Prostate Cancer

The most common cancer in American men — risk stratification, clinical presentation, and treatment from surveillance to metastatic hormone-sensitive disease

Key Points

• Prostate cancer is the most commonly diagnosed non-skin cancer in American men; ~300,000 new cases and ~35,000 deaths annually in the US.
• Most prostate cancers are slow-growing and clinically indolent; risk stratification (NCCN criteria, Gleason/Grade Group) is essential to avoid overtreatment.
• Active surveillance is the standard of care for very-low and low-risk localized prostate cancer in appropriately selected men.
• BRCA2 germline mutations confer a substantially elevated risk of aggressive, early-onset prostate cancer.
• Rising PSA after definitive local therapy (biochemical recurrence) often precedes clinical metastasis by years.
• Metastatic hormone-sensitive prostate cancer (mHSPC) is now treated with androgen deprivation therapy (ADT) + intensification with either ARPI (enzalutamide/apalutamide/darolutamide) or docetaxel.
• PARP inhibitors (olaparib, rucaparib) are approved for metastatic castration-resistant prostate cancer (mCRPC) with HRR gene mutations (BRCA1/2, ATM).

Epidemiology & Incidence

Prostate cancer is the most frequently diagnosed non-skin cancer in men in the US. In 2024, ~299,010 new cases and ~35,250 deaths were projected. It is the second leading cause of cancer death in American men, after lung cancer. The lifetime risk of diagnosis is approximately 1 in 8; the lifetime risk of dying from prostate cancer is approximately 1 in 41, reflecting the indolent nature of most prostate cancers. Incidence is highest in Black men (60% higher than White men) and lowest in Asian American men. Black men also have 2× higher mortality, attributable to both biologic factors (higher…

Genetic Predispositions & Risk Factors

Hereditary prostate cancer accounts for approximately 5–10% of cases. Key germline mutations include: • BRCA2: Most important hereditary risk gene for prostate cancer — 4–8× increased risk; associated with high-grade (Gleason 8–10), node-positive, and early-onset disease. Also associated with substantially worse clinical outcomes. BRCA2 carriers should be offered PSA screening starting at age 40. • BRCA1: More modest risk increase (~2–3×); primarily relevant for female relatives (breast/ovarian cancer). • HOXB13 G84E: Common founder variant in Northern European populations; ~4× increased…

Clinical Presentation

Most prostate cancers detected in the PSA era are asymptomatic, discovered by elevated PSA on screening. When symptoms occur, they often reflect either locally advanced disease (invasion of urethra, bladder neck, or neurovascular bundles) or metastatic disease. Local disease symptoms (often overlap with benign prostatic hyperplasia, BPH): • Lower urinary tract symptoms (LUTS) — urinary frequency, urgency, nocturia, decreased stream, hesitancy • Hematuria or hematospermia (blood in semen) • Dysuria or pelvic discomfort • Erectile dysfunction (involvement of neurovascular bundles) Locally…

Staging & Risk Stratification

Prostate cancer is staged using TNM (AJCC 8th) and risk-stratified by the NCCN classification system: TNM: T1 (clinically inapparent), T2 (confined to prostate, a/b/c by lobe extent), T3 (extracapsular extension ± seminal vesicle invasion), T4 (invasion of adjacent structures: bladder neck, external sphincter, rectum, pelvic floor). NCCN risk groups: • Very low: T1c, Grade Group 1, PSA 40 or >4 cores with Grade Group 4–5 • Metastatic: regional lymph node (M0) or distant (M1) Grade Group (International Society of Urological Pathology system): • GG 1 = Gleason 6 (3+3) • GG 2 = Gleason 3+4=7 •…

Stage I (Very Low & Low Risk) Treatment

For very-low and low-risk localized prostate cancer, active surveillance (AS) is the recommended standard of care for most men, given that the risk of the cancer causing harm during a man's lifetime is low, and immediate treatment carries risks of urinary, bowel, and sexual side effects without established survival benefit. Active surveillance protocol: PSA every 3–6 months, DRE annually, repeat biopsy (systematic ± MRI-targeted) at 1 year and then every 2–3 years. mpMRI before confirmatory biopsy is standard. Reclassification to higher grade on re-biopsy triggers discussion of definitive…

Stage II–III (Intermediate & High Risk) Treatment

Intermediate-risk localized prostate cancer: Definitive treatment (RP or RT) is standard; AS may be appropriate for selected favorable intermediate-risk men after thorough counseling. Short-term ADT (4–6 months) + RT improves outcomes for unfavorable intermediate-risk (RTOG 9408, D'Amico). High-risk and locally advanced (stage III) prostate cancer: EBRT + long-term ADT (18–36 months) is the standard of care, with strong OS benefit in multiple randomized trials. EBRT dose escalation to ≥75.6 Gy ± pelvic lymph node irradiation is standard. Adding docetaxel to ADT + RT is under investigation.…

Stage IV (Metastatic & Castration-Resistant) Treatment

Metastatic hormone-sensitive prostate cancer (mHSPC): ADT (surgical castration or GnRH agonist/antagonist — degarelix preferred acutely to avoid testosterone flare) is the backbone. Intensification is now mandatory: • High-volume mHSPC (CHAARTED definition — visceral metastases or ≥4 bone metastases with ≥1 beyond axial): ADT + docetaxel × 6 cycles (survival benefit — CHAARTED, STAMPEDE); or ADT + abiraterone/prednisone; or ADT + enzalutamide; or ADT + apalutamide; or ADT + darolutamide + docetaxel (ARASENS). • Low-volume: ADT + enzalutamide, apalutamide, or abiraterone preferred over…