Prostate Cancer Therapeutics

prostate cancer: prevalence

~299,010 new cases in US 2024
• most common cancer in men
• 1 out of every 8 men will be diagnosed w/ this cancer in their lifetime

~35,250 deaths in US 2024
• 2nd leading cause of cancer deaths, behind lung

median age of diagnoses = 67

5-year relative survival rate
• localized >99%
• regional >99%
• distant 34%
→ treat like chronic disease

prostate cancer: risk factors

age - rare in men <40yo; IF yes → genetic counsel

family history - 1st degree relative

ethnicity - more common in African American men & Caribbean men of African ancestry

germline mutations
• Lynch syndrome
• BRCA1 & BRCA2 mutations

diet - link between high dairy consumption & Ca²⁺ diet

prostate cancer: pathogenesis

dysregulation of signaling pathways are involved in initiation & progression - however, exact genes & pathways NOT fully understood

associated w/ hereditary breast & ovarian cancer syndrome (HBOC) & Lynch syndrome

tumor cells may have mutations in MLH1, MSH2, MSH6 or PMS2 → microsatellite instability (MSI) or deficient mismatch repair (dMMR)

NCCN guidelines - recommend next generation gene sequencing as standard of care for metastatic prostate cancer

prostate cancer: s/s

difficulty urinating, weak urine stream OR increase in frequency of urination

loss of bladder control

blood in urine

erectile dysfunction

weight loss

fatigue

bone pain - IF metastatic

prostate cancer: screening

controversial w/ differing recommendations from several orgs

balance of screening to prevent mortality in often-indolent malignancy vs. harms of over-treatment

most often occurs in asymptomatic men
• prostate specific antigen (PSA) - glycoprotein produced by epithelial cells of prostate; specific to prostate but NOT specific for cancer
➢ can be elevated due to infection, recent instrumentation, trauma, untreated BPH
• +/- digital rectal examination (DRE) - should NOT be used as stand-alone test, ONLY in combination w/ PSA

prostate cancer: screening recommendations

2018 US Preventative Services Task Force (USPSTF) - PSA screening for men recommended for ages 55-69
• should be decided on individual pt basis
• NO guidance for pts <55yo
• recommends against screening men 70+yo → treatment causes more harm

NCCN
• choice of pt & provider to screen starting 45yo (10 years earlier)
• recommend against screening at 75yo

when further workup warranted
• general agreement IF PSA >4 ng/mL
• some MAY argue once PSA >2.5 ng/mL

depends on guidelines
• screening every 1-4 years
• normal range PSA ≤4 ng/mL
• PSA >10 = >67% chance having prostate cancer

prostate cancer: screening harm vs. benefit

benefit
• possible reduction in morbidity
• lower grade/stage
• catch prostate cancer early

risk
• surgical & radiation complications
• complications of overtreatment = ADEs
• overdiagnosis → overtreatment
• complications from biopsy - punch biopsy = uncomfortable

prostate cancer treatment: risk stratification

stage of cancer (TNM)

grade group

PSA

prostate cancer: Gleason grade & score

biopsy positive → assign grade then score

Gleason grade range 1-5
• grade 5 = most abnormal
• grade 1 = most similar to normal prostate tissue

Gleason score range 2-10
• 2 areas make up most of cancer may have different grades
• score = sum of 2 grades (3+4 = Gleason score 7)
➢ grade of most predominant pattern + grade of 2nd most predominant pattern = Gleason score

prostate cancer: 4 treatment options

radical prostatectomy (RP) - appropriate therapy for ANY pt w/ clinically localized prostate cancer who have life expectancy of 10 yrs or more; complete removal
• risks - urinary incontinence, erectile dysfunction

radiation therapy (RT)
• external beam radiation therapy (EBRT)
• brachytherapy (unique) - involves placing radioactive sources into prostate tissue
➢ advantage - treatment completed in 1 day
➢ disadvantage - use of general anesthesia & risk of acute urinary retention
• 2 methods
➢ low dose → permanent seed implantation
➢ high dose → temporary insertion of radiation source
➢ seed implantation → small radioactive pellets

androgen deprivation therapy (ADT) - mainstay; pharmacists can help w/ this
• goal - reduce levels of male hormones to castrate levels of testosterone
• prostate cancer often driven by androgens
• NOT able to cure prostate cancer alone; often used in combination w/ another treatment options

chemotherapy

prostate cancer: observation vs. active surveillance

observation → low risk
• H&P every 12 months
• most likely PSA every 12 months
• IF pts become symptomatic, may undergo full workup

active surveillance → higher risk group; regular follow up
• PSA every 6 months
• DRE no more often than every 12 months
• may repeat prostate biopsies every 12 months
• repeat MRI every 12 months

prostate cancer treatment: very low risk group

likely no treatment
• <10 yrs expected survival → observation
• 10-20 yrs expected survival → active surveillance
• >20 yrs expected survival → active surveillance (preferred), EBRT or brachytherapy, radical prostatectomy

prostate cancer treatment: low risk group

likely no treatment
• <10 yrs expected survival → observation
• ≥10 yrs expected survival → active surveillance (preferred), EBRT or brachytherapy, radical prostatectomy

prostate cancer treatment: favorable intermediate risk group

likely no treatment
• 10 yrs or less expected survival → observation (preferred) or EBRT or brachytherapy
• >10 yrs expected survival → active surveillance (preferred), EBRT or brachytherapy, radical prostatectomy

prostate cancer treatment: unfavorable intermediate risk group

1st time pharmacologic treatment recommended
• 10 yrs or less expected survival → observation or EBRT, brachytherapy, ± androgen deprivation therapy (ADT)
• >10 yrs expected survival → radical prostatectomy ± pelvic lymph node dissection or EBRT/brachytherapy, + ADT

prostate cancer treatment: high & very high risk group

likely need treatment
• ≤5 yrs & asymptomatic expected survival → observation or androgen deprivation therapy (ADT) or EBRT
• >5 yrs or symptomatic expected survival → EBRT + ADT or EBRT + brachytherapy + ADT or EBRT + ADT + abiraterone (very high risk only)

prostate cancer: castration sensitive vs. resistant

castration sensitive - pts who have NOT received ANY treatment; newly diagnosed
• castrate levels of testosterone <50 ng/dL (normal level 300-1050 ng/dL)

castration resistant - most men w/ advanced disease eventually stop responding to traditional ADT
• considered castration-resistant prostate cancer (CRPC)
• even IF pt becomes castration resistant, continue ADT - do NOT stop

prostate cancer: treatment road map

castration sensitive prostate cancer (CSPC)
• non-metastatic castration sensitive
• metastatic castration sensitive

castration resistant prostate cancer (CRPC)
• non-metastatic castration resistant
• metastatic castration resistant

prostate cancer treatment options: non-metastatic castration sensitive

androgen deprivation therapy (ADT)
• LHRH agonist + anti-androgen - short term
• LHRH antagonist
• LHRH agonist or antagonist + abiraterone - very high risk ONLY

luteinizing hormone-releasing hormones (LHRH)

non-metastatic castration sensitive: luteinizing hormone-releasing hormone (LHRH) agonists

aka gonadotropin-releasing hormone (GnRH) agonists

reversable method of androgen ablation = as effective as orchiectomy

testosterone flare
• due to increasing LHRH - can cause bone pain & increased urinary symptoms
• resolves ~2 wks
• how to avoid - antiandrogen therapy started 7 days prior to LHRH; can use for up to 2-4 wks

negative feedback loop - block production of testosterone

4 agents - goserelin, leuprolide, triptorelin, histrelin
• leuprolide 22.5 mg q3mo (most common option); 45 mg q6mo (advantage)

non-metastatic castration sensitive: LHRH agonists - adverse events

acute - tumor flare, gynecomastia, hot flashes, erectile dysfunction, edema, injection site reaction, hyperglycemia

long-term - osteoporosis (BIG → DEXA scan recommended), clinical fracture, obesity, insulin resistance, alteration in lipids, increased risk of diabetes & CV events

non-metastatic castration sensitive: antiandrogens

androgen receptor inhibitors - competitive inhibitor for binding of dihydrotestosterone & testosterone within prostate cancer cell

blocks testosterone from binding

common AEs - diarrhea, nausea, elevated LFTs

usually utilized short term before LHRH initiated & 2-4 wks after to prevent tumor flare - NEVER long term

combined androgen therapy (LHRH + antiandrogen) - may be used IF pt becomes resistant to LHRH alone
• also may be considered 1st line but MORE adverse events

3 agents - flutamide, bicalutamide, nilutamide

non-metastatic castration sensitive: antiandrogens - adverse events

diarrhea, hematuria, nausea, elevated LFTs

nilutamide - disulfiram-like reaction, interstitial pneumonia

non-metastatic castration sensitive: luteinizing hormone-releasing hormone (LHRH) antagonist

approved for advanced prostate cancer

MOA - binds reversibly to LHRH receptors in anterior pituitary gland
• decreases testosterone levels within 4-7 days; faster than LHRH agonists (2 wks)
• NO tumor flare

adverse events - fatigue, hot flashes, weight gain, increased LFTs, injection site reactions, QTc prolongation, increase serum glucose, increase in TG, myalgia

2 agents
• degarelix SQ q28days → qmo & expensive = why NOT used common
• relugolix PO daily

non-metastatic castration sensitive: abiraterone (Zytiga) + prednisone

2nd gen antiandrogen

MOA - selectively & irreversibly inhibits CYP17 & enzyme required for androgen biosynthesis; inhibits formation of DHEA which is precursor to testosterone

1000 mg qD
must be used concurrently w/ LHRH
should be taken on empty stomach

AEs - HTN, hypoK⁺, peripheral edema, LFT elevations (look at 2-3 mo; then qmo), hot flashes, fatigue, muscle discomfort

non-metastatic castration sensitive: abiraterone + ADT

abiraterone - can be added to EBRT + ADT x2 yrs in pts w/ very high risk prostate cancer

prostate cancer treatment options: metastatic castration sensitive
*pt presents to clinic w/ metastatic disease but w/ NO previous treatment

ADT + one of following
• abiraterone
• apalutamide
• enzalutamide

ADT + docetaxel (1st chemo agent) + abiraterone OR darolutamide (very toxic)
*ONLY recommended for pts w/ high-volume disease who are fit for chemotherapy

ADT + EBRT to primary tumor ± abiraterone or docetaxel

metastatic castration sensitive AND non-metastatic castration resistant*: apalutamide & enzalutamide
*PSA doubling time in less than 10 months

MOA - pure androgen receptor signaling inhibitor & inhibits androgen receptor nuclear translocation, DNA binding & causes apoptosis; 2nd generation

apalutamide 240 mg PO daily
enzalutamide 160 mg PO daily

AEs - CNS effects (seizures, altered mental status, cognitive dysfunction), HTN, fatigue, metabolic abnormalities, anemia, GI disturbances

metastatic castration sensitive AND non-metastatic castration resistant*: darolutamide
*PSA doubling time in less than 10 months

MOA - competitive androgen receptor inhibitor; inhibits androgen receptor translocation & androgen receptor-mediated transcription

600 mg PO BID

AEs - fatigue, increase LFTs, cardiovascular effects
*NO documented risk of seizures - does NOT cross BBB → better option

metastatic castration sensitive: docetaxel + ADT + abiraterone or darolutamide

docetaxel IV 75 mg/m² day 1 q21days - NOT well tolerated
• MOA - stabilizes microtubules in cell & results in inhibition of DNA, RNA & protein synthesis
• premedication w/ dexamethasone the day prior to docetaxel - required to prevent fluid retention & rash
• ADEs - alopecia, fluid retention, rash, peripheral neuropathy, bone marrow suppression, elevated LFTs, hypersensitivity reactions, nail changes

prostate cancer treatment options: non-metastatic castration resistant

ALWAYS continue ADT

PLUS* 1 of 2nd generation androgens
• apalutamide
• enzalutamide
• darolutamide - less CNS effects
*PSA doubling time 10 months or less

prostate cancer treatment options: metastatic castration resistant

ALWAYS continue ADT

PLUS 1 of following
• abiraterone + prednisone
• docetaxel + prednisone
• enzalutamide
• sipuleucel-T* - novel
• radium-223* - novel
• mitoxantrone - palliation in symptomatic pts w/ visceral metastatic who cannot tolerate other therapies; old drug
• 2ndary hormone therapy
*pt must meet certain criteria

next generation sequencing (NGS) should be sent
• test designed to detect actionable oncologic targets by sequencing tumor samples w/ blood or tumor samples

actionable targets
• microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (DMMR) → pembrolizumab (Keytruda)
➢ universal indication for ANY solid tumor that expresses above tumor markers
• BRCA mutation → niraparib/abiraterone or olaparib/abiraterone
• homologous recombination repair (HRR) mutation → talazoparib/enzolutamide

prostate cancer: supportive care

bone modifying agents in non-metastatic setting (osteoporosis)
• zoledronic acid (Reclast) 5 mg IV yearly - renally eliminated
• denosumab (Prolia) 60 mg SQ every 6 months - good option for poor kidney fxn
• alendronate 70 mg PO weekly

bone modifying agents in metastatic setting (bone metastasis, bone pain)
• zoledronic acid (Zometa) 4 mg IV every 4 weeks OR every 12 weeks (preferred) - renally eliminated
• denosumab (Xgeva) 120 mg SQ every 4 weeks - good option for poor kidney fxn

prostate cancer: supportive care - bone modifying agents in non-metastatic setting

ADT increases risk for osteoporosis

calcium 1200 mg + vitamin D3 800-1000 daily for ALL men >50yo

baseline DEXA scan prior to initiating bone modifying agents

NCCN recommendations
• zoledronic acid (Reclast) 5 mg IV yearly - renally eliminated
• denosumab (Prolia) 60 mg SQ every 6 months - good option for poor kidney fxn
• alendronate 70 mg PO weekly

prostate cancer: supportive care - bone modifying agents in metastatic setting

bone metastasis, bone pain
• zoledronic acid (Zometa) 4 mg IV every 4 weeks OR every 12 weeks (preferred) - renally eliminated
• denosumab (Xgeva) 120 mg SQ every 4 weeks - good option for poor kidney fxn