab or zoledronic acid is given every 4 weeks. Repeat DXA every 1–3 years according to risk.
• Hot flashes — avoid triggers; options (none formally approved) include medroxyprogesterone 20 mg daily, megestrol 20 mg BID (monitor for disease progression), cyproterone 50–100 mg daily, gabapentin 900 mg daily, and venlafaxine 75 mg daily (cyproterone and medroxyprogesterone outperformed venlafaxine in Irani 2010); intermittent ADT and acupuncture may help.
• Breast events — tamoxifen is more effective than radiotherapy (10–12 Gy) for both prophylaxis and treatment (radiotherapy has no benefit once gynaecomastia is established); routine prophylaxis is not recommended.
• Other — exercise for fatigue; hematology referral for severe or unexpectedly steep anaemia; sex-therapy referral and PDE5 inhibitors for sexual dysfunction; monitor for cognitive decline and depression; consider intermittent ADT to improve quality of life.

Metastatic Hormone-Sensitive Prostate Cancer

Metastatic hormone-sensitive prostate cancer (mHSPC) was historically treated with ADT alone, but several agents first proven in castrate-resistant disease now improve survival when added to ADT up front. The modern standard is treatment intensification — ADT plus at least one of an AR-pathway inhibitor (abiraterone, enzalutamide, apalutamide, or darolutamide), docetaxel chemotherapy, or, for low-volume disease, radiation to the prostate. Disease volume guides the choice.

Defining Disease Volume

Two definitions recur and are easily confused:

• CHAARTED high-volume — visceral metastases, or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.
• LATITUDE high-risk — ≥2 of: visceral metastasis, ≥3 bone lesions, Gleason ≥8.

ADT Plus an AR-Pathway Inhibitor

Agent (added to ADT)	Trials	Key result
Abiraterone + prednisone	LATITUDE (Fizazi 2017, n=1,199 high-risk), STAMPEDE (James 2017, n=1,917)	OS improved (LATITUDE HR 0.62, median not reached vs 34.7 mo); rPFS 33.0 vs 14.8 mo (HR 0.47); STAMPEDE improved overall and failure-free survival
Enzalutamide	ENZAMET (Davis 2019, n=1,125), ARCHES (Armstrong 2019, n=1,150)	OS improved (HR 0.67; 3-yr 80% vs 72%), more fatigue and seizures; rPFS HR 0.39 in both high- and low-volume disease
Apalutamide	TITAN (Chi 2019, n=525)	Improved radiographic progression-free and overall survival
Darolutamide	ARASENS (Smith 2022, n=1,306)	Added to ADT + docetaxel ("triplet therapy"), improved overall survival

ADT Plus Docetaxel

Docetaxel is a taxane that inhibits microtubule assembly, arresting the cell cycle. Key toxicities are neutropenia (febrile neutropenia is the commonest serious event), anaemia, thrombocytopenia, neuropathy, alopecia, fluid retention, dyspnoea, and gastrointestinal upset.

• CHAARTED (Sweeney 2015; 790 men) — ADT ± docetaxel improved median OS by 13.6 months (57.6 vs 44.0 mo, HR 0.61) overall, but on stratified analysis the benefit was significant only in high-volume disease.
• STAMPEDE (James 2016; 2,692 men, including non-metastatic disease) — adding docetaxel (75 mg/m² for six 3-weekly cycles with prednisolone 10 mg daily) to standard ADT improved OS by ~10 months (81 vs 71 mo, HR 0.78), along with failure-free and cancer-specific survival; zoledronic acid added no survival benefit.

The 2019 NCCN guideline recommends ADT + docetaxel for M1 castration-naïve disease, reserving ADT monotherapy for asymptomatic metastatic men with a life expectancy ≤5 years.

Radiation to the Primary

STAMPEDE (Parker 2018; 1,061 newly diagnosed metastatic men with no prior radical treatment) randomized prostate radiotherapy versus standard of care. There was no overall survival benefit overall (HR 0.92, 95% CI 0.80–1.06), but radiotherapy improved failure-free survival (HR 0.76) and — critically — improved OS in the low-metastatic-burden subgroup (HR 0.68, 95% CI 0.52–0.90) but not the high-burden subgroup (HR 1.07). This established prostate radiotherapy as standard for low-volume metastatic disease.

Castrate-Resistant Prostate Cancer

Castrate-resistant prostate cancer (CRPC) is disease progression despite castrate testosterone (<50 ng/dL), shown by a rising PSA, progression of existing disease, and/or new metastases. ADT almost always eventually fails this way, but the androgen receptor stays active — so ADT is continued for life and layered with successive agents. The field has expanded rapidly: chemotherapy, AR-pathway inhibitors, a radiopharmaceutical, a radioligand, immunotherapy, and PARP inhibitors all extend survival in the metastatic setting.

Definition and Workup

Men on ADT are monitored with PSA (the first sign of progression, preceding bone-scan changes while the patient is still asymptomatic), imaging (bone scan and CT), and serum testosterone (to confirm castrate levels — useful if non-compliance is suspected or if prior therapy was non-steroidal anti-androgen monotherapy, which may not sustain castration). Consider neuroendocrine differentiation in a man who progresses clinically or radiologically without a matching PSA rise; biopsy an accessible lesion and treat with platinum-based chemotherapy (cisplatin or carboplatin with etoposide).

The most important urologic sequela of advanced disease is obstructive uropathy, and paraneoplastic effects include anaemia, weight loss, fatigue, hypercoagulability, and increased infection risk. Eight prognostic factors are PSA, PSA doubling time, performance status, visceral metastases, bone pain, extent of disease on bone scan, LDH, and alkaline phosphatase; a PSADT under 3 months signals a rapid course warranting aggressive management.

General Principles

• Continue ADT for life — the AR remains active in most CRPC, and trials of newer agents mandate ongoing castration.
• Anti-androgen withdrawal — in men on combined AR-antagonist + LHRH-agonist therapy, simply stopping the anti-androgen produces a >50% PSA decline in 15–30% (median 3.5–5 months), because the antagonist has begun acting as an agonist; overall survival is not improved.
• Changing the anti-androgen or adding corticosteroids ± ketoconazole gives transient PSA responses in ~30% but no meaningful outcome benefit.

Non-Metastatic CRPC

Stop any first-generation anti-androgen, then stratify by PSA doubling time:

• PSADT ≥10 months — observation or secondary hormonal manipulation.
• PSADT <10 months (high-risk) with life expectancy >5 years — apalutamide, enzalutamide, or darolutamide, each with continuous ADT.

Three practice-changing trials (all enrolled PSADT ≤10 months, all used metastasis-free survival as the primary endpoint, and all improved MFS by ~22 months and OS by ~12 months):

Trial	Agent	Metastasis-free survival	Overall survival
SPARTAN	Apalutamide 240 mg/day	40 vs 16 mo (HR 0.28)	74 vs 60 mo (HR 0.78)
PROSPER	Enzalutamide 160 mg/day	37 vs 15 mo (HR 0.28)	67 vs 56 mo (HR 0.73)
ARAMIS	Darolutamide 600 mg BID	40 vs 18 mo	83% vs 77% at 3 yr

Monitor for metastases with bone scan and CT chest/abdomen/pelvis — every 3–6 months if PSADT <10 months or PSA >20, every 6–12 months if PSADT >10 months (the role of PSMA-PET is not yet defined).

Metastatic CRPC

About 90% of men with CRPC develop bone metastases (causing pain, pathological fracture, spinal cord compression — an emergency — and marrow failure); visceral metastases are much less common and rarely occur without bone disease. Because most tumour burden is in bone, radiographic progression-free survival is preferred over response rate as a trial endpoint.

Approved Systemic Therapies

Class / Agent	Setting	Pivotal trial(s)	Key result
Docetaxel (taxane)	First-line	TAX 327	OS 18.9 (3-weekly) vs 16.4 mo (mitoxantrone); standard first-line chemo
Cabazitaxel (taxane)	Post-docetaxel	TROPIC	OS 15.1 vs 12.7 mo vs mitoxantrone; 82% grade 3–4 neutropenia — use growth-factor support
Enzalutamide (AR antagonist)	Pre- or post-docetaxel	AFFIRM (post), PREVAIL (pre)	OS 18.4 vs 13.6 mo (AFFIRM); OS HR 0.71 (PREVAIL)
Abiraterone + prednisone (CYP17 inhibitor)	Pre- or post-docetaxel	COU-AA-301 (post), COU-AA-302 (pre)	OS 14.8 vs 10.9 mo (301); rPFS 16 vs 8 mo (302)
Radium-223 (α-emitter)	Bone pain, no visceral mets, nodes ≤3 cm	ALSYMPCA	OS 14.9 vs 11.3 mo; do not combine with abiraterone (ERA 223: more fractures)
¹⁷⁷Lu-PSMA-617 (radioligand)	PSMA-positive after an ARPI + taxane	VISION, TheraP	Improved PFS and OS (VISION); better PSA response than cabazitaxel (TheraP)
Sipuleucel-T (vaccine)	Asymptomatic/minimally symptomatic, no visceral mets	IMPACT	OS 26 vs 22 mo; no change in PFS or PSA
Olaparib (PARP inhibitor)	HRR mutation after an ARPI	PROfound	rPFS 7.4 vs 3.6 mo; OS 19.1 vs 15.7 mo (BRCA/ATM cohort)
Rucaparib (PARP inhibitor)	BRCA1/2 after an ARPI + taxane	TRITON-2 (phase II)	Activity in BRCA-altered disease
Pembrolizumab (checkpoint inhibitor)	MMR-deficient / MSI-high mCRPC	KEYNOTE-199	Durable responses in the MMR/MSI-H subset (tumour-agnostic indication)

Key nuances:

• Mitoxantrone improves pain and quality of life but not survival — a palliative option only.
• Docetaxel is dosed 75 mg/m² every 3 weeks with prednisone; weekly dosing did not improve survival (TAX 327). Toxicities include neutropenia, fatigue, neuropathy, peripheral oedema, hyperlacrimation, and nail dystrophy. FIRSTANA showed cabazitaxel is not superior to docetaxel first-line.
• Abiraterone blocks adrenal and intratumoral androgen synthesis (sources LHRH analogues miss); on radium-223, alkaline phosphatase tracks activity better than PSA.
• HRR mutations occur in 20–30% of metastatic disease (most commonly BRCA2); defective repair makes the tumour susceptible to PARP inhibition (synthetic lethality).
• Checkpoint inhibitors have disappointed — pembrolizumab gave objective responses in only 3–5% (KEYNOTE-199), and ipilimumab did not improve overall survival (CA184-043). Cabozantinib (COMET-1/-2) failed its survival and pain endpoints despite bone-scan activity.

Treatment Sequence

• Chemotherapy-naïve, asymptomatic or minimally symptomatic — first-line abiraterone 1000 mg/day + prednisone or enzalutamide 160 mg/day; reserve docetaxel for second-line (or earlier with poor hormonal response or visceral disease).
• Moderate or severe symptoms — docetaxel; radium-223 (every 4 weeks × 6) for bone pain without visceral disease; abiraterone or enzalutamide if docetaxel is refused or not tolerated.
• After docetaxel — five options improve survival: cabazitaxel, radium-223, and (if not used earlier) abiraterone or enzalutamide. Docetaxel re-challenge and mitoxantrone offer palliation without a proven survival gain.

The optimal sequence is unknown, but changing the mechanism of action with each line is thought to give better, more durable responses.

Bone-Targeted Therapy and Supportive Care

In mCRPC with bone metastases, give denosumab 120 mg SC or zoledronic acid 4 mg IV every 4 weeks, plus daily calcium and vitamin D, to prevent skeletal-related events (pathological fracture, spinal cord compression, bone surgery, or radiation to bone):

• Zoledronic acid is the only bisphosphonate proven to reduce disease-related SREs (Saad 2004); avoid it if creatinine clearance is <30 mL/min, and watch for osteonecrosis of the jaw and hypocalcaemia.
• Denosumab (anti-RANK-ligand) beat zoledronic acid on time to first SRE (20.7 vs 17.1 months) with no survival difference, and needs no renal dose adjustment; ONJ occurs in 2–4%.
• ONJ risk rises after ~2 years — encourage oral hygiene, a baseline dental review, and avoidance of invasive dental work on therapy. Neither agent is approved for castrate-sensitive disease or for preventing bone metastases.

Palliative radiotherapy controls focal bone pain (exclude a pathological fracture first). Malignant spinal cord compression is an emergency — image with MRI and treat with radiation plus steroids, debulking surgery, or vertebrectomy with stabilisation.

Urothelial Cancer of the Prostate

Urothelial carcinoma can involve the prostate by extension from bladder cancer or, rarely, as a primary tumour. It is almost always tied to bladder urothelial cancer — particularly carcinoma in situ — and the depth of prostatic involvement drives both treatment and prognosis.

Background and Risk Factors

• 90% of prostatic urothelial carcinomas occur in men with a history of bladder urothelial cancer (chiefly bladder CIS), yet only 3% of men with primary bladder urothelial cancer go on to develop it.
• 40% of men undergoing radical cystectomy for urothelial cancer are found to have urothelial carcinoma of the prostate.
• Primary urothelial carcinoma of the prostate without bladder involvement is uncommon (1–4% of all prostate carcinomas).
• Spread is usually by direct extension of bladder cancer into the prostatic urethra, though pagetoid spread beneath normal-appearing urothelium also occurs; intraductal and infiltrating disease accompanies higher-stage bladder tumours.

Five risk factors for prostatic urethral involvement: bladder CIS, previous intravesical chemotherapy, multifocal disease, tumours at the trigone or bladder neck, and high-risk NMIBC.

Staging (AJCC 8th Edition, Prostatic Urethra)

Stage	Definition
Ta	Non-invasive papillary carcinoma
Tis	Carcinoma in situ — Tis pu (prostatic urethra) or Tis pd (prostatic ducts)
T1	Invasion of subepithelial connective tissue
T2	Invasion of prostatic stroma
T3	Invasion of periprostatic fat or bladder neck (extraprostatic extension)
T4	Invasion of adjacent organs (e.g. bladder or rectal wall)

Importantly, in the bladder cancer staging system only prostatic stromal invasion (direct or indirect) qualifies as T4a bladder cancer; extension into the prostatic urethra without stromal invasion is staged under the urethra, not the bladder, and does not carry an adverse prognosis. (For reference, penile-urethra T-stages run T1 subepithelial connective tissue → T2 corpus spongiosum → T3 corpus cavernosum → T4 adjacent organs.)

Diagnosis

Transurethral resection and biopsy of the prostatic urethra is the primary detection method. For the highest yield, biopsy any suspicious area plus the 5 and 7 o'clock (precollicular) positions at the verumontanum, where prostatic ducts are most concentrated. Indications include positive urine cytology with a negative bladder biopsy, recurrent bladder cancer after multiple courses of intravesical chemotherapy, and a visible prostatic-urethral tumour.

Management

Treatment follows the depth of involvement:

• CIS of the prostatic urethra (Tis pu) or a visible prostatic-urethral tumour with concurrent NMIBC — TURP then BCG (TURP first for accurate staging and to increase BCG efficacy by exposing more surface area).
• CIS of the prostatic ducts (Tis pd) — controversial; consider TURP + BCG with re-biopsy after BCG, because ductal disease can invade and, once invasive, carries a high metastatic risk.
• Recurrent high-grade disease after TURP + BCG — consider radical cystectomy + urethrectomy; for a bladder-sparing approach, repeat BCG or intravesical gemcitabine.
• Prostatic stromal invasion (T2) — radical cystectomy ± urethrectomy (urethrectomy especially if tumour is at or near the margin); stromal invasion is a poor prognostic factor, treated with multimodal chemotherapy plus radical cystectomy.

Prognosis

Five-year survival varies sharply with depth: up to 100% with urethral mucosal involvement, 50% with ductal/acinar/glandular involvement, and 40% with stromal invasion.