Prostate Cancer

Early detection:

• Individualized informed decision-making for prostate cancer screening (DRE and PSA)

• Discuss risks and benefits:

  • Age 45–75 at average risk

  • Age 40–75 at high risk (Black/African American, family history, germline mutations)

    
    

Definitive diagnosis:

• Requires prostate biopsy, Gleason grading, and TNM staging.

Clinical Pearls:

• Think of Prostate Cancer treatment on a "spectrum":

  • Localized Disease → Biochemical recurrence (BCR) → Non-metastatic castrate resistant prostate cancer (NMCRPC) or Metastatic Castrate Sensitive Prostate Cancer (MCSPC) → Metastatic Castrate Resistant Prostate Cancer (MCRPC)

• Post- radical prostatectomy (RP) PSA should be undetectable. Post-radiation PSA should not, monitor for the nadir to determine BCR. 

• BCR is defined as:

  • After RP: PSA ≥ 0.2 after RP or 2 rising PSA’s from nadir after RP (should be 0 after RP)

  • After RT: : PSA increase by ≥2 above nadir PSA after radiation (Phoenix Criteria)

  • Consider PSA doubling time of ~ 6-10 months.

Androgen Deprivation therapy (ADT): 

• LHRH agonist (goserelin, leuprolide, triptorelin)

  • Causes initial testosterone surge (typically start bicalutamide before Lupron to prevent tumor flare)

• GnRH antagonists (degarelix, relugolix)

  • Consider relugolix if patient has cardiovascular comorbidities

• Side effects: “manopause” with night sweats, hot flashes, weight gain, sexual dysfunction, mood changes, cardiovascular side effects, DVT, hypertension, osteoporosis.

• Monitor DEXA scans q2 years

Neoadjucant Hormonal Therapy (NHT):

• Abiraterone + Prednisone

  • If taken without prednisone, can cause HTN and hypokalemia due to hyperaldosteronism

  • Side effects: hepatotoxicity, HTN, hypokalemia and fluid retention (from mineralocorticoid excess), hyperglycemia (due to prednisone), cardiovascular adverse events, adrenal insufficiency

  • Need to monitor LFT

• Enzalutamide

  • Can cause falls and lower seizure threshold

• Darolutamide

• Apalutamide

Localized prostate cancer:

Risk stratification based on NCCN guideline:

• Very low risk

  • T1c

  • + Grade Group 1

  • + PSA <10

  • + Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core

  • + PSA density <0.15

• Low risk

  • T1–T2a

  • + Grade Group 1

  • + PSA <10

• Intermediate risk

  • No high- or very-high-risk features + one or more intermediate risk factors:

    • T2b–T2c

    • Grade Group 2 or 3

    • PSA 10–20

  • Favorable intermediate:

    • intermediate risk factors and Grade Group 1-2 and <50% biopsy cores positive

  • Unfavorable intermediate:

    • 2-3 intermediate risk factors and/or Grade Group 3 and/or ≥ 50% biopsy cores positive

• High risk

  • T3a OR

  • Grade Group 4 or Grade Group 5 OR

  • PSA > 20

• Very high risk

  • T3b–T4 OR

  • Primary Gleason pattern 5 OR

  • 4 cores with Grade Group 4-5

Treatment:

• If undergoing radical prostatectomy:

  • Check if any adverse features are present on final pathology.

    • Positive margins

    • Seminal vesicle involvement

    • Extracapsular extension

    • Detectable PSA

  • If any adverse feature is seen can either monitor or EBRT +/- ADT

  • Expect PSA to become undetectable after radial prostatectomy.

• Very low risk localized prostate cancer:

  • Active surveillance (in patients with >10 years anticipated survival)

  • Observation (in patients with <10 years anticipated survival)

• Low risk localized prostate cancer:

  • Active surveillance

  • RT

  • Radical prostatectomy

  • Observation (in patients with <10 years anticipated survival)

• Intermediate risk localized prostate cancer:

  • Favorable:

    • Active surveillance

    • RT

    • Radical prostatectomy + PLND (in patients with >10 years survival)

  • Unfavorable:

    • Baseline bone and soft tissue imaging

    • Radical prostatectomy + PLND (in patients with >10 years survival)

    • RT + 4-6 months ADT (5-10 years survival)

    • Observation (5-10 years survival)

• High Risk/Very High Risk localized prostate cancer:

  • Baseline bone and soft tissue imaging needed

  • >5 years survival or symptomatic:

    • RT + ADT x2 years + Abiraterone/Prednisone (if very-high risk) x2 years

    • Radical prostatectomy + PLND

  • <5 years survival and asymptomatic:

    • Observation

    • ADT

    • EBRT

• Node positive, M0:

  • >5 years survival or symptomatic:

    • EBRT + ADT + Abiraterone (preferred)

  • < 5 years survival and asymptomatic:

    • Observation or ADT

• Biochemical Recurrence:

  • Obtain imaging to rule out local recurrence or distant metastasis:

    • If negative: Salvage RT + ADT x2 years

    • If positive for pelvic recurrence: RT + ADT + Abiraterone/Prednisone x2 years

    • If distant metastasis: treat as M1 disease

• Non-metastatic castrate resistant prostate cancer (nmCRPC):

  • Definition of castrate resistance: elevated PSA despite testosterone <50

  • ADT + Neoadjuvant Hormonal Therapy (Apalutamide, Enzalutamide, Darolutamide)

Metastatic prostate cancer:

Treatment:

• Metastatic castrate sensitive prostate cancer (mCSPC):

  • mCSPC low volume:

    • ADT + NHT (Abiraterone, Enzalutamide, Apalutamide)

    • Consider addition of SABR (Stereotactic Ablative Body Radiotherapy)

  • mCSPC high volume: presence of visceral mets or 4+ bony mets with at least 1 beyond vertebra or pelvis (CHAARTED)

    • Docetaxel + ADT + Abiraterone (PEACE-1)

    • Docetaxel + ADT + Darolutamide (ARASENS)

    • If poor PS (not able to tolerate triplet therapy) can use ADT + NHT

• Metastatic castrate resistance prostate cancer (mCRPC):

  • Cabazitaxel if progressed on Docetaxel (TROPIC)

  • Olaparib (if BRCA positive)

  • Rucaparib (if BRCA positive)

  • PARP inhibitor + NHT

    • Olaparib + Abiraterone

    • Talazoparib + Enzalutamide

  • Pembrolizumab (If MSI-high/MMRd)

  • Radium-223 (Xofigo, for bone only disease)

  • Lutetium-PSMA  (if fails Docetaxel) 

    • Radioligand delivers beta-particle radiation to PSMA-expressing cells (VISION)

    • Approved for patients with symptomatic bone metastases but no signs of visceral disease

    • Causes bone marrow toxicity

  • Sipuleucel-T recommended if:

    • Asymptomatic/minimally symptomatic

    • No liver metastases

    • Life expectancy > 6 months

    • ECOG 0-1

Clinical Pearls

• If patient has rapid progression of disease discordant from PSA, consider neuroendocrine differentiation

  • Treat with with cisplatin/etoposide

• Bisphosphonate decreases skeletal related events in patients with castration-resistant prostate cancer and bone mets

  • No clear benefit to using bisphosphonate in patients with castration sensitive disease as it has not shown to reduce skeletal related events

• Germline testing may be considered in patients with:

  • Intermediate risk prostate cancer with intraductal/cribriform histology

  • History of prostate cancer + history of pancreatic, colon, gastric, melanoma, urothelial, GBM, bile duct, small intestinal cancer

  • High risk/very high risk/node positive/metastatic prostate cancer