Prostate Cancer

*** A list of abbreviations is provided at the end of this note.

Background:

• Most commonly diagnosed non-cutaneous malignancy in men

• Second leading cause of cancer death among men in the US

• Key risk factors:

  • Age: mostly in men >50 (median age at diagnosis ~66)

  • Family history: first-degree relative increases the risk 2-3 times

  • Race: significantly higher incidence in African American, earlier onset and 2× mortality

    • No biological differences in tumor genomics

  • Germline mutations: BRCA2 (most significant), BRCA1, HOXB13, ATM

Early detection:

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

• Discuss risks and benefits:

  • Age 45–75 for average risk

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

• Based on PSA level:

  • PSA <1 → Rescreen every 2-4 years

  • PSA 1–3 → Rescreen every 1-2 years

  • PSA >3 or PSA >4 for age >75 or suspicious DRE → mpMRI and consider biomarkers

    • If high suspicion → Biopsy

    • If low suspicion → follow up in 6-12 months with PSA ± DRE

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)

• PSA after radical prostatectomy (RP) should be undetectable.

• Radiation kills prostate cells gradually, so PSA declines slowly rather than immediately. It may continue falling for 18-36 months before reaching its lowest value (PSA nadir).

  • 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

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

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

Grading:

• Gleason pattern =

  • Primary (most predominant) pattern + Secondary (second most predominant) pattern

• Although both 3+4 and 4+3 equal 7, 4+3 is more aggressive because pattern 4 is the predominant component.

• This classification applies adenocarcinoma and squamous carcinomas but not to sarcoma or transitional cell carcinomas.

Staging:

• T1 = clinically inapparent (not palpable); T1c = found on needle biopsy

• T2 = palpable, organ-confined

• T3 = extraprostatic extension

• T4 = invades adjacent structures

• N1 = regional LN metastases

• M1a = nonregional LN metastases; M1b = bone; M1c = other sites (visceral)

Risk stratification:

Risk stratification of localized prostate cancer 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 4-5 OR

  • PSA > 20

• Very high risk

  • T3b–T4 OR

  • Primary Gleason pattern 5 OR

  • 4 cores with Grade Group 4-5

Androgen Deprivation Therapy (ADT): 

• ADT achieves castrate testosterone levels (<50 ng/dL) via:

  • LHRH agonist (leuprolide, goserelin, triptorelin)

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

  • GnRH antagonists (degarelix, relugolix)

    • No flare risk

    • Consider relugolix if patient has cardiovascular comorbidities

  • Bilateral orchiectomy (surgical castration)

• Side effects: hot flashes, weight gain, sexual dysfunction, mood changes, cardiovascular risk, DVT, hypertension, osteoporosis.

• Monitor DEXA scans q2 years

Androgen Receptor Pathway Inhibitor (ARPI):

• Target androgen signaling by either:

  • Blocking the androgen receptor

    • Enzalutamide

      • Can cause falls and lower seizure threshold

    • Apalutamide

    • Darolutamide

  • Suppressing androgen synthesis

    • Abiraterone (CYP17 inhibitor)

      • Abiraterone also inhibits cortisol synthesis (unintended effect) → low cortisol → high ACTH → stimulates the adrenal cortex → mineralocorticoid excess/ hyperaldosteronism

        • Abiraterone should be given with prednisone (low-dose prednisone replaces the missing cortisol)

      • Side effects:

        • Hepatotoxicity: needs LFT monitoring

        • Mineralocorticoid excess: HTN, hypokalemia and fluid retention, cardiovascular events (worsening heart failure, arrhythmias, ischemic events)

        • Prednisone-related adverse effects: hyperglycemia, adrenal suppression/insufficiency (if stopped abruptly after chronic use)

Non-Metastatic Prostate Cancer

Treatment:

• Very low risk localized prostate cancer:

  • Active surveillance (if >10 years anticipated survival)

  • Observation (if <10 years anticipated survival)

• Low risk localized prostate cancer:

  • Active surveillance

  • RT

  • RP

  • Observation (if <10 years anticipated survival)

• Intermediate risk localized prostate cancer:

  • Favorable:

    • Active surveillance

    • RT

    • RT + PLND (if >10 years survival)

  • Unfavorable:

    • Baseline bone & soft tissue imaging

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

    • RP + PLND (if >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 ± Abiraterone/Prednisone (if very-high risk) for 2 years

    • RP + 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 + ARPI

• If patient had RP:

  • Check adverse features on final pathology:

    • Positive margins

    • Extraprostatic extension (T3a)

    • Seminal vesicle invasion (T3b)

  • Check PSA:

    • PSA after RP should be undetectable.

• If detectable or recurrent PSA develops:

  • If life expectancy ≤5:

    • Observation/ Palliative therapy

  • If life expectancy >5:

    • Obtain imaging to rule out local recurrence or metastasis:

      • No evidence of M1:

        • EBRT ± ADT (based on pathologic features and recurrence risk)

      • Evidence of M1:

        • Work up and treatment of mCSPC

Metastatic Prostate Cancer

Treatment:

• Metastatic castrate-sensitive prostate cancer (mCSPC):

  • Low volume mCSPC:

    • Metachronous oligorecurrent:

      • MDRT

      • MDRT + short-term ADT (6 months)

    • Synchronous (de novo) oligometastatic:

      • ADT + ARPI (preferred option)

        • ADT + Abiraterone/Enzalutamide/Apalutamide (category 1)

        • ADT + darolutamide (category 2B)

      • ADT + EBRT to the primary tumor

      • ADT + ARPI + EBRT to the primary tumor

      • ADT + ARPI + docetaxel (triplet therapy) (category 2B)

  • High volume mCSPC: 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 + ARPI

• Metastatic castrate-resistance prostate cancer (mCRPC):

  • Cabazitaxel if progressed on Docetaxel (TROPIC)

  • Olaparib (if BRCA positive)

  • Rucaparib (if BRCA positive)

  • PARP inhibitor + ARPI

    • 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, glioblastoma multiforme, bile duct cancers, small intestinal cancer

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

*** Abbreviations:

• ADT: Androgen Deprivation Therapy

• ARPI: Androgen Receptor Pathway Inhibitor

• BCR: Biochemical Recurrence

• EBRT: External Beam Radiation Therapy

• MDRT: Metastasis-Directed Radiation Therapy

• mCRPC: Metastatic Castrate Resistant Prostate Cancer

• mCSPC: Metastatic Castrate Sensitive Prostate Cancer

• nmCRPC: Non-metastatic Castrate Resistant Prostate Cancer

• PLND: Pelvic Lymph Node Dissection

• RP: Radical Prostatectomy

• RT: Radiation Therapy