Prostate cancer

Overview

• Epidemiology (US 2025): ~314,000 new cases, ~36,000 deaths; most common cancer in men. ↑↑ in Black men. 1 in 8 lifetime risk; 15% of men >50 y/o and 70% >80 y/o have occult prostate ca.
• Risk factors: age, family history, African ancestry, ↑ alpha-linolenic acid, testosterone supplementation (not shown to increase prostate cancer risk in trials; long-term and high-baseline-risk safety less certain).
• Genetic risk factors: HOXB13 (↑ risk x20), BRCA1 (x3), BRCA2 (x3 to 8), MMR/Lynch genes (x3), RAD51D and PALB2.
• Check germline mutations if:
  • Metastatic, regional node-positive, or high-risk localized prostate ca, regardless of family history.
  • Strong FHx: ≥ 1 relative with prostate ca <50 y/o, colorectal <50 y/o, male breast, ovarian, or exocrine pancreatic cancer; Ashkenazi Jewish ancestry.

Anatomy, Diagnosis, and Histology

• Anatomic zones:
  • Peripheral zone: palpated by DRE; 70% of prostate cancers.
  • Transition zone (surrounds the urethra): 20% of prostate cancers.
  • Anterior portion: generally not biopsied; do MRI, especially if ↑ PSA and biopsy is negative.
  • Apical (apex) and seminal vesicle involvement ↑ risk of R1 resection; consider RT + ADT instead of RP.
• Diagnosis:
  • 12-core biopsy is SOC. Trans-rectal or trans-perineal approach.
  • Multiparametric MRI (PI-RADS) before biopsy helps avoid unnecessary biopsy and improves detection. PRECISION trial: MRI-guided vs standard TRUS-guided biopsy, 28% avoided biopsy, clinically significant ca in 38% vs 26%.
  • PSMA PET (PSMA agents: Ga-68 PSMA-11, F-18 piflufolastat/Pylarify, F-18 flotufolastat/Posluma; F-18 fluciclovine and C-11 choline are older non-PSMA PET agents). Approved at biochemical recurrence and for suspected metastatic disease; preferred staging for high-risk localized, BCR, and mCRPC.
• Histology / IHC:
  • Prostate ca: CK7 and CK20 negative; AR, PSA, and NKX3.1 positive.
  • Urothelial ca (for contrast): CK7, CK20, and GATA3 positive; PSA and NKX3.1 negative.
  • Prostatic intraepithelial neoplasia (PIN): precursor lesion, not cancer; high-grade PIN carries ~20 to 25% risk of cancer on repeat extended-core biopsy (higher if multifocal).
  • 99% are adenocarcinomas; <1% pure ductal, mucinous, or small-cell (neuroendocrine, associated with AURKA and N-myc; suspect with rapid progression, new visceral (especially liver) metastasis, and no rising PSA); rare rhabdomyosarcoma, leiomyosarcoma.

Screening (PSA)

• ACS: ≥ 50 y/o (average risk); ≥ 45 y/o if Black or with a first-degree relative; ≥ 40 y/o if more than one first-degree relative was diagnosed before age 65.
• NCCN: average-risk discussion at 45, high-risk at 40. AUA: baseline PSA at 45 (40 to 45 if increased risk), then every 2 to 4 yr at ages 50 to 69.
• USPSTF 2018: no screening ≥ 70; individualize 55 to 69 y/o (Grade C).
• Harms: ED, incontinence, and other symptoms from interventions (RP or RT).
• ERSPC and Goteborg were positive (both ↓ prostate ca death and ↓ metastatic disease; ERSPC ~20%, Goteborg ~40% relative reduction in PCa death); PLCO (US) showed no OS benefit.
• Prevention: ineffective; vitamin E is harmful; 5-alpha reductase inhibitors (finasteride, dutasteride) ↓ low-grade ca but ↑ risk of high-grade ca.

PSA facts

• PSA is prostate specific but not cancer specific.
• After prostatectomy, PSA should be undetectable (<0.2).
• PSA half-life 48 to 72 h.
• PSA >4 ng/mL → ↑ risk of prostate ca.
• PSA 4 to 10 ng/mL: repeat a newly elevated PSA and assess absolute PSA, PSA density, DRE, MRI, and risk calculators; PSA velocity alone (historically ≥ 0.75 ng/mL/yr) is not a validated biopsy trigger.

Staging and Grading

• T1 → clinically inapparent, not palpable (T1a ≤ 5%, T1b >5%, T1c on biopsy for elevated PSA, not palpable).
• T2 → palpable, confined to prostate (T2a ≤ 50%, T2b >50%, T2c both lobes).
• T3 → extraprostatic, not fixed (T3a extraprostatic extension (also includes microscopic bladder-neck invasion; gross invasion of adjacent structures is T4), T3b seminal vesicle).
• T4 → invades external sphincter, rectum, bladder, levator muscles, and/or pelvic wall.
• There is no pathologic T1 classification.
• LN+ in true pelvis (below common iliac bifurcation) → N1 → stage IVA (RT + ADT x2 yrs + abiraterone x2 yrs).
• LN+ common iliac or higher → M1a → stage IVB.

The three "Gleasons"

• Gleason grade characterizes morphology from well differentiated (grade 1, many glands) to poorly differentiated (grade 5, loss of glandular tissue). Range 1 to 5.
• Gleason score is the sum of the two most predominant grades. Example: 4+3 = 7. Gleason 7 (3+4) and 7 (4+3) differ: the first number is the predominant histology, so 7 (4+3) is more aggressive than 7 (3+4).
• Grade group (ISUP), see table.

Risk Stratification and Localized Treatment

• Tip: first split into Low vs High. For low risk you need ALL criteria; for high risk any one criterion is enough. Then subclassify.

• Very low risk: <3 biopsy cores, ≤ 50% cancer in any core, PSA density <0.15 ng/mL/g, Gleason 6, T1c, PSA <10 → definitely AS.
• Favorable intermediate: only 1 intermediate-risk factor (T2b to T2c, Gleason 7, or PSA 10 to 20) AND Gleason 6 or 7 (3+4) AND <50% positive cores.
• Unfavorable intermediate: ≥ 50% positive cores, Gleason 7 (4+3), or multiple intermediate-risk factors.
• Very high risk: LN+, or LN- with T3b to T4, or primary Gleason pattern 5, or >4 cores Gleason 8 to 10 → RT + 2 yrs ADT + 2 yrs abiraterone.

Watchful waiting vs active surveillance

• Watchful waiting: no intervention until symptomatic progression; good if life expectancy <5 years.
• Active surveillance: PSA monitoring, DRE, MRI, serial biopsy; for low-risk or favorable intermediate.
• Decipher (22-gene RNA assay) predicts metastasis and prostate-cancer-specific mortality; guides AS selection and use of adjuvant/salvage RT after prostatectomy.
• Prostatectomy can improve urinary obstruction; RT can worsen obstructive symptoms initially. AEs: incontinence, ED.
• RT: irritative urinary/bowel symptoms, proctitis. Avoid brachytherapy with significant LUTS.
  • Immediate adjuvant RT after RP (pT3a/pT3b, R1 margins): ↑ biochemical PFS.
  • Salvage RT after RP: give at earliest evidence of BCR; better symptom profile than adjuvant RT.
• Adjuvant ADT: after surgery if pLN+; after RT for 4 to 6 mo (intermediate risk) and 1.5 to 2 yrs (high risk).

Biochemical Recurrence (BCR)

• Definitions: after RP, PSA ≥ 0.2 ng/mL; after RT, PSA ↑ by 2 ng/mL above nadir (Phoenix criteria).
• Workup: PSMA PET (Pylarify, Posluma) if PSA ≥ 0.2 post-RP or rising post-RT.
• Salvage RT +/- ADT (RTOG 9601): for post-RP BCR; give at earliest evidence. SPPORT: pelvic RT + ADT improves outcomes.
• Early (BCR) vs delayed (mets) ADT (TROG, ELAAT): early ADT ↑ PFS; TOAD also showed ↑ OS with immediate ADT (5 yr OS 91% vs 86%, HR 0.55); ↓ QOL.
• Continuous vs intermittent ADT: continuous preferred for true metastatic disease; intermittent = ADT for 8 months, then stop and restart when PSA >10 ng/mL and no mets.
• PSA bounce: transient rise 18 to 24 months after RT, 0.1 to 0.5 ng/mL above nadir; do not confuse with progression.
• EMBARK (non-metastatic CSPC with high-risk PSA doubling time after definitive RP/RT):
  • Enzalutamide + leuprolide: 5 yr MFS 87.3% vs 71.4% (HR 0.42); 8 yr OS 78.9% vs 69.5% (HR 0.60; Shore NEJM 2026).
  • Enzalutamide alone: also better than leuprolide alone.
  • FDA Nov 16, 2023 for nmCSPC with high-risk biochemical recurrence and short PSA doubling time.

Advanced Disease: Disease States and Treatment

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

• Standard 1L: ADT + ARSI +/- docetaxel ("triplet" therapy).
• CHAARTED, STAMPEDE: ADT + docetaxel ↑ OS in high-volume mHSPC.
• LATITUDE, STAMPEDE: ADT + abiraterone + prednisone ↑ OS (high risk: at least 2 of Gleason ≥ 8, ≥ 3 bone lesions, visceral mets).
• TITAN: ADT + apalutamide ↑ OS.
• ARCHES, ENZAMET: ADT + enzalutamide ↑ OS.
• Triplet (PEACE-1, ARASENS): ADT + docetaxel + abiraterone OR + darolutamide ↑ OS in high volume.
• ARANOTE (Saad J Clin Oncol 2024): ADT + darolutamide (no docetaxel) vs ADT alone, rPFS HR 0.54. FDA Jun 3, 2025 for darolutamide + ADT in mHSPC (extends darolutamide beyond the ARASENS triplet indication).
• AMPLITUDE (Rathkopf ASCO 2025 plenary; NCT04497844): mHSPC with HRR alteration (BRCA1/2, PALB2, CHEK2, BRIP1, CDK12, FANCA, RAD51B, RAD54L; ATM not included), niraparib + abiraterone/prednisone + ADT vs placebo + AAP + ADT. rPFS HR 0.63 overall (HR 0.52 BRCA-mut); trend to OS. FDA Dec 12, 2025 for niraparib + AAP in BRCA2-mutated mCSPC (label restricted to BRCA2). Moves niraparib + AAP earlier into HRR+ mHSPC; complements the TALAPRO-2 (mCRPC) paradigm.
• CAPItello-281 (Fizazi Ann Oncol 2025; NCT04493853): PTEN-deficient (by IHC) mHSPC, capivasertib + AAP + ADT vs placebo + AAP + ADT. rPFS 33.2 vs 25.7 mo (HR 0.81); OS immature; more diarrhea, hyperglycemia, rash. FDA Jun 12, 2026 for capivasertib + abiraterone/prednisone in PTEN-deficient mHSPC.
• PSMAddition: PSMA PET+ mHSPC, Lu-177-PSMA-617 + ARPI + ADT vs ARPI + ADT, rPFS HR 0.72 (OS immature). FDA Jul 31, 2026 for Pluvicto with an ARPI in PSMA+ mHSPC.

Castration-Resistant Prostate Cancer (CRPC)

• Definition: progression on ADT with testosterone <50 ng/dL.

Non-metastatic CRPC (nmCRPC)

• Same paradigm (high risk = PSA doubling time ≤10 mo): enzalutamide (PROSPER), apalutamide (SPARTAN), darolutamide (ARAMIS), all ↑ MFS and OS.
• LN size <2.0 cm (except <1.5 cm in PROSPER).

Metastatic CRPC (mCRPC)

• 1L depends on prior therapy (abi or enza often already used in mHSPC):
• Abiraterone + prednisone (COU-AA-301/-302).
• Enzalutamide (AFFIRM, PREVAIL).
• Docetaxel (TAX 327).
• Sipuleucel-T (Provenge) for asymptomatic mCRPC: autologous dendritic cell vaccine (PAP-GM-CSF fusion, PA2024); IMPACT trial ↑ OS, same PFS.
• Radium-223 (Xofigo) for symptomatic bone-predominant mCRPC (ALSYMPCA); alpha-emitter; avoid concurrent abiraterone (↑ fracture risk); add bone-modifying agent.
• CONTACT-02 (Agarwal Lancet Oncol 2025): mCRPC with measurable extra-pelvic soft-tissue mets post-1 ARSI, cabozantinib + atezolizumab vs 2nd ARSI. Met PFS co-primary (mPFS 6.3 vs 4.2 mo, HR 0.65) but OS not significant and toxicity higher. FDA declined approval; not routine.
• PARP inhibitors for HRR mutations:
  • Olaparib (PROfound): BRCA1/2, ATM and other HRR-altered; mOS benefit.
  • Olaparib + abiraterone (PROpel, Clarke NEJM Evid 2022): FDA May 31, 2023 for BRCA-mut 1L mCRPC (US label restricted to BRCA1/2 despite all-comer enrollment).
  • Niraparib + abiraterone (MAGNITUDE / Akeega, Chi Ann Oncol 2023): FDA Aug 11, 2023 for BRCA-mut 1L mCRPC.
  • Talazoparib + enzalutamide (TALAPRO-2, Agarwal Lancet 2023): FDA Jun 20, 2023 for HRR-altered 1L mCRPC (broader HRR label than PROpel/MAGNITUDE).
  • Rucaparib (TRITON3, Fizazi NEJM 2023): BRCA-mut mCRPC post-ARSI; FDA regular approval Dec 17, 2025 (accelerated approval May 2020).
• Lu-177-PSMA-617 (Pluvicto):
  • VISION (Sartor NEJM 2021; PMID 34161051): PSMA PET+ mCRPC after ARPI + taxane, mOS 15.3 vs 11.3 mo (HR 0.62), rPFS 8.7 vs 3.4 mo. FDA Mar 23, 2022.
  • PSMAfore (Sartor ESMO 2023, Morris et al., Lancet 2024): taxane-naive mCRPC post-ARPI, rPFS 12.0 vs 5.6 mo (HR 0.43), ORR 50% vs 14%. FDA Mar 28, 2025, label expanded to PSMA PET+ mCRPC post-ARPI when appropriate to delay taxane.
• Cabazitaxel (TROPIC, CARD): post-docetaxel; superior to ARSI switch in some pts (CARD: after docetaxel and abi/enza, ↑ PFS and OS).
• Resistance: AR-V7 splice variant confers resistance to abiraterone and enzalutamide; abi, enza, and darolutamide have high cross-resistance (do not switch among them, especially if ARV7+). Substituting dexamethasone for prednisone can improve sensitivity to abiraterone.

ADT Pharmacology

• Abiraterone: oral irreversible CYP17 inhibitor (like ketoconazole) → ↓ testosterone and ↓ cortisol → ↑ ACTH → ↑ aldosterone (HTN, ↓K, fluid retention). Add prednisone 5 mg daily (castration-sensitive) or 5 mg BID (castration-resistant). Alternative dosing 250 mg with a low-fat meal is a guideline-listed option (phase II PSA-endpoint noninferiority); the labeled dose is 1000 mg fasting and equivalent OS is not established. AEs: fluid retention/edema, ↓K, CVA, atrial fibrillation, HTN, ↑ LFTs, UTIs, arthralgia.
• AR antagonists: inhibit androgen binding to AR, ↓ nuclear translocation, and ↓ AR/DNA interaction.
  • Apalutamide: fatigue, ↑ HTN, seizure, rash, fractures, mental impairment, falls.
  • Enzalutamide (with or without food): fatigue, fractures, mental impairment, CVA, seizure, PRES (<1%).
  • Darolutamide: fewer AEs, fatigue, ↓ CNS penetration, ↓ CNS side effects.
• GnRH agonists: leuprolide, goserelin, triptorelin. Cause an initial testosterone surge; give an antiandrogen (bicalutamide) ~2 weeks before initiation, especially with metastatic disease and concern for spinal cord compression or urinary obstruction.
• GnRH antagonists: degarelix and relugolix (oral). No testosterone flare; flare is also not a concern with surgical castration.
• Older nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide): competitive inhibitors; antiandrogen withdrawal may produce a clinical or PSA response.
• Castration AEs: impotence, ↓ libido, weakness, fatigue, hot flashes, loss of muscle mass, anemia, depression, CVA, bone loss (baseline DEXA and at 1 yr), possible dementia (conflicting data).
• ADT response: PSA drop <4 ng/mL in ~60%, ↓ tumor size by 50% in ~40%, symptom improvement in ~60%. Bone scan flare can occur 3 to 4 months after ADT; do not confuse with progression.

Bone Health and Supportive Care

• Zoledronic acid: infusion reactions, renal failure, ONJ, ↓Ca. Monthly or q3 months for bone mets, annual for osteoporosis. individualize duration by ongoing SRE risk, renal function, and toxicity; every-12-week dosing is an option (no routine 2-year stop).
• Denosumab: ↓Ca more common; can use in kidney disease. 120 mg monthly for mCRPC bone mets; 60 mg q6 months for fragility fracture prevention. Duration individualized; do not stop abruptly (rebound vertebral fractures): transition to another antiresorptive if discontinued.
• Dental clearance before treatment; give concurrent calcium and vitamin D with both agents.
• Bone health on ADT: monitor BMD; vitamin D + calcium; bisphosphonate if osteoporosis.
• Hot flashes: SSRIs, gabapentin, megestrol.
• Neuroendocrine / small-cell prostate ca: aggressive, AR-negative; treat like SCLC (platinum + etoposide).

High-Yield Prostate Pearls

• Triplet therapy (ADT + docetaxel + ARSI) for high-volume mHSPC (PEACE-1, ARASENS).
• EMBARK: enzalutamide + leuprolide for high-risk biochemically recurrent disease.
• VISION: Lu-177-PSMA post-ARSI + taxane. PSMAfore: Lu-177-PSMA in taxane-naive mCRPC (label expanded 2025).
• PROfound, PROpel, MAGNITUDE, TALAPRO-2, TRITON3: PARP inhibitors for HRR/BRCA mutations.
• Active surveillance is preferred for low-risk localized disease.
• Germline testing for all metastatic, high-risk localized, and BRCA family history.
• PSMA PET is preferred staging for high-risk localized, BCR, and mCRPC.
• Radium-223: symptomatic bone mets, no visceral mets (nonbulky nodes <3 cm allowed).
• TAX 327: docetaxel established the mOS benefit in mCRPC.