Prostate Cancer

Pathology & Pre-Cancerous Lesions

PIN

• Low-grade or unifocal high-grade — no increased risk of developing prostate cancer; monitor PSA + DRE (biopsy only if suspicion)
• Multifocal high-grade (2 or more cores) — cancer risk ≈ 30%; monitor PSA + DRE and repeat biopsy in 1–3 years
  • A single core of PIN needs no re-biopsy — just monitor PSA and DRE
  • It matters to distinguish PIN from ductal or intraductal carcinoma — a uropathologist's call
• In an elderly patient with HGPIN found on TURP, often no further workup is instituted; in a younger man a more aggressive workup to exclude clinically significant tumour may be warranted

AAH (Adenosis)

• Atypical adenomatous hyperplasia — no risk of cancer

ASAP

• HMWCK positive
• Suspicious but non-diagnostic
• Does not alter PSA
• → Re-biopsy in 3–6 months, focusing on the atypical regions
• Cancer risk: 40–60%

Prostate Cancer Histology

• HMWCK negative
• Types:
  • Acinar (most common — > 95% of adenocarcinomas; 85% arise in the peripheral zone, multifocal in >85%)
  • Ductal (normal PSA) CI to AS
  • Intraductal — a rare and aggressive variant (Gleason 4+4); grows into the urethral lumen and usually presents with obstructive voiding symptoms + hematuria; does not alter PSA. CI to AS
  • Non-adenocarcinoma is < 5%, of which transitional cell is the most common

Why HMWCK staining answers the question

• Prostate adenocarcinoma arises from prostate epithelial cells, which stain positive for prostatic acid phosphatase (PAP) and PSA
• Normal prostate has a basal cell layer, which stains positive for HMWCK and negative for PAP and PSA
• Prostate adenocarcinoma NEVER has a basal cell layer
• So: stain with HMWCK → positive = basal layer present = benign; negative = no basal layer = malignant, and it will stain positive for PAP and PSA

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Risk Factors

• African ancestry (incidence Black > White > Hispanic > Asian)
• Age >40
• Germline mutations: BRCA2 (most aggressive), BRCA1, CHEK2, Lynch (MLH1/MSH2/MSH6/PMS2)
• TMPRSS2:ERG fusion in ~50% sporadic PCa
• Mets pattern: LN → bone (osteoblastic) → lung → bladder → liver

Family history — relative risk

Family history	Relative risk	95% CI
None	1	—
Father affected	2.17	1.90–2.49
Brother affected	3.37	2.97–3.83
First-degree relative affected, age < 65 at diagnosis	3.34	2.64–4.23
> 2 first-degree relatives affected	5.08	3.31–7.79
Second-degree relative affected	1.68	1.07–2.64

• A brother affected carries higher risk than a father affected

Chromosomal and germline detail

• Chromosome 8 — typically loss of the p arm and gain of the q arm; the most common chromosomal abnormality in advanced prostate cancer
• Chromosomes 10 and 7 are also altered; others — 13q, 16q, 17p, 18q
• PTEN is more frequently altered in advanced disease
• BRCA2 is the most common germline mutation in metastatic prostate cancer, and is associated with lethal disease
• BRCA2 and Lynch syndrome each raise the risk of developing prostate cancer 2–6 fold
• BRCA1, BRCA2 and ATM are inherited DNA damage-repair genes that increase the risk of aggressive disease

Germline vs Somatic Testing

	Germline	Somatic
Origin	Inherited from parents at conception	Acquired after conception
Heritable?	Can be passed to the next generation	Cannot be transmitted
Who can be tested	Persons with and without cancer	Only patients
Sample	Blood (lymphocytes), buccal swab, or saliva	Cancer tissue is a must
Predicts	Risk of developing future cancer	—

• Most mutations in prostate cancer are somatic

Indications for germline testing

1. High-risk prostate cancer
2. N1 or M1 disease
3. Significant family history — first-degree, younger age at diagnosis (< 65), number of members affected
4. Ductal, intraductal or cribriform patterns

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PSA Biology & Interpretation

• Half-life: 2–3 days; a glycoprotein, molecular weight 33 kD, 7% carbohydrate
• Bound to: α1-antichymotrypsin, α1-protease inhibitor
• ↑ by: BPH, prostatitis, UTI, biopsy (↑6–8 ng/mL, normalizes 2–3 wk), TURP, cycling
• Minimal effect: DRE, catheterization, TRUS without biopsy
• 5-ARIs halve PSA at 12 mo → double observed value
• 25–40% of newly elevated PSAs normalize → repeat before biopsy

Other Markers

Before diagnosis — after a previously negative biopsy

Type	Test	What it does
Serum	4kScore, Prostate Health Index (PHI)	Risk-stratify the likelihood of high-grade cancer on repeat biopsy
Urine	PCA3, ExoDx, SelectMDx	SelectMDx evaluates mRNA in urine after DRE — useless if the patient has a urinary diversion
Tissue	ConfirmMDx	Epigenetic evaluation of hypermethylation in three genes, on tissue from the previous negative biopsy (within the prior 30 months)

After diagnosis — biopsy-based genomic tests

Test	What it measures
Decipher	mRNA expression of 22 genes
Prolaris	mRNA expression of cell cycle progression genes; predicts CSM and recurrence
Oncotype DX	Predicts adverse pathology — T3 or Gleason 4

• These three predict adverse pathology, metastasis or cancer-specific mortality — and are NOT indicated prior to a diagnosis of prostate cancer

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Screening

• PSA elevation occurs 6–13 years before prostate cancer causes symptoms
• An abnormal PSA should be repeated in the same lab after 4–6 weeks
• Start screening at 50; if high risk, start at 40 — family history, African ancestry, germline mutations
• Men aged 40–49 have a median PSA of 0.7 ng/mL — a man in this age group above the median is at higher risk of developing prostate cancer with an aggressive subtype
• Annual screening is advised for: African ancestry, family history, or a PSA above the median for the age group

Age 70–75 — the decision point

PSA at 70–75	Risk of dying from prostate cancer	Implication
< 3	Very low — ≤ 3%	Further screening unlikely to benefit
> 3	7%	More likely to benefit from further PSA testing

Screening intervals

Body	Interval
American Cancer Society	PSA < 2.5 → every 24 months; PSA > 2.5 → annual ± DRE
AUA	Every 2 years, with or without DRE

DRE

• Prostate cancer is found in 30% of suspicious DREs
• DRE raises PSA by only 0.26 ng/mL — not a reason to defer testing

PSA density

• PSAD = PSA ÷ prostate volume; suspect cancer if PSAD > 0.15

Free PSA — the higher the free PSA%, the lower the risk

Free PSA	Probability of prostate cancer
< 10%	56%
> 25%	8%

• Do not use free PSA in ESRD patients on haemodialysis
• Cystoscopy raises free PSA

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MRI & PI-RADS

PI-RADS	Cancer Risk	csPCa (GG≥2)
1–2	~25%	~7%
3	~33%	12–15%
4	~62%	39–48%
5	~66% (GS ≥3+4; 37% GS 4+3)	~72%

• PI-RADS 5 with negative biopsy → repeat MRI then biopsy
• Hypoechoic lesion on TRUS → ~57% cancer
• Post-biopsy: wait 6–8 weeks before MRI

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Factors Suggesting Need for Biopsy

• Abnormal DRE
• Abnormal PSA, PSAV, or PSAD (single abnormal PSA alone should not trigger biopsy → repeat first)
• Abnormal MRI (PI-RADS ≥3)
• PSA fails to decline on 5-ARI
• After TRUS biopsy: ~75% negative | False-negative rate 20–30%
• Most common complication post-biopsy: hematospermia

PSA velocity thresholds

• > 0.35 ng/mL/yr when PSA < 4
• > 0.75 ng/mL/yr when PSA 4–10

Technique

• Minimum 12 cores [AUA]
• Ciprofloxacin is the pre-procedure antibiotic of choice
• A second biopsy must target the midline peripheral zone, the anterior apical peripheral zone, and the anterior transition zone — these are where cancer hides when the first biopsy was falsely negative

Seminal Vesicle Biopsy — Indications

• Suspected SV invasion
• Planning salvage cryotherapy after radiation
• PSA > 15, or a large tumour at the base of the prostate

Prognostic Factors on TRUS Biopsy

• Gleason score / Grade Group
• Number & % of positive cores
• SV involvement
• Periprostatic invasion
• Perineural invasion
• Cribriform / intraductal patterns

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TNM Staging (AJCC 8th)

T

Stage	Definition
T1a	Incidental histologic finding in ≤ 5% of tissue resected
T1b	Incidental histologic finding in > 5% of tissue resected
T1c	Identified by needle biopsy, not palpable
T2a	One-half of one side or less
T2b	More than one-half of one side, but not both sides
T2c	Both sides
T3a	Extracapsular extension (unilateral or bilateral)
T3b	Seminal vesicle invasion
T4	Fixed, or invades adjacent structures — external sphincter, rectum, bladder, levator muscles, pelvic wall

N

• N1: regional LN
• The side on which the lymph nodes are involved does not affect the N stage

M

• M1a: non-regional LN | M1b: bone | M1c: other (liver, lung, brain)
• When more than one site of metastasis is present, the most advanced category is used

Pathologic Stage

Stage	Definition
pT2	Organ confined
pT3a	Extraprostatic extension (unilateral or bilateral) or microscopic invasion of the bladder neck
pT3b	Seminal vesicle invasion
pT4	Fixed, or invades adjacent structures

• There is no pathologic T1 classification
• A positive surgical margin is indicated by an R1 descriptor — residual microscopic disease

Assigning the Gleason Grade

On prostatectomy

• Primary grade = the most predominant pattern
• Secondary grade = the second most predominant pattern
• If there are 3 different grades, a tertiary pattern is reported if it is higher than the secondary grade

On biopsy

• Primary grade = the most predominant pattern
• Secondary grade = the highest non-predominant pattern — the most dangerous one, not the second most common

Worked examples

Patterns present	Prostatectomy	Biopsy
Gleason 3 (60%) + Gleason 4 (40%)	3+4 = 7	3+4 = 7
Gleason 3 (100%) — pure	3+3 = 6 (the only pattern is doubled)	3+3 = 6
Gleason 3 (60%) + 4 (30%) + 5 (10%)	3+4 = 7, tertiary pattern 5	3+5 = 8

• Gleason score is difficult to characterise accurately in a patient who has received ADT

Gleason → ISUP Grade Group

GG	Gleason	Morphology
1	≤6	Only individual discrete well-formed glands
2	3+4=7	Predominantly well-formed glands with a lesser component of poorly-formed/fused/cribriform
3	4+3=7	Predominantly poorly-formed/fused/cribriform with a lesser component of well-formed
4	8	Only poorly-formed/fused/cribriform glands — or predominantly well-formed with a lesser component lacking glands — or predominantly lacking glands with a lesser component of well-formed
5	9–10	Lacks gland formation (or with necrosis), with or without poorly-formed/fused/cribriform

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Risk Stratification

Risk level	Criteria
Very Low	PSA < 10 & PSAD < 0.15 & clinical stage T1c & GG1 & ≤ 50% cancer per core & ≤ 3 positive cores
Low	PSA < 10 & GG1 & clinical stage T1–T2a & does not meet very-low criteria
Intermediate	No high-risk features and one or more of: PSA 10–20, GG 2–3, clinical stage T2b–T2c
Favorable intermediate	GG1 & PSA < 10 & T2b–T2c · or GG1 & PSA 10–20 & T1–T2a · or GG2 & PSA < 10 & T1–T2a
Unfavorable intermediate	GG1 & PSA 10–20 & T2b–T2c · or GG2 & PSA 10–20 & T1–T2a · or GG2 & PSA ≤ 20 & T2b–T2c · or GG3 & PSA ≤ 20 & ≤ T2c
High	PSA > 20 or GG ≥ 4 or clinical stage ≥ T3

• GG1 means Gleason ≤ 6 with no pattern 4 or 5
• When a lesion is biopsied with MRI-, TRUS- or DRE-guided targeting, all positive cores from that lesion count as a single positive core. For systematic biopsies this assumes ≥ 10 cores were taken
• NCCN additionally requires cancer in < 50% of biopsy cores as a mandatory criterion for favorable intermediate disease

Very Low (Epstein)

• PSA <10, GG1, ≤3 cores, ≤50% involvement, PSAD <0.15, T1c

Low

• PSA <10 AND GG1 AND ≤T2a

→ AS first choice | alternatives: RP, EBRT, brachy → No imaging indicated

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Intermediate — Favorable

• GG1 + PSA <20 OR GG2 + PSA <10

→ LE >10 yr: AS, RP ± PLND (if nomogram >2%), OR EBRT ± brachy → LE <10 yr: Observation (preferred) OR EBRT ± brachy → Imaging: bone scan optional; cross-sectional imaging only if a nomogram indicates > 10% risk of regional node metastasis (see Imaging Indications)

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Intermediate — Unfavorable

• GG2 + PSA 10–20 OR GG3 + PSA <20

→ LE >10 yr: RP + PLND (first choice) OR EBRT + short-term ADT → LE <10 yr: Observation OR EBRT + short-term ADT → Imaging: A/P + bone

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High Risk

• PSA >20 OR GG4–5 OR ≥T3

→ LE >5 yr: RP + PLND OR EBRT + long-term ADT (preferred) → LE <5 yr: Observation OR ADT OR EBRT → Imaging: A/P + bone

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Treatment Options in Order, by Risk

Risk	Order
Low	1. Active surveillance · 2. RP · 3. XRT · 4. Cryotherapy · 5. HIFU
Intermediate	1. RP + PLND · 2. XRT · 3. AS (favorable only — see below) · 4. Cryotherapy · 5. HIFU
High (localized)	1. RP + PLND · 2. XRT

• AS for favorable intermediate is acceptable when the tumour is T2a or less, PSA < 10, < 10% Gleason pattern 4, and < 33% of cores positive

Cryotherapy

• For very low, low and intermediate risk, with no history of TURP, prostate size < 40 cc, and able to undergo transrectal ultrasound
• An alternative to RP in the obese patient, or after previous pelvic surgery or pelvic radiation
• Side effects — AUR, genital swelling, penile paraesthesia, ED, urinary incontinence, fistula, rectal pain, urethral sloughing
• Local recurrence after cryotherapy tends to occur at the apex

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Imaging Indications

Initial imaging to assess for metastasis in men without cancer-related symptoms

Risk group	Bone scan	Abdominal-pelvic cross-sectional (CT or MRI)
Very low	No	No
Low	No	No
Favorable intermediate	Optional *	Recommended if a nomogram indicates > 10% risk of regional node metastasis
Unfavorable intermediate	Yes	Yes
High	Yes	Yes

* Bone scan is optional per AUA, not recommended per NCCN or EAU. Cross-sectional imaging is optional per AUA, not recommended per EAU; NCCN recommends CT or MRI if a nomogram indicates > 10% risk of regional node metastasis. mpMRI may detect nodal metastasis better than CT. NCCN prefers mpMRI over CT for pelvic nodes; AUA and EAU express no preference.

• Obtain a bone scan regardless if there is bone pain or a high ALP

Bone Scan

• Unfavorable or high risk
• Bone pain
• Elevated ALP

PSMA-PET

• Biochemical recurrence after local therapy
• High-risk disease (initial staging)
• ~27% higher accuracy than conventional imaging (proPSMA)

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Management Overview

• Localized → risk-stratified (see above)
• Locally advanced (T3 or N1):
  • Neoadjuvant ADT + EBRT + Adjuvant ADT (preferred)
  • RP + PLND ± XRT ± ADT
• Metastatic → systemic therapy (see below)

Watchful waiting

• The intent is to give palliative therapy if the cancer progresses to the point where cancer-related symptoms are imminent or present
• Typically used in men with non-metastatic (M0) prostate cancer whose life expectancy is under 5–10 years

When to start ADT on watchful waiting

• PSA > 50

• PSADT < 12 months

• High PVR or ureteric obstruction

• PSADT is the single most predictive factor for prostate cancer mortality

• M1 disease is not curable — the patient will never be labelled disease-free

Clinical N0M0 → pathologic N1 (prostatectomy already done)

• ADT — lifelong (the best established evidence to date)
• ADT ± XRT
• Observation

Clinical N1

• Life expectancy < 5 years → watchful waiting
• Life expectancy > 5 years → 1st: RP + long-term ADT + XRT · 2nd: XRT + long-term ADT

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Active Surveillance Protocol

• PSA every 6 months; DRE annually

• Confirmatory biopsy at 1 year

• Then biopsy or MRI every 2–5 years after the confirmatory biopsy

• mpMRI to augment (does NOT replace biopsy)

• Surveillance biopsy must include the anterior apical peripheral zone and the anterior transition zone

• AS is mainly for low and very low risk. If the patient has > 20 years life expectancy, is of African ancestry, or has high volume (> 2 cores), the risk of progression is higher — therapeutic options are better

Triggers for Intervention

• Grade reclassification (GG≥2)
• Volume reclassification
• Rapidly rising PSA — a rise > 0.7/yr is the point to worry
• Patient preference

Contraindications to Active Surveillance

• Intraductal carcinoma
• Small cell / neuroendocrine variant — treatment is upfront chemotherapy, as it is resistant to ADT

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Radical Prostatectomy

• Ideal candidates for nerve-sparing — T2 or less, low risk, good baseline erection
• Bladder neck preservation does not improve the degree of incontinence, but may allow continence to return sooner
• Surgery is deferred 6–8 weeks after prostate biopsy and 12 weeks after TURP

Complications

Complication	Figure
ED	Almost 100% if no nerve-sparing technique
Loss of penile length	Mean 1 cm (range 0–5 cm)
Bladder neck contracture	1–2%
Stress incontinence	Almost 100% at the beginning; permanent in 5%
VTE	—

• After RP, incontinence is usually secondary to intrinsic sphincter deficiency
• Risk factors for SUI — surgeon experience, baseline continence, OAB, diabetes, cancer extension, prior radiotherapy, previous TURP
• A patient needing acute transfusion for hypotension after RP should be explored to evacuate the pelvic hematoma — this reduces the likelihood of bladder neck contracture and incontinence

Prognostic Factors from RP Pathology

• Positive margins — 50% of patients with positive margins do not recur
• Capsular penetration · SV involvement · Gleason 8 or higher · lymph nodes (pathologic or gross)
• These factors are what drive the choice of salvage vs adjuvant radiotherapy

Risk factors for positive margins

• Gleason 8 or higher

• T2b–T4

• Higher number of positive cores

• PSA > 10

• The most common site for a positive margin is the apex, followed by posterior, then posterolateral

Recovery of Erectile Function

Three factors matter:

1. Age — younger than 65
2. Status of potency preoperatively
3. Ability to preserve both neurovascular bundles intraoperatively

• On-demand dosing of PDE5 inhibitors appears to be the most effective method to aid recovery of sexual function

The Neurovascular Bundle

• The NVB lies outside the prostate, between the layers of lateral pelvic fascia — the levator fascia and the prostatic fascia
• It is formed by a sympathetic component via the hypogastric nerve (T12–L1), joining the parasympathetic component (S2–S4) just below the base of the prostate
• There is a 3–5 mm separation between the NVB and the prostatic capsule — which is why most men with localized disease can be offered nerve-sparing surgery

Dissection planes

Plane	Where	Consequence
Interfascial	Prostatic fascia remains on the prostate	The correct nerve-sparing plane
Intrafascial	Beneath the prostatic fascia, directly on prostatic parenchyma	Less bleeding from capsular vessels, but high risk of positive margins

Deciding when to excise the NVB

• No definite decision is made preoperatively — the call is made at surgery
• When the endopelvic fascia is opened: if induration is palpable in the lateral pelvic fascia, the NVB on that side is widely excised. If there is no induration but the NVB appears fixed to the prostate as it is released, it is also excised

High anterior release of the NVB at the apex

• Associated with significantly earlier recovery and return to baseline sexual function, and speeds recovery of continence
• Do NOT do a high anterior release if 2 or more of these are present: PSA > 10 · Gleason 6 or higher · biopsy core involvement on that side > 20% · cores with tumour on that side > 33% · abnormal DRE
• Because recovery at 12 months after unilateral high release equalled bilateral, it is now routinely done on one side only — the side with the more favorable pathology

Urine Leak After RP

• Contrast extravasation is usually posterior, along the weakest point of the anastomosis
• Diagnosis: fluid creatinine, cystogram or CT cystogram; CT urogram if ureteric injury is a concern

Management, in order

1. Ensure the urethral catheter is patent — adequate bladder drainage is the most important step. Side-fenestrated catheters drain better and should replace other types
2. Check on CT whether the drain is lying on the anastomosis — if so, adjust it; drain any collections
3. Keep the drain off suction
4. If those fail, put the Foley on suction — low intermittent wall suction, or an underwater pleural suction system. Avoid continuous suction, which may suck in bladder mucosa instead
5. Divert the urine — bilateral nephrostomy, or bilateral open-ended ureteric catheters with the distal ends exteriorized alongside the urethral catheter, rendering the anastomosis dry
6. If all fail — reconstruction

Rectal Injury

• Minor lacerations in a preoperatively prepped rectum can be repaired primarily with multilayered, non-overlapped sutures
• Moderate to extensive injuries — especially after salvage prostatectomy following radiation — are best managed with primary repair + diverting colostomy
• Postoperatively: low-residue diet and broad-spectrum antibiotics for 3–7 days

PLND

• All high-risk patients
• For intermediate risk, the nomogram threshold differs by body:

Body	Threshold
NCCN	Nomogram ≥ 2%
EAU	Nomogram ≥ 5%
AUA	Unfavorable intermediate risk

• Complications — VTE, obturator nerve injury, lymphocele
• The internal iliac lymph nodes are the primary landing zone for nodal metastasis

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Radiation Therapy

• Definitive dose 76–82 Gy
• Intermediate risk → ADT for 6 months
• High risk → ADT for 2–3 years
• Post-RP radiotherapy must be at least 64–65 Gy

PSA bounce

• May last 6–18 months after radiotherapy (some sources report up to 5 years)
• Occurs at a mean of 9 months from therapy

XRT field and ADT duration by risk

Risk level	XRT field	ADT duration
Very low / Low	Prostate ± SV	None
Favorable intermediate *	Prostate ± SV ± pelvic LN	Optional (4–6 months)
Unfavorable intermediate	Prostate + SV + pelvic LN	Recommended (4–6 months)
High	Prostate + SV + pelvic LN	Recommended (2–3 years)
N1M0	Prostate + SV + pelvic LN	Recommended (2–3 years)

ADT here means castration with or without a first-generation antiandrogen, typically starting 2 months before XRT. * If classified favorable intermediate on PSA/DRE/grade but molecular tests suggest more aggressive cancer, treat as unfavorable intermediate. Nomograms predicting SV and regional node involvement help decide whether those areas are radiated.

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Post-Prostatectomy Management

Indications for Adjuvant / Salvage RT

• Positive surgical margin (most common site = apex)
• Extracapsular extension
• SV invasion (T3)
• Detectable PSA

Indication for ADT after RP

• Positive lymph nodes (pN1)

Salvage RT

• Start at PSA ≤0.5 for best outcomes
• Minimum dose: 64 Gy to prostatic bed
• Add ADT if PSA >0.6 (RTOG 96-01)

Adjuvant vs Salvage Radiotherapy

	Adjuvant	Salvage
Setting	Detectable post-op PSA, or high risk of future recurrence on RP pathology	PSA undetectable post-op, then detectable later
When to give	PSA < 0.5, preferably at 0.1–0.2	PSA < 0.5
Timing	Usually 4–6 months post-op, once erectile function and continence have returned	On detection
Dose	—	At least 64–65 Gy

• Ideal salvage candidates — PSA < 1, long PSADT, recurrence > 1–2 years after RP, life expectancy > 10 years
• The data show no difference between them, so salvage is the better default. The RADICALS and RAVES trials found no difference in overall survival, but the adjuvant group had more urinary tract and GI toxicity

Selection for salvage radical prostatectomy — the patient must have:

• Biopsy-proven radio-recurrent prostate cancer
• At least 10 years of life expectancy
• No identifiable metastasis on imaging
• PSA < 10 ng/mL

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Recurrence

PSA Persistence (> 0.1 ng/mL)

• 5–20% of men have PSA persistence at 4–8 weeks post-operatively
• Persistent PSA after RP is associated with more advanced disease — positive surgical margins, pathologic stage > T3a, positive nodal status, ISUP grade ≥ 3
• Repeat PSA after 8 weeks. If still persistent → PSMA. If local → XRT + ADT

Distinguish this from biochemical recurrence, where the PSA became undetectable first and rose later.

After RP

• PSA ≥0.2 with confirmatory rise
• Imaging if mets suspected: CT, bone scan, or PSMA-PET
• Risk assessment → Salvage RT ± ADT
• If local → salvage XRT + ADT — 6 months if PSA < 1, 2 years if PSA > 1
• If mets → treat as M1 disease

After RT

• PSA ≥nadir + 2
• Imaging if mets suspected: CT, bone scan, or PSMA-PET
• Biopsy the prostate and seminal vesicles
  • If localized → Salvage RP, cryotherapy, brachy ± ADT
  • If negative biopsy → ADT alone

Contraindications OF Radiotherapy (ST-LIAR)

Letter	Contraindication
Size	Prostate >60 cc (brachy — ↑ urinary toxicity)
TURP	Prior TURP if defect prevents seed placement (absolute for brachy)
LUTS	Significant baseline voiding symptoms
IBD	Active inflammatory bowel disease
Ataxia telangiectasia	(absolute — severe radiation response)
Radiation	Prior pelvic radiotherapy

After HIFU or Cryotherapy

• No end-points have been validated against clinical progression for these modalities

• Do PSMA and a prostate biopsy plus SV biopsy

• If mets → treat as M1 disease

• If local → salvage radical prostatectomy or salvage cryoablation

• It usually takes about 8 years from the onset of biochemical recurrence until radiological metastases appear

Biochemical Recurrence

Workup

• PSMA-PET — recommended as the initial imaging in biochemical recurrence [EAU]
• Conventional CT/bone scan: low yield
• mpMRI performs better than PET/CT for identifying local recurrence, especially at low levels of biochemical failure

Management

• Local failure → Salvage (see above)
• Distant failure → Treat as mHSPC (see below)

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Androgen Deprivation Therapy (ADT)

Goal

• Testosterone <50 ng/dL (or <1.7 nmol/L)

General Principles

• Intermittent ADT reduces ADT-related side effects compared with continuous ADT without compromising cancer control or survival
• Prostate cancer responds to castration for an average of 2–3 years before CRPC develops — though the range runs from months to > 10 years
• In men with CRPC, some cancer cells still respond to androgen suppression — so castration must be CONTINUED while other therapies are given
• ADT side effects: hot flushes, low libido, lethargy, ED, gynecomastia
• Megestrol acetate 20 mg twice daily significantly reduces the frequency of hot flushes
• Patients on an LHRH agonist need an annual bone density scan plus regular calcium and vitamin D

Time to castrate testosterone

Therapy	Initial T flare	Subsequent T microsurge	Time to castrate T
Orchiectomy	No	No	3 hours (2–12 h)
Ketoconazole	No	Unknown	8 hours (8–72 h)
LHRH agonists	Yes	Yes (~10% of the time)	30 days
GnRH antagonists	No	No	Degarelix 3 days · Relugolix 15 days
Oral DES	No	Unknown	10–60 days

Mechanisms

Androgen biosynthesis inhibition

Ketoconazole

• A competitive inhibitor of several cytochrome P450 enzymes, including 11β-hydroxylase and CYP17
• Inhibiting CYP17 reduces androgen synthesis in the adrenal glands and testicles
• Inhibiting 11β-hydroxylase reduces aldosterone and glucocorticoid synthesis — so mineralocorticoids and steroids are necessary

Abiraterone (Zytiga) — take on an empty stomach

• A selective, irreversible inhibitor of CYP17
• In the adrenal glands, inhibiting CYP17 reduces androgens and glucocorticoids but increases mineralocorticoids

	Abiraterone	Ketoconazole
Selectivity	Selective for CYP17	Nonselective (CYP17 + 11β-hydroxylase)
Potency	Potent	Weak
Reversibility	Irreversible	Reversible (competitive)
Effect on aldosterone	Increases it (inhibits only CYP17)	Decreases it (also inhibits 11β-hydroxylase)

Abiraterone side effects

• Hyperaldosteronism / mineralocorticoid excess — fluid retention or edema 27%, hypokalemia 28%, hypertension 9%, alkalosis
• Fatigue, musculoskeletal pain, nausea, vomiting, hot flushes, diarrhoea, cough, headache
• High LFTs are the most common toxicity — requires dose reduction or stopping the drug
• If the patient develops fatigue soon after starting, increase the prednisone dose

Steroids are mandatory with abiraterone

• mCSPC → prednisone 5 mg once daily
• mCRPC → prednisone 5 mg twice daily

Monitoring on abiraterone: blood pressure, potassium, phosphate, LFTs, fluid retention, and signs of adrenocortical insufficiency — every 2 weeks for the first 3 months, then monthly

• Abiraterone is approved for mCRPC before and after chemotherapy, but not for non-metastatic CRPC

1st-gen anti-androgens

Nonsteroidal antiandrogens are FDA-approved with castration, but not approved for monotherapy.

Drug	Dose	Side effects
Flutamide	250 mg PO TID	Hepatotoxicity, gynecomastia, diarrhoea, nausea, vomiting — GI effects are the dose-limiting factor
Bicalutamide (Casodex)	50 mg PO OD — half-life 6 days	Similar to flutamide but less GI effect. Given to prevent flare with LHRH agonist induction
Nilutamide	300 mg PO OD for 30 days, then 150 mg OD	Visual disturbances, alcohol intolerance, rarely interstitial pneumonitis, nausea/vomiting

• Mastodynia on hormonal therapy (from flutamide, nilutamide or bicalutamide) → stop the drug if possible, or give tamoxifen, or breast XRT 15 Gy, or breast reduction surgery

2nd-gen anti-androgens

• These inhibit multiple steps in the AR signalling pathway; all are metabolized by hepatic cytochrome P450
• Shared side effects: fatigue, hot flushes, nausea, diarrhoea, hypertension, asthenia, falls, bone fracture, musculoskeletal pain, seizure, mental impairment, ischaemic heart disease

Drug	Distinguishing feature
Enzalutamide	Crosses the blood-brain barrier and inhibits GABA receptors → seizure risk
Apalutamide	Also crosses the BBB and inhibits GABA receptors; the only one in the class with an appreciable rate of hypothyroidism
Darolutamide	Crosses the BBB in negligible amounts → fewer CNS side effects; does not increase serum testosterone, whereas enzalutamide and apalutamide can

FDA-approved indications

Drug	nmCRPC	mCSPC	mCRPC
Darolutamide	Approved	No	No
Apalutamide	Approved	Approved	No
Enzalutamide	Approved	Approved	Approved

LHRH Agonists

• Agents — leuprolide (Lupron), goserelin (Zoladex) 10.8 mg q3-monthly, triptorelin
• Causes testosterone flare → cover with 1st-gen anti-androgen(Bicalutamide)
• Flare is prevented by starting the antiandrogen either at the time the LHRH agonist starts, or up to 7 days before, and continuing it for 4 weeks

GnRH Antagonists

• Degarelix (Firmagon): 280 mg induction → 80 mg q28 days
• No flare | castration in ~3 days
• Relugolix (Orgovyx) — an oral GnRH antagonist; castration in ~15 days
  • Do not use relugolix with abiraterone, enzalutamide, darolutamide or apalutamide — potential drug interactions; it has not been adequately studied in combination with chemotherapy or any of those agents

Hormonal Interventions — Overview

Class	Drugs	Site of action	Mechanism
GnRH agonists	Leuprolide, goserelin, triptorelin	Pituitary	Stimulate LH release; the feedback loop ultimately decreases LH production. Mainstay for metastatic disease; leads to an increase in FSH
GnRH antagonists	Degarelix, abarelix, cetrorelix	Pituitary	Bind receptors and block GnRH release. Prevent the testosterone surge; lead to a decrease in FSH
Adrenal-targeting	Ketoconazole, abiraterone, orteronel, galeterone	Adrenal	Decrease androgen production from steroid precursors by blocking cytochrome P450. Given with low-dose prednisone; side effects include hypertension, edema, hypokalemia
1st-gen AR antagonists	Flutamide, nilutamide, bicalutamide	Prostate	Inhibit binding of testosterone and DHT to the AR. Monotherapy not indicated; associated with gynecomastia
2nd-gen AR antagonists	Enzalutamide, apalutamide	Prostate	Block the AR, minimize nuclear translocation, diminish AR-mediated transcription. Associated with falls, fatigue, decreased appetite
5α-reductase inhibitors	Finasteride, dutasteride	Prostate	Inhibit testosterone → DHT. Not indicated for prostate cancer management

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Metastatic Prostate Cancer

• 55% of patients with no metastases on bone scan or CT actually have metastases on PSMA-PET

Prognostic factors

• Number of bone metastases · location of bone metastases · visceral metastases · ISUP grade · initial PSA · performance status · PSA level after 7 months of ADT

mCSPC

Do these in every metastatic patient

• Genetic counselling and germline testing
• Assess disease burden and symptoms
• Start calcium and vitamin D
• Start denosumab or zoledronic acid if bone metastases are present
• Add steroids if giving abiraterone or docetaxel

High volume (visceral mets OR ≥4 bone mets with ≥1 outside vertebrae/pelvis)

• ADT + docetaxel OR 2nd-gen AR agent (Apalutamide,Enzalutamide,Darolutamide)

*CHAARTED: ADT + docetaxel benefit only in high-volume disease (OS +14 mo)

Low volume — absence of visceral metastasis, any number of nodal metastases, and any of: no bone metastasis · 1–4 bone metastases in any distribution · > 4 bone metastases all confined to the vertebral bodies and pelvis

• ADT + 2nd-gen AR agent (Apalutamide,Enzalutamide,Darolutamide)
• ± prostate radiation (STAMPEDE) — men on lifelong ADT (± upfront docetaxel) randomised to prostate radiation or none
  • Low volume: improved failure-free survival AND overall survival (+8% OS at 3 years)
  • High volume: improved failure-free survival, but NOT overall survival

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mCRPC

Definition of CRPC: castrate serum testosterone < 50 ng/dL (< 1.73 nmol/L) plus either:

1. Biochemical progression — three consecutive rises in PSA, at least one week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL

OR

2. Radiological progression — new lesions: either two or more new bone lesions on bone scan, or a soft tissue lesion

• Symptomatic progression alone is NOT sufficient to diagnose CRPC

# No prior docetaxel

Prior 2nd-gen AR	Options
No	ADT + Docetaxel or Enzalutamide or Apalutamide, Radium-223 (symptomatic bone mets, no visceral, LN ≤3 cm)
Yes	ADT + Docetaxel, Sipuleucel-T, Pembrolizumab (MMR/MSI-H), Olaparib/Rucaparib (BRCA2/HRR)

# Prior docetaxel

Prior 2nd-gen AR	Options
No	ADT + Cabazitaxel, Enzalutamide, Apalutamide, Radium-223, Sipuleucel-T
Yes	Cabazitaxel, Radium-223, Sipuleucel-T, Pembrolizumab (MMR/MSI-H), Olaparib/Rucaparib (BRCA2/HRR)

Radium-223 — the full criteria

• Indicated for men with ALL of: symptomatic bone metastases, no visceral metastases, and malignant lymphadenopathy ≤ 3 cm
• Do NOT combine radium-223 with chemotherapy — cumulative myelosuppression
• Do NOT combine radium-223 with abiraterone — increased fractures and mortality

Sipuleucel-T — not recommended in men with any of:

• Using opioids to control cancer-related pain

• Visceral metastasis

• Rapidly progressive disease

• Life expectancy < 6 months

• Large tumour burden

• ECOG performance status ≥ 2

• Small cell or neuroendocrine prostate cancer

• Antihistamines must be given with sipuleucel-T

Chemotherapy

Docetaxel — a mitotic inhibitor that prevents cell division. Give with prednisone 5 mg BID. For high-volume metastatic disease.

• Side effects — bone marrow suppression, fatigue, neutropenia, anaemia, nausea, vomiting, diarrhoea, sensory neuropathy, alopecia, nail dystrophy, dysgeusia, stomatitis, dyspnoea, peripheral edema

Cabazitaxel — same mechanism. Approved for mCRPC previously treated with a docetaxel-containing regimen.

• Side effects similar to docetaxel, but additionally low platelets, neutropenia (including febrile neutropenia) and diarrhoea — but generally NOT neuropathy
• Cabazitaxel is not susceptible to MDR1, which is why it retains efficacy in docetaxel-resistant cancers

Platinum agents

• Indicated in small cell prostate cancer, and perhaps in other mCRPC subsets — combined TP53 and PTEN inactivation, or DNA repair deficiency mutations
• Neuroendocrine tumours are invariably unresponsive to hormonal manipulation, but are transiently sensitive to radiotherapy and chemotherapy — platinum-etoposide or platinum-taxane combinations

AR-V7 — a blood-based biomarker used to help choose therapy in mCRPC

• AR-V7 positive → may benefit more from taxane chemotherapy
• AR-V7 negative → may benefit similarly from either AR-directed therapy or chemotherapy

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nmCSPC

Not curable, and local therapy has failed.

• Asymptomatic → surveillance or ADT
• Symptomatic → ADT

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nmCRPC

• PSADT >10 months → observe
• PSADT <10 months + LE >5 yr → ADT + AR-targeted therapy (Apalutamide / Enzalutamide / Darolutamide)

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Bone Health in CRPC with Mets

• Denosumab 120 mg SC q4wk OR Zoledronate 4 mg IV q4wk + Ca + vitamin D
• Denosumab vs zoledronate: superior time-to-first SRE; no OS difference
• Zoledronate contraindicated if CrCl <30; denosumab no renal adjustment
• Denosumab is not eliminated by the kidney; zoledronic acid is — denosumab SC, zoledronic acid IV
• Both cause osteonecrosis of the jaw

How denosumab works

• When cancer metastasises to bone it increases RANK ligand, which activates more RANK receptor, driving osteoclast activity

• Denosumab is a monoclonal antibody that binds RANK ligand, preventing it from binding the RANK receptor — breaking the link that causes bone resorption

• NOT approved for SRE prevention in mHSPC

Spinal Cord Compression

• Emergency — MRI is diagnostic
• → Dexamethasone (10 mg load, 4 mg q6h) + RT ± surgical decompression
• Surgery first if: unknown tissue dx, prior RT to area, pathological fracture with instability

Palliative RT for Bone Pain

• Single fraction 800 cGy = preferred for uncomplicated non-spinal bone mets