Megan May, Pharm.D., BCOP Oncology Clinical Pharmacy ...s3.proce.com/res/pdf/794.pdf · 3 Nelson WG, et al. N Engl J Med. 2003;349:366-81. Hoffman RM. N Engl J Med. 2011:1-7. Prostate

1

Megan May, Pharm.D., BCOPOncology Clinical Pharmacy SpecialistBaptist Health Lexington

Describe the etiology and pathophysiology of prostate cancer

Explain the mechanism of action of available therapeutics for prostate cancer

Outline the efficacy and safety of treatment options for prostate cancer

Explain how to evaluate the appropriate selection of therapy for specific prostate cancer patients

2

CDC Website. Expected New Cancer Cases and Deaths in 2010. https://www.cdc.gov/cancer/dcpc/research/articles/cancer_2020_incidence.htm

Prostate Cancer Incidence

Hormonal Testosterone is a growth signal to the prostate

Genetic Mendelian inheritance of a rare, autosomal

dominant allele Inherited gene mutations BRCA1, BRCA2, and HOXB13

Prostatic intraepithelial neoplasia (PIN)

3

Nelson WG, et al. N Engl J Med. 2003;349:366-81.Hoffman RM. N Engl J Med. 2011:1-7.

Prostate Cancer

Race

Aging

HormonesDiet

Family History

Digital Rectal Exam (DRE) Historical standard

Prostate-Specific Antigen (PSA) Test Measures the level of free and bound PSA in

the blood Cut-off point: 4 ng/mL

U.S. Preventive Services Task Force: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening1Hoffman RM. N Engl J Med. 2011:1-7.

4

Controversy over recommended screening for prostate cancer in men over 70 years old

Screening and treatment for prostate cancer can cause harm

Screening most benefits men 55-69 years old

U.S. Preventive Services Task Force: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening1Hoffman RM. N Engl J Med. 2011:1-7.

Low risk of prostate cancer (n = 18,882) Randomized to receive finasteride 5mg PO

daily or placebo

Thompson IM, et al. NEJM 2003;349:215‐224.Thompson IM, et al. NEJM 2013;369:603-610

Primary 2003 Report Updated 2013 Report

Prostate-Cancer Grade

Relative Risk (95% CI)

P value Relative Risk (95% CI)

P value

Any Grade 0.75 (0.69-0.81) <0.001 0.70 (0.65-0.76) <0.001

Low Grade 0.62 (0.56-0.68) <0.001 0.57 (0.52-0.63) <0.001

High Grade 1.27 (1.07-1.50) 0.005 1.17 (1.00-1.37) 0.05

5

American Society of Clinical Oncology and the American Urological Association guidelines

Symptomatic men with a PSA ≤ 3.0 ng/mL who are regularly screened with PSA for early detection of prostate cancer may benefit from dutasteride or finasteride for 7 years

Graham L. Am Fam Physician. 2010;81(1):76-77.

Urinary hesitancy/retention Decreased force of stream of urine Hematuria Hematospermia Lower extremity edema Pelvic discomfort Bone pain Prostate gland lump

Nelson WG, et al. N Engl J Med. 2003;349:366-81.Hoffman RM. N Engl J Med. 2011:1-7.

6

DRE PSA Test Transrectal Ultrasound (TRUS) Biopsy Methods Transperineal prostate biopsy Transrectal prostate biopsy Transurethral prostate biopsy

http://www.prostate-cancer.com/prostate-cancer-treatment-overview/overview-trus.htmlHoffman RM. N Engl J Med. 2011:1-7.

Tumor growth rate Histology of 2 samples

are graded (1-5) Sum of grades =

Gleason score Range of 2-10 2: nonaggressive cancer 10: very aggressive

cancer

http://training.seer.cancer.gov/prostate/abstract-code-stage/morphology.html

7

Tumor size

Node involvement

Metastasis

Cancer grade

American Joint Committee on Cancer: Prostate Cancer Staging. 7th Edition. 2009.

Initial stage, grade, and PSA level at the time of definitive therapy

Absolute level of PSA Rate of change in the

PSA level Overall 5-year survival

rate = 98.2%

NIH SEER: Cancer Stat Facts: Prostate Cancer. https://seer.cancer.gov/statfacts/html/prost.html.

8

Tumor Factors Tumor Stage

Growth Rate

Aggressiveness

Treatment-Related Factors

Patient Factors Patient’s Age

Comorbid Conditions

Projected Life Expectancy

Recurrence Risk Initial Therapy

Very LowT1c, GS ≤ 6, PSA < 10ng/mL, < 3 positive bx cores (< 50% cancer in each core), PSA density < 0.15 ng/mL/g

Active surveillance

LowT1-T2a, GS ≤ 6, PSA < 10ng/mL

Active surveillance, radical prostatectomy, or radiation

Favorable IntermediateT2b-T2c or GS = 7 or PSA 10-20 ng/mL, and percentage of positive biopsy cores <50%

Radical prostatectomy, radiation with or without hormonal therapy

Unfavorable IntermediateT2b-T2c or GS = 7 or PSA 10-20 ng/mL

Radical prostatectomy, radiation withhormonal therapy

HighT3a-T4 or GS 8-10 or PSA ≥ 20 ng/mL

Radical prostatectomy, radiation withhormonal therapy

Sanda MG, et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline.NIH: Prostate Cancer Treatment (PDQ). https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq#section/_62

9

Slow growing tumors with no symptoms

Requires frequent check-ups Conversion to treatment if disease

progression

Bill-Axelson, et al. N Engl J Med. 2005;352:1977-84.Johansson E, et al. Lancet Oncol. 2011;12(9):891-899.

Radical prostatectomy versus observation Scandinavian Prostate Cancer Group Study

Number 4 (SPCG-4) Prostate Testing for Cancer and Treatment Trial

(PIVOT) Radical prostatectomy versus radiation

versus observation Prostate Cancer Intervention versus Observation

Trial (ProtecT)Bill-Axelson, et al. N Engl J Med. 2014;370:932-942.Wilt TJ, et al. N Engl J Med. 2012;367:203-213.Hamdy FC, et al. N Engl J Med. 2016;375:1415-1424.

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Involves removal of All or part of prostate gland Surrounding tissue Lymph nodes

Complications Early mortality Bladder contracture Urinary incontinence Impotence

http://www.prostate-cancer.com/prostatectomy/treatment-description/prostatectomy-description.html

High-powered energy used to kill cancer cells External beam radiation therapy Brachytherapy

▪ Seed implantation

Proton radiation therapy Option for non-surgical candidates Complications Painful, frequent, and urgent urination Loose and painful stools Erectile dysfunction

Slater JD. Int J Radiation Oncology. 2004:59(2):348-352.

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Suppresses, blocks, or eliminates testosterone

Goal serum testosterone <20 ng/dL 1 month after initiation

http://chemoregimen.com/Prostate-Cancer-c-51-61.html

Surgical castration Bilateral orchiectomy

Medical castration Luteinizing hormone-releasing hormone

(LHRH) agonist or antagonist Anti-androgens

12

Surgical removal of testicles Adverse effects Infection Hot flashes Diminished libido Erectile dysfunction

May lower testosterone levels more quickly than other treatment options

http://www.upmccancercenters.com/cancer/prostate/hormoneorchtherapy.html

Acute adverse effects Tumor flare, gynecomastia, hot flashes, sexual dysfunction, edema,

injection site reactions Long term adverse effects Osteoporosis, clinical fracture, obesity, insulin resistance, lipid

alterations, increased CV eventsMedication Dosage for metastatic cancerLeuprolide (Lupron®, Eligard®) 7.5mg SQ every month

22.5mg SQ every 3 months 45mg SQ every 6 months

Goserelin (Zoladex®) 3.6mg SQ every month 10.8mg SQ every 3 months

Triptorelin (Trelstar®) 3.75mg IM every 4 weeks 11.25mg IM every 12 weeks 22.5mg IM every 24 weeks

Histrelin (Vantas®) 50mg implant surgically inserted every 12 monthsEligard [package insert]. Bridgewater, NJ: Sanofi-aventis; 2012. Vantas [package insert]. Malvern, PA: Endo Pharmaceuticals Solutions; 2004.

Zoladex [package insert]. Wilmington, DE: AstraZeneca; 1989. Trelstar [package insert]. Irvine, CA: Allergan; 2002.

13

Adverse effects Injection site reactions

Medication Dosage for metastatic cancerDegarelix (Firmagon®) LD: 240mg injection

MD: 80mg every 28 days (beginning 28 days after initial LD)

Firmagon [package insert]. Parsippany, NJ: Ferring Pharmaceuticals; 2015.

Prevent testosterone from reaching the cancer cells Adverse effects Diarrhea, gynecomastia, hot flashes, nausea/vomiting

Medication Dosage for metastatic cancerBicalutamide (Casodex®) 50mg PO daily

Flutamide (Eulexin®) 250mg PO TID

Nilutamide (Nilandron®) 300mg PO daily for 30 days then decrease to 150mg PO daily

Casodex [package insert]. Princeton, NJ: Zydus Pharmaceuticals; 2009.

Eulexin [package insert]. Kenilworth, NJ: Schering Corporation; 1999.

Nilandron [package insert]. Baudette, MN: ANI Pharmaceuticals; 2015.

14

Initiation of ADT PSA > 50 ng/mL Rapid PSA velocity Long life expectancy

Goal of treatment: palliative care

Anti-androgen withdrawal Steroids Aminoglutethamide Ketoconazole Megestol acetate

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Prostate Cancer. London, England: Times Mirror International Publishers Ltd; 1996: 143.

Prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels

Defined as testosterone < 20 ng/dL and disease progression

1996

Mitoxantroneplus

prednisone

2004

Docetaxel plus prednisone

2010

Sipuleucel-T

2010

Cabazitaxelplus

prednisone

2011

Abirateroneplus predisone

2012

Enzalutamide

2013

Radium 223

2018

Apalutamide

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Docetaxel (Taxotere®) 75mg/m2 IV over 1 hour every 3 weeks x 10 cyclesPrednisone 5mg PO BID

Docetaxel 30mg/m2 IV over 30 min weekly x 5 weeks then every 6 weeks x 5 cyclesPrednisone 5mg PO BID

Mitoxantrone (Novantrone®) 12mg/m2 IV over 30 min every 3 weeks x 10 cyclesPrednisone 5mg PO BID

Dagher R, et al. Clin Cancer Res. 2004,10(24):8147-8151.Tannock IF, et al. N Engl J Med. 2004,351(15):1502-1512.

Lorenzo GD, et al. Nature Reviews Clinical Oncology. 2011;8:551-561.

APC: Antigen Presenting CellsPAP: Prostatic Acid PhosphataseGM-CSF: Granulocyte Macrophage Colony-Stimulating Factor

17

Administration IV every 2 weeks for 3 doses

Available Doses Minimum of 50 million activated cells

Infusion Time 60 minutes

Dosage Adjustments No adjustments

Monitoring Infusion reactions (pre-medicate)

Storage Do not remove from insulated shipping box until administration

Black Box Warnings None

Kantoff FW. N Engl J Med. 2010:363;5:411-422.


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Sipuleucel-T Placebo

Overall survival (months) 25.8 21.7

Time to progression (weeks) 14.6 14.4

PSA response 2.6% 1.3%

De Bono JS, et al. Lancet. 2010; 376:1147-1154.

Sipuleucel-T (n = 338) Placebo (n = 168)

Adverse Reaction All Grades Grade 3-5 All Grades Grade 3-5

Chills 183 (54.1%) 4 (1.2%) 21 (12.5%) 21 (12.5%)

Fatigue 132 (39.1%) 4 (1.2%) 64 (38.1%) 3 (1.8%)

Back Pain 132(39.1%) 12 (3.6%) 61 (36.3%) 8 (4.8%)

Pyrexia 99 (29.3%) 1 (0.3%) 23 (13.7%) 3 (1.8%)

Nausea 95 (28.1%) 2 (0.6%) 35 (20.8%) 0

Arthralgia 54 (16.0%) 1 (0.3%) 8 (4.8%) 0

Vomiting 33 (9.8%) 2 (0.6%) 8 (4.8%) 0

Headache 33 (9.8%) 0 6 (3.6%) 0

Anemia 25 (7.4%) 2 (2%) 5 (3.0%) 0

Limb Pain 17 (5.0%) 0 4 (2.4%) 0

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Asymptomatic or minimally symptomatic patients with metastatic CRPC

May be considered for: Good performance status Life expectancy > 6 months No visceral disease


De Bono JS, et al. Lancet. 2010; 376:1147-1154.Jevtana [package insert]. Bridgewater, NJ: Sanofi-aventis; 2010.

Microtubule inhibitor Binds to tubulin and promotes its

assembly into microtubules while simultaneously inhibiting disassembly

Poor affinity for multidrug resistance proteins

20

Administration 20mg/m2 IV every 3 weeks + prednisone 10mg/day

Available Doses 60mg/1.5mL single dose vial

Infusion Time 1 hour

Pharmacokinetics Primarily CYP3A4 metabolism

Storage Stable for 8 hours at RT or 24 hours in refrigerator

Dosage Adjustments No adjustments

Monitoring Infusion reaction (premedicate)

Black Box Warnings Bone marrow suppression, hypersensitivity reactions

De Bono JS, et al. Lancet. 2010; 376:1147-1154.Jevtana [package insert]. Bridgewater, NJ: Sanofi-aventis; 2010.

De Bono JS, et al. Lancet. 2010; 376:1147-1154.Sartor AO, et al. ASCO. 2010:9(abstract)

Patients• 755 patients

with metastatic CRPC

• Progressed during and after docetaxel treatment

Randomized 1:1

Cabazitaxel25mg/m2

every 3 weeks + prednisone

N=378Primary Endpoints:• Overall

Survival

Secondary Endpoints:

• Progression-free survival, response rate, and safety

• QOL• Time to PSA

ProgressionMitoxanrone

12mg/m2 every 3 weeks +

prednisone N=377

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Cabazitaxel Mitoxantrone

Median overall survival (months) 15.1 12.7

Tumor response rate (%) 14.4 4.4

PSA response rate (%) 39.2 17.8

Pain response rate (%) 9.2 7.7

Time to PSA progression (months) 6.4 3.1



Cabazitaxel (n=378) Mitoxantrone (n=377)


Neutropenia 347 (94%) 303 (88%) 325 (88%) 215 (58%)

Leukopenia 355 (96%) 253 (68%) 343 (92%) 157 (42%)

Anemia 361(97%) 39 (11%) 302 (81%) 18 (5%)

Thrombocytopenia 176 (47%) 15 (4%) 160 (43%) 6 (2%)

Diarrhea 173 (47%) 23 (6%) 39 (11%) 1 (<1%)

Fatigue 136 (37%) 18 (5%) 102 (27%) 11 (3%)

Asthenia 76 (20%) 17 (5%) 46 (12%) 9 (2%)

Nausea 127 (34%) 7 (2%) 85 (23%) 1 (<1%)

Vomiting 84 (23%) 7 (2%) 38 (10%) 0

Constipation 76 (20%) 4 (1%) 57 (15%) 2 (1%)

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Second line treatment after docetaxel treatment for metastatic CRPC

First treatment to prolong survival in patients

May be considered for: Failed docetaxel therapy


http://www.medscape.com/viewarticle/722776_4

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Administration CRPC: 1000mg PO once daily + prednisone 5mg PO BIDCastration-sensitive prostate cancer: 1000mg PO once daily + prednisone 5mg PO once daily

Available Doses 250mg tablet and 500mg tablet

Dosage Adjustments Liver impairment

Drug Interactions Inhibits CYP2D6

Monitoring LFTs


De Bono, et al. N Engl J Med. 2011:364(21):1995-2005




• Failed 1 or 2 chemotherapies, one containing docetaxel

Randomized 2:1

Abiraterone1000mg oral

daily + prednisone

5mg BID

N=797

Primary Endpoints:• Overall

Survival


• Progression-free survival

• PSA response• QOL• Time to PSA

Progression

PlaceboN=398

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Abiraterone Placebo


Time to progression (months) 5.6 3.6

PSA response 38% 10.1%


Abiraterone (n = 797) Placebo (n = 398)


Fatigue 346 (44%) 66 (8%) 169 (43%) 39 (10%)

Fluid Retention and Edema

241 (31%) 18 (3%) 88 (23%) 4 (1%)

Back Pain 233 (30%) 47 (6%) 129 (33%) 38 (10%)

Nausea 233 (30%) 13 (2%) 124 (32%) 10 (3%)

Arthralgia 215 (27%) 33 (4%) 89 (23%) 16 (4%)

Constipation 206 (26%) 8 (1%) 120 (31%) 4 (1%)

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Ryan CJ, et al. N Engl J Med. 2012:368(2):138-148.


with progressive, metastatic CRPC

• Chemotherapy naive

Randomized 1:1


daily + prednisone

5mg BID

N=544

Primary Endpoints:• Overall

Survival• Progression-

free survival


• Time to chemotherapy initiation

• PSA response• Cancer pain

PlaceboN=544

De Bono, et al. N Engl J Med. 2011:364(21):1995-2005.Kluetz PG, et al. Clin Cancer Res. 2013:19:6650-6656.

Abiraterone Placebo

Overall survival (months) Not reached 27.2

Progression free survival (months) Not reached 8.3

Time to chemotherapy initiation (months) 25.2 16.8


Abiraterone Placebo


Progression free survival (months) Not reached 8

26

Fizazi K, et al. N Engl J Med. 2017:377:352-360.

Patients• 1199 patients with

progressive, metastatic castration-sensitive prostate cancer

• Chemotherapy naive

Randomized 1:1


daily + prednisone 5mg

daily

N=597

Primary Endpoints:• Overall Survival• Progression-free

survival

PlaceboN=602

Abiraterone Placebo

Overall survival (months) Not reached 34.7

Progression free survival (months) 33 14.8


Time to pain progression (months) Not reached 16.6

Median time to next symptomatic skeletal-related event (months)

Not reached Not reached

Median time to chemotherapy (months) Not reached 38.9

Median time to subsequent prostate cancer therapy (months)

Not reached 21.6

Fizazi K, et al. N Engl J Med. 2017:377:352-360.

27

First line therapy Chemotherapy naïve Metastasized CRPC and castration-sensitive prostate cancer

Second line therapy Metastasized CRPC First-line hormonal therapy has failed

May be considered for: Symptomatic or asymptomatic Visceral disease Therapy naïve or failed docetaxel

De Bono, et al. N Engl J Med. 364(21):1995-2005.Kluetz PG, et al. Clin Cancer Res. 2013:19:6650-6656.

Administration 500mg PO once daily + methylprednisolone 4mg PO BID

Available Doses 125mg tablet

Dosage Adjustments Liver impairment

Drug Interactions Inhibits CYP2D6

Monitoring LFTs


Yonsa [abiraterone acetate]. Cranbury: Sun Pharmaceutical Industries, Inc., NJ: 2018.

28

Blocks androgen receptor from moving into the nucleus and activating growth genes

Scher HI, et al. N Engl J Med. 2012:367(13):1187-1197.


Administration 160mg PO once daily

Available Doses 40mg capsule

Dosage Adjustments None

Drug Interactions CYP2C8 and CYP3A4

Monitoring LFTs


29




• Failed docetaxeltreatment

Randomized 2:1

Enzaluatmide160mg oral

daily

N=800 Primary Endpoints:• Overall

Survival


• PSA level response

• QOL• Time to PSA

Progression

PlaceboN=399

Enzalutamide Placebo


Time to radiographic progression (months) 8.3 2.9

PSA 90% reduction from baseline (%) 25 1


30


Enzalutamide (n = 800) Placebo (n = 399)


Fatigue 269 (34%) 50 (6%) 116 (29%) 29 (7%)

Diarrhea 171 (21%) 9 (1%) 70 (18%) 1 (<1%)

Hot Flashes 162 (20%) 0 41 (10%) 0

Musculoskeletal Pain

109 (14%) 8 (1%) 40 (10%) 1 (<1%)

Headache 93 (12%) 6 (<1%) 22 (6%) 0

Cardiac Disorder 49 (6%) 7 (1%) 30 (8%) 8 (2%)


progression on androgen deprivation with metastatic CRPC

• Chemotherapy naïve

Randomized 1:1

Enzaluatmide160mg oral

daily

N=872Primary Endpoints:• Overall Survival• Progression free

survival

PlaceboN=845

Beer TM, et al. Eur Urol. 2017:71:151-154.

31



Time to radiographic progression (months) Not reached 3.7

Median time to chemotherapy initiation (months)

28.0 10.8

PSA 90% reduction from baseline (%) 41 1

Beer TM, et al. Eur Urol. 2017:71:151-154.

Patients• 1401 patients with

non-metastatic CRPC

• Chemotherapy naïve

Randomized 2:1

Enzaluatmide160mg oral daily

N=933 Primary Endpoints:• Metastasis-free

survival

PlaceboN=468

Hussain M, et al. N Eng J Med. 2018:378:2465-2474.

32


Metastasis-free survival (months) 36.6 14.7

First use of new prostate cancer therapy (months)

39.6 17.7

PSA progression 37.2% 3.9%

Overall survival Not reached Not reached

Death on study 32 (3.4%) 4 (0.9%)

Hussain M, et al. N Eng J Med. 2018:378:2465-2474.

First line therapy Non-metastasized and metastasized CRPC

Second line therapy Metastasized CRPC First-line hormone therapy has failed

May be considered for: Symptomatic or asymptomatic Visceral disease Therapy naïve or failed docetaxel

Does not have to be administered with prednisone Administered with gonadotropin-releasing

hormone if no bilateral orchiectomyScher HI, et al. N Engl J Med. 2012:367(13):1187-1197.

33

Binds directly to the ligand-binding domain of the androgen receptor and by inhibiting androgen receptor nuclear translocation, DNA binding, and androgen receptor-mediated transcription

Smith MR, et al. N Engl J Med. 2018:378:1408-1418.


Administration 240mg PO once daily

Available Doses 60mg tablet

Dosage Adjustments None

Drug Interactions Inhibits CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1

Monitoring None


34


with non-metastatic CRPC

Randomized 2:1

Apalutamide240mg oral

daily

N=860 Primary Endpoints:• Metastatic-

free Survival


• Time to symptomatic Progression

PlaceboN=401



Apalutamide Placebo

Metastasis-free survival (months) 40.35 16.2

Median progression-free survival (months) 40.5 14.7

Median overall survival (months) Not reached 39

Median time to PSA progression (months) No reached 3.7

35


Apalutamide (n = 803) Placebo (n = 398)


Fatigue 244 (30%) 7 (1%) 84 (29%) 1 (<1%)

Hypertension 199 (25%) 115 (14%) 79 (20%) 47 (12%)

Rash 191 (24%) 42 (5%) 22 (5%) 1 (<1%)

Diarrhea 163 (20%) 8 (1%) 60 (15%) 2 (<1%)

Nausea 145 (18%) 0 63 (16%) 0

Weight Loss 129 (16%) 9 (1%) 25 (6%) 1 (<1%)

Arthralgia 128 (16%) 0 30 (8%) 0

Falls 125 (16%) 14 (2%) 36 (9%) 3 (<1%)

First line therapy Non-metastasized CRPC

May be considered for: Symptomatic or asymptomatic Therapy naïve

Administered with gonadotropin-releasing hormone if no bilateral orchiectomy


36

Osteoporosis prevention and treatment Calcium 1200mg/qd and vitamin D3 800-1000 IU/qd Bisphosphonates or denosumab

Long-term effects of prolonged ADT Fatigue Diabetes Weight gain

Bone metastasis Zoledronic acid, denosumab, radiation

▪ Monitor SrCr, osteonecrosis of the jaw, and hypocalcemia

The key to successful prostate cancer treatment is early detection

Clinical staging is important in determining the appropriate treatment

There are now treatment options for men with CRPC

Treatment always should be individualized

37

Megan May, Pharm.D., BCOPOncology Clinical Pharmacy SpecialistBaptist Health Lexington

Documents

Megan May, Pharm.D., BCOP Oncology Clinical Pharmacy ...s3.proce.com/res/pdf/794.pdf · 3 Nelson WG, et al. N Engl J Med. 2003;349:366-81. Hoffman RM. N Engl J Med. 2011:1-7. Prostate