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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P.Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and BiologySenior Investigator, Medical Oncology BranchCenter for Cancer ResearchNational Cancer Institute, NIH

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Presentation Outline

I. Prostate Cancer detection and prognosis

II. Standard Local Therapy

III. Standard Systemic Therapy

a. Androgen deprivation therapy (ADT)

b. Chemotherapy

c. Bone targeted therapy

d. Immunotherapy

IV. Future Directions

Disease Continuum in Prostate Cancer

Tumor volume

Time

Castration

Docetaxel*

Death

LocalTherapy

Metastatic

Symptoms

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

2nd-line Hormonal therapy

Sipuleucel-T*

Cabazitaxel*Abiraterone*Enzalutamide*Alpharadin?

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Death from Prostate Cancer

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Introduction

• ~241,740 new cases in 2012

• ~28,170 deaths in 2012• 1 in 6 men will develop clinically significant

prostate cancer

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Risk Factors Age (median age 71 y/o; <15% younger than 65)Family HistoryGeographic locationRace

For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die.

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Detection May be detected due to symptoms, physical finding or through PSA screening.Most patients in the US are asymptomatic at the time of diagnosis.

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Digital Rectal ExamA – Central zoneB – Fibromuscular zoneC – Transitional zoneD – Peripheral zoneE – Periurethral zone

Seminal VesiclesSeminal Vesicles

ProstateProstate

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250

200

150

100

50

01975 1980 1985 1990 1995 2000

New

Pro

stat

e C

ance

r Cas

es a

nd D

eath

s(p

er 1

00,0

00 m

en)

New cases

Deaths

(G. Welch, “Should I Be Tested for Cancer?”, 2004)

PSA Screening

Incidence vs. MortalityProstate Cancer in the U.S.

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Does Screening Save Lives?

• PLCO Trial

– N=76,693 men (screen vs. no screen)

– After 7 years 50 vs. 44 deaths from PC

– ?Too early

– PSA test too available?

• ERSPC Trial

– N=182,000 (screen vs. no screen)

– At a median of 9 years, a 20% reduction in PC death

– Different patient population than US?

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Histologic Grading• Gleason Grade

– most common grading system

– Tumors are graded from 1-5 with the

– higher number indicates a more aggressive tumor

– Two most predominant patterns added together for a score from 2-10

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Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a

T4N1M1 and is metastatic.

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Prognosis

• PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors

• Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy.

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Treatment

• Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance

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Active Surveillance

The chance of dying

of prostate cancer decreases with:

Lower Gleason scoreOlder age (more competing causes of mortality)

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ADT as Primary Therapy

• For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease

• 985 pts randomized in EORTC trial– HR 1.25 (favoring immediate ADT)

• No earlier time to CRPC despite earlier ADT• Disease specific survival reportedly not different

in this trial raising some questions

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Treatment - continued

• Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years– Radical Prostatectomy – External-beam Radiation– Brachytherapy

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Radical Prostatectomy

• Surgical removal of the prostate• May be done with a retropubic, perineal, or

laproscopic approach• Most common side effects are impotence and

incontinence

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Randomized Trial Comparing Surgery and Watchful Waiting

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Randomized Trial Comparing Surgery and Watchful Waiting

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External-beam Radiation

• Radiation to the prostate (and pelvis) from outside the body

• Evidence that higher doses are associated with better efficacy

• IMRT aims to increase radiation delivery and to decrease toxicity

• Most common side effects are impotence and rectal irritation

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RTRP

Average multi-item sexual domain summary scores

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Prostate anatomy

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RTRP

Average multi-item incontinence summary scores

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RTRP

Average multi-item bowel summary scores

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Brachytherapy

• Radiation implants placed directly into the prostate under ultrasound or CT guidance

• Very high dose radiation to the prostate with little radiation outside the prostatic bed

• Acute urinary symptoms common, some patients with impotence

• Procedure completed in one day

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Treatment of Locally Advanced Disease

• Conservative management

• Hormonal therapy plus radiation

• Hormonal therapy plus surgery

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EORTC Trial

• Randomized trial of radiotherapy ± ADT

• Locally advanced prostate cancer (n=415)

• Concurrent + adjuvant ADT continued for 3 years

• Improved outcomes for combination:

– Local control

– metastases free survival

– overall survival (62% vs. 78% 5 yr survival p=0.0002)

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ECOG (Messing et al.)

• Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes

• 98 eligible patients enrolled

• Deaths by 11.9 years f/u

– 17/47 immediate anti-androgen

– 28/51 delayed therapy group (HR 1.84; p=0.04)

• Criticisms

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Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival.

Disease Continuum in Prostate Cancer

Tumor volume Local

Therapy

Metastatic

Symptoms

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

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Biochemical Recurrence

• May be occult local or metastatic disease

• Options include additional local therapy, hormonal treatment or watchful waiting

• Virtually impossible to predict the impact of treatment on survival

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Pound Data

• Probably the most important report on this population because of the limited use of radiation and hormonal therapy

• Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse.

• Of the 304, 103 (34 %) developed metastatic disease.

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Pound Data (continued)• No patients received hormonal therapy without clinically

evident metastatic disease.

• Median time from PSA elevation to metastatic disease was 8 years

• Median time to death after metastatic disease was 5 years.

• Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time.

Disease Continuum in Prostate Cancer

Tumor volume Local

Therapy

Metastatic

Symptoms

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

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Metastatic PC

• Prostate Cancer tends to spread to bone and lymph nodes

• However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs.

• Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use.

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• 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone.

• 1966 Nobel Prize in Medicine

ADT Treatment of metastatic PC

Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT

Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus.

Action of Androgens in Prostate Cells. DHT receptor complex alters gene

expression

Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein.

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• Testosterone lowering therapies– GnRH agonists (e.g., Leuprolide and Goserelin)

• Both agents are expensive

• May initially result in an increase in testosterone

– GnRH antagonist (e.g., Degarelix)• Similar cost issues without an increase in testosterone

• Monthly injections

– Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more.

ADT Treatment of metastatic PC

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Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function.

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Androgen Receptor Antagonists

• bicalutamide, nilutamide, flutamide and enzalutamide• Do not ↓Testosterone, bind androgen receptor and

prevent anabolic (growth related) effects• Different dosing schedules and potency• Different side effect profile• Similar activity and all may show “withdrawal

response”

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Combined Androgen Blockade

• Combination of anti-androgen with orchiectomy or GnRH-A

• Controversial results• Not significantly more effective, but more

expensive and may add toxicity

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5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or

Flutamide) vs AS Alone

Treatment Better by 2.9% (SE 1.3) Logrank P=0.005

Time Since Randomization (Years)

Pro

po

rtio

n A

liv

e (

%)

24.7%

27.6%

6500 Men in 20 Trials of Nilutamide/Flutamide

Androgen Suppression Only Androgen Suppression Antiandrogen

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Other Hormonal Agents

• Ketoconazole• Abiraterone (recently approved)• Patients may respond to multiple sequential

hormonal manipulations

Disease Continuum in Prostate Cancer

Tumor volume Local

Therapy

Metastatic

Symptoms

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

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Chemotherapy

• Studies prior to 2004 disappointing• Quality of life measurements• Difficulty in evaluating response

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Mitoxantrone + Glucocorticoids

• Improved quality of life when compared to Glucocorticoids alone

• No survival advantage• FDA approval for the palliation of painful lesions

in 1996

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Castration Resistant ProstateCancer

RA

ND

OM

IZE

RA

ND

OM

IZE

Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily

Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily

Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily

1006 Patients Entered

TAX327A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer

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TAX 327: Survival Advantage Only Shown for Q3W Docetaxel

Mediansurvival Hazard

(mos) ratio P-value

D 3wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

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Cabazitaxel• Novel taxane active in docetaxel resistant cell lines

• 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone.

• Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm.

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15.112.7Median OS (months)

0.59–0.8395% CI<.0001P-value

0.70Hazard Ratio

CBZPMP

Primary Endpoint: Overall Survival (ITT Analysis)

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PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death.

2.81.4Median PFS (months)

0.64–0.8695% CI<.0001P-value

0.74Hazard Ratio

CBZPMP

Progression-Free Survival (PFS) Results

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Abiraterone

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Randomized trial of Prednisone with

Abiraterone vs. Placebo

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Randomized trial of Prednisone with Abiraterone vs. Polaceb

1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM

2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++

3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -

4. Coactivator recruitment• DHT: ++++• Bicalutamide: ++• MDV3100: -

Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

Ligand1

2

3

4

DNA

POL II

HS

P 9

0

LB

D

HD

DBD

NTD

Waterfall Plot of Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65)>50% Decline

51% (38/75)>50% Decline

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Prostate cancer survival curve

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Alpharadin

Survival curve

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Therapeutic Vaccines

APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office.

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IMPACT: Randomized Phase 3 Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression.

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Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Per

cent

Sur

viva

l

Survival (Months)

P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]

Median Survival Benefit = 4.1 Mos.Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.

Placebo (n = 171)Median Survival: 21.7 Mos.

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Developed at NCICRADA with BN

PSA

Pox Vector Vaccine: PSA TRICOM (PROSTVAC)

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Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival.

PROSTVAC Significantly Extended Overall Survival by 8.5 months

20

40

60

80

100

0 12 24 36 48 60

Ove

rall

sur

viva

l (%

pat

ient

s)

0

Months

ControlPROSTVAC

Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system.

Time

Tu

mo

r B

urd

en

†† †

Vaccine

Cytotoxic Therapy

Tumor Growth Rate

PROSTVAC – Interesting Case History

Age

PSA

Gleason grade: 4 + 3 = 7 Age at which

Doubling time PSA would equal 1000

Trend before radical prostatectomy ( ) 5.8 months 65 years

Trend after radical prostatectomy. External beam radiation ( ) 9.6 months

75 years

Trend after first vaccine trial ( ) 28.6 months 93 years

Trend after second vaccine trial ( ) 27 years

Radical prostatectomy Vaccine treatment

External beam radiation

Second vaccine treatment

-No other therapy for prostate cancer-Normal testosterone

Current and Emerging Therapies in CRPC

Planned Phase III Randomize patients into Arm A: PSA TRICOM vaccine with GM-CSF (n = 400); Arm B: PSA TRICOM vaccine + placebo (n = 400); Arm C: Empty Vector + placebo GM-CSF (n = 400) Primary endpoint: OSPower = 90%  α = 0.005Critical HR 0.82

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Summary• Localized Disease

– RP, EBRT, Brachytherapy

• Androgen Deprivation Therapy (ADT)

– High risk disease with EBRT

– LN+ disease following RP

– Metastatic disease

• Sipuleucel-T

• Chemotherapy

– Docetaxel with prednisone

– Cabazitaxel with prednisone

• Abiraterone

• Enzalutamide

• Zoledronate or denosumab (decrease skeletal related events)

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Future Directions

• Which patient needs treatment?• Adjuvant systemic therapy for high risk patients• Timing of hormonal therapy• Multimodality therapy• New agents / combinations / sequencing