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Prostate Cancer

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Srimoyee Chakraborty

on 18 April 2013

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Transcript of Prostate Cancer

A disease state overview with a focus on metastatic castration-resistant prostate cancer (mCRPC) and current therapy options Objectives Overview Fast Facts Understand the basics of prostate cancer

Differentiate between metastatic castration-resistant prostate cancer and the general disease state

Learn the treatment options for mCRPC Anatomy and physiology

Signs and symptoms

Diagnosis and screening options

Stages of prostate cancer

General treatment options

Metastatic castration-resistant prostate cancer and treatment options According to the American Cancer Society, in 2013: Risk Factors Signs and Symptoms mCRPC Tumors progress despite testosterone levels
< 50 ng/dl
Known as 'castrate range'

Use of LHRH agonists and antagonists decrease androgen levels to a 'castrate range'
Eventually, tumors learn to make their own
androgens
Increases in PSA levels show signs of resistance Screening and Diagnosis Staging kkk Treatment Options for Prostate Cancer Prostate Cancer Srimoyee Chakraborty
PharmD Candidate 2013
Northeastern University About 238,590 new cases of prostate cancer will be diagnosed
About 29,720 men will die of prostate cancer Prostate cancer is the second deadliest cancer for men after lung cancer About 1 in 36 men die from prostate cancer When including all men with prostate cancer: Relative 5-year survival rate is 100%
Relative 10-year survival is 98%
Relative 15 year survival is 93% Anatomy and Physiology Prostate Cancer Age Race/Ethnicity
or Nationality Diet Family History/
Genetics Difficulty starting or stopping urination

Weak or interrupted stream

Feelings of incomplete urination

Pain and burning upon urination

Blood in urine or semen

Sexual dysfunction

Distant disease - bone pain Screening and Diagnosis Screening Digital Rectal Examination
(DRE) Prostate Specific Antigen
(PSA) Diagnosis Transrectal Ultrasound
(TRUS) Biopsy Examines prostate for irregular size, shape, and texture
Distinguish between PCA and BPH Levels under 4 ng/mL are usually considered normal
Levels between 4 and 10 ng/mL are usually considered elevated and requires evaluation
Levels over 10 ng/mL are usually considered highly elevated; malignancy suspected Uses sound waves to capture an image of the prostate STAGE 1 STAGE 4 Early stage of cancer that is confined to a small area
Cancer cells at this stage are thought to be non-aggressive Cancer at this stage is considered to be aggressive
The cancer has grown larger and may have affected both sides of the prostate gland The cancer has spread beyond the prostate to the seminal vesicles or other nearby tissues The cancer has metastasized
May have spread to the bladder, lymph nodes, bones, lungs or other organs Active Surveillance Prostatectomy Radiation Therapy External Beam Radiation Therapy

Proton Therapy

Brachytherapy Chemotherapy Hormone Therapy LHRH Agonists
Leuprolide
Triptorelin
Goserelin LHRH Antagonist
Degarelix Anti-Androgens
Bicalutamide
Flutamide
Nilutamide
Abiraterone
Enzalutamide Estramustine Docetaxel Mitoxantrone Cabazitaxel Defined as having testosterone levels < 50 ng/dl
Resistant to hormone therapy
Failed docetaxel therapy So what exactly is
mCRPC anyways? STAGE 2 STAGE 3 Walnut sized gland found in males
Produces prostate-specific antigen (PSA)
Contains zones - central, peripheral, and
transitional Age: PCA is most common in men above the age of 50; most are diagnosed at 65

Ethnicity or Nationality: most common in African American men, least common in Japanese men

Family/Genetics: chances of PCA increase if there is a 1st degree relative who has it; genes involved in PCA are BRCA2, EPAC2, and MSR1

Diet: it is hypothesized that diets high in saturated fats are linked to PCA but not enough sound data Positive metastases

Use denosumab or zoledronic acid if
bone metastases
present Symptomatic? Symptomatic? YES NO Docetaxel

Mitoxantrone

Abiraterone

Enzalutamide Sipuleucel - T

Secondary Hormone Therapy

Docetaxel * Cabazitaxel (post-docetaxel)

Abiraterone (post-docetaxel)

Enzalutamide (post- docetaxel)

Sipuleucel - T

Docetaxel rechallenge Efficacy
Sipuleucel-T: 22% risk reduction for death
Median overall survival: 25.8 months vs. 21.7 months
Median time to objective disease progression: 3.7 months vs. 3.6 months
PSA reduction of at least 50%
2.6% in sipuleucel-T group
1.3% in placebo group Safety
General adverse effects
Chills, fever, fatigue, back pain, joint aches, nausea, and headache
3/338 (0.9%) in sipuleucel-T group unable to receive infusions due to infusion related AEs
Most adverse events consistent with release of cytokines
No anaphylaxis reports
Deaths
210 (61.6%) in sipuleucel-T group
121 (70.8) in placebo group Sipuleucel-T: Safety and Efficacy Design
Double-blind, placebo-controlled, multicenter study
2:1 randomization between sipuleucel-T and placebo
Outcomes
Primary: overall survival
Secondary: time to objective disease progression
Results
Median overall survival: 25.8 months vs. 21.7 months
Median time to objective disease progression: 3.7 months vs. 3.6 months Sipuleucel-T Post-docetaxel Therapy
Sipuleucel-T Immunotherapy for CRPC Efficacy
Cabazitaxel: 30% risk reduction for death
Median overall survival: 15.1 months vs. 12.7 months
Median progression free survival: 2.8 months vs. 1.4 months
Significantly higher tumor and PSA response rates in cabazitaxel vs. mitoxantrone Safety
General adverse effects
Neutropenia, anemia, thrombocytopenia, diarrhea, nausea and vomiting
Peripheral neuropathy: 14% vs. 3%
Peripheral edema: 9% vs. 9%
Deaths
227 (61%) in cabazitaxel group
275 (74%) in mitoxantrone group
Most frequent cause of death in cabazitaxel group = neutropenia Cabazitaxel: Safety and Efficacy Design
Randomized, open-label study
1:1 randomization between cabazitaxel and mitoxantrone
Outcomes
Primary: overall survival
Secondary: progression-free survival, PSA response, tumor response
Results:
Median overall survival: 15.1 months vs. 12.7 months
Median progression free survival: 2.8 months vs. 1.4 months
Significantly higher tumor and PSA response rates in cabazitaxel vs. mitoxantrone Cabazitaxel Post-docetaxel Therapy
The TROPIC trial Efficacy
Enzalutamide: 37% risk reduction for death
Overall survival: 18.4 months vs. 13.6 months
PSA level response: 54% vs. 2%
QOL response: 43% vs. 18%
Progression-free survival: 8.3 months vs. 2.9 months
Time to PSA progression: 8.3 months vs. 3.0 months
Time to 1st skeletal-related event: 16.7 vs. 13.3 months Safety
General adverse effects
Fatigue, diarrhea, hot flashes, musculoskeletal pain, headache
Median time to adverse event: 12.6 months vs. 4.2 months
Cardiac disorders: 6% vs. 8%
Hypertension: 6.6% vs. 3.3%
5 of 800 patients in enzalutamide group experienced a seizure vs. none in placebo group
Deaths:
Enzalutamide 308/800 (39%)
Placebo: 212/399 (53%) Enzalutamide: Safety and Efficacy Design
International, randomized, double-blind, placebo-controlled study
2:1 randomization between enzalutamide and placebo in patients who received prior chemotherapy with docetaxel
Outcomes
Primary: overall survival
Secondary: PSA level response, quality of life (QOL) response, progression free-survival
Results
Overall survival: 18.4 months vs. 13.6 months
PSA level response: 54% vs. 2%
QOL response: 43% vs. 18%
Progression-free survival: 8.3 months vs. 2.9 months Enzalutamide Post-Docetaxel Therapy
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy FDA approved in 2012 for treatment of mCRPC in patients with previous docetaxel therapy Xtandi® (enzalutamide) Efficacy
Abiraterone + prednisone: 35.4% risk reduction for death
Median overall survival: 14.8 months vs. 10.9 months
PSA response rate: 29% vs. 6%
Radiographic progression-free survival: 5.6 months vs. 3.6 months
Consistently improved pain palliation in abiraterone group vs. placebo group Safety
General adverse effects
Back pain, nausea, constipation, bone pain, arthralgia
Fluid retention/edema: 31% vs. 22%
Hypokalemia: 17% vs. 8%
Tachycardia: 3% vs. 2%
Atrial fibrillation: 2% vs. 1%
Changes in LFTs: 10% vs. 8%
Death due to AE: 12% vs. 15%
Pregnancy category X Abiraterone: Safety and Efficacy Abiraterone Post-docetaxel Therapy
Abiraterone and Increased Survival in Metastatic Prostate Cancer Design
Multinational, randomized, double-blind, placebo-controlled study
2:1 randomization between abiraterone and placebo in patients who received prior docetaxel therapy
Outcomes
Primary: overall survival
Secondary: PSA response rate, time to PSA progression, and others
Results (all p-values < 0.001)
Overall survival: 14.8 months vs. 10.9 months
PSA response rate: 29% vs. 6%
Time to PSA progression: 10.2 months vs. 6.6 months FDA approved in 2010 for treatment of mCRPC in patients with previous docetaxel therapy Jevtana® (cabazitaxel) FDA approved in 2011 in combination with prednisone for the treatment of mCRPC Zytiga® (abiraterone acetate) FDA approved in 2010 for symptomatic or asymptomatic treatment of mCRPC Provenge® (sipuleucel-T) Mechanism of action: Androgen biosynthesis inhibitor which targets CYP17 – decreases androgen levels
Dose: 1000mg daily + prednisone 5mg BID
Warnings and precautions:
Cardiovascular – mineralocorticoid excess
Adrenocortical insufficiency
Hepatotoxicity
Exposure with food
Drug interactions: CYP2D6 inhibitor, CYP2C8 inhibitor, CYP3A4 substrate Mechanism of action: Androgen receptor inhibitor – inhibits testosterone from binding to tumor receptors

Dose: 160mg once daily

Warnings and precautions: seizure risk

Drug Interactions: CYP2C8 substrate, CYP3A4 inducer (strong), CYP2C9, CYP2C19 inducer (moderate) Mechanism of action: microtubule inhibitor
Dose: 25mg/m2 every 3 weeks + prednisone 10mg (daily)
Warnings and precautions:
Febrile neutropenia
Hypersensitivity
Severe diarrhea
Renal failure
Drug interactions: CYP3A4 substrate Mechanism of action: Autologous cellular immunotherapy which targets PAP (antigen expressed in PCA)

Dose: 3 complete doses at 2 week intervals

Warnings and precautions:
Acute infusion reactions
Use with concomitant chemotherapy?

Drug interactions: no studies have been completed How do all these fit together? In the works... Alpharadin (radium-223)
Calcium mimetic used to target bone metastases
Intravenous administration
Once injected, takes about 10 minutes to reach bones – limits exposure to other tissues
Low toxicity profile
Excreted by gut
Phase III trial underway since 2008 (ALSYMPCA)
900 patients with hormone-refractory late stage prostate cancer 1. Docetaxel is still standard of care
2. Sipuleucel-T is considered to be an alternative first line agent
3. Abiraterone was mainly a post-docetaxel therapy but now evidence shows it can be used prior to chemotherapy
4. Enzalutamide and cabazitaxel are considered second-line therapy Wrapping things up... Prostate cancer mainly affects men above the age of 50
Screening should start at age 50 or age 45 if he has multiple risk factors
Prognosis and survival is very good if caught early
Metastatic cancer is more difficult to treat but there are new therapeutic options Vaccine: Sipuleucel - T Questions?
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