SYSTEMIC THERAPY OF PROSTATE CANCER:

Androgen Receptor and Immune System Targeting

Walter Stadler, MD, FACPWalter Stadler, MD, FACP

University of ChicagoUniversity of Chicago

Androgen Ablation

Androgen Ablation & Prostate Ca

• The androgen receptor is the most important The androgen receptor is the most important therapeutic target in PCatherapeutic target in PCa– Targeting AR is effective in >90%Targeting AR is effective in >90%– The AR is critical even in the “hormone refractory” The AR is critical even in the “hormone refractory”

statestate– Targeting AR is not curativeTargeting AR is not curative

• Androgen ablation has toxicityAndrogen ablation has toxicity– Bone, muscle, sexBone, muscle, sex– Toxicity minimal in comparison to other cancer Toxicity minimal in comparison to other cancer

therapiestherapies

Natural History of Rising PSA

Makarov, et al; J Urol:179:156, 2008

Prostate Ca System Therapy Philosophy

• Natural history can be very longNatural history can be very long– Chronic disease managementChronic disease management– Competing mortality/morbidityCompeting mortality/morbidity– Therapy toxicity can have significant functional Therapy toxicity can have significant functional

signficancesignficance• Natural history is highly variableNatural history is highly variable

– Some patients have rapid disease progressionSome patients have rapid disease progression– Disease mortality and morbidity not insignificantDisease mortality and morbidity not insignificant

• Care is often fragmentedCare is often fragmented– UrologistsUrologists– Medical oncologistsMedical oncologists– Primary carePrimary care

Endocrine Axis in Prostate Cancer

Orchiectomy

GnRH agonist

Adrenal Blockade

Tumor AndrogensAntiandrogens

Androgen Ablation: Early vs Late

• VA studies early vs delayed orchiectomy (1960’s)VA studies early vs delayed orchiectomy (1960’s)– Advanced metastatic cancerAdvanced metastatic cancer– No survival differencesNo survival differences

• MRC trial of delayed vs immediate hormonal therapyMRC trial of delayed vs immediate hormonal therapy– 934 pts, asymptomatic clinical mets934 pts, asymptomatic clinical mets– Immediate LHRH/orchiectomy vs at symptomsImmediate LHRH/orchiectomy vs at symptoms– Decreased morbidity, improved survival with immediateDecreased morbidity, improved survival with immediate

• DOD prostate cancer databaseDOD prostate cancer database– Early hormonal therapy delayed clinical metastases in patients with Early hormonal therapy delayed clinical metastases in patients with

Gleason >7 and PSA doubling < 12 moGleason >7 and PSA doubling < 12 mo

• Swiss immediate vs delayed orchiectomySwiss immediate vs delayed orchiectomy– 197 pts no primary tumor therapy, most without mets197 pts no primary tumor therapy, most without mets– Immediate delayed time to pain, urinary obstruction, or metsImmediate delayed time to pain, urinary obstruction, or mets

EORTC 30891: Immediate vs Delayed

• T0-4, N0-2, no metsT0-4, N0-2, no mets• Refused or ineligible for definitive local rxnRefused or ineligible for definitive local rxn• Immediate androgen ablation vs. at Immediate androgen ablation vs. at

symptomatic progressionsymptomatic progression• 1002 pts randomized1002 pts randomized• Reasons for starting deferred (n=245)Reasons for starting deferred (n=245)

– Symptoms Symptoms objective findings: 56% objective findings: 56%– Asymptomatic objective findings: 10%Asymptomatic objective findings: 10%– Asymptomatic marker rise: 26%Asymptomatic marker rise: 26%

EORTC 30891: Survival

HR: 1.25 (1.05 – 1.48)

EORTC 30891: Causes of Mortality

Prostate Ca Mortality Non-Prostate Ca Mortality

But in meta-analysis of RT ADT pts on ADT had higher incidence of fatal MI (D’Amico, et al, JCO 25:2420, 2007)

Adjuvant Data Supports “Early” ADT

• Prostatectomy LN positive immediate vs delayed Prostatectomy LN positive immediate vs delayed ADTADT– Improved survival Improved survival (Messing, et al, Lancet Oncol, 2006(Messing, et al, Lancet Oncol, 2006))

• Clinical T3 (or high risk) radiotherapyClinical T3 (or high risk) radiotherapy– Survival advantage with long term adjuvant (EORTC, Survival advantage with long term adjuvant (EORTC,

RTOG 85-31) RTOG 85-31) (Bolla, et al, Lancet, 2002; Pilepich, et al Int J Rad Oncol Biol (Bolla, et al, Lancet, 2002; Pilepich, et al Int J Rad Oncol Biol Phy, 2005)Phy, 2005)

– Survival advantage with long vs short term ADT Survival advantage with long vs short term ADT (EORTC) (EORTC) (Bolla, et al NEJM, 2009)(Bolla, et al NEJM, 2009)

– Disease-free and metastases-free survival advantage Disease-free and metastases-free survival advantage with combined plus long term versus combined plus short with combined plus long term versus combined plus short term (RTOG 92-02) term (RTOG 92-02) (Horwitz, et al, J Clin Oncol, 2008)(Horwitz, et al, J Clin Oncol, 2008)

Morbidity of Androgen Ablation

• Hot flashesHot flashes

• Loss of libido and impotenceLoss of libido and impotence

• GynecomastiaGynecomastia

• Weight gain and loss of muscle massWeight gain and loss of muscle mass

• Exacerbation of hypertension and diabetesExacerbation of hypertension and diabetes

• FatigueFatigue

• Osteoporosis and fracturesOsteoporosis and fractures

• Cognitive effects (?)Cognitive effects (?)

Unadjusted Fracture-free Survival among Patients with Prostate Cancer

Shahinian, V. et al. N Engl J Med 2005;352:154-164

Timing of Bisphosphonates

• Risk of osteonecrosis and renal failureRisk of osteonecrosis and renal failure– Increases with duration of exposureIncreases with duration of exposure– Risk benefit of use for hormone sensitive Risk benefit of use for hormone sensitive

disease uncleardisease unclear

• CALGB 90202CALGB 90202– Immediate versus delayed zoledronate for Immediate versus delayed zoledronate for

hormone sensitive bone scan positive pts.hormone sensitive bone scan positive pts.

Fatigue, Muscle Loss and Elderly Prostate Cancer Patients

Bylow, et al, Cancer, 2007

Diabetes and CV Risk ADT

• Case control, Case control, – Ontario Ontario (Alibhai, JCO, 2009)(Alibhai, JCO, 2009)

• Median 6.5 yr follow upMedian 6.5 yr follow up• DM HR (time to event): 1.16 (1.12 – 1.21)DM HR (time to event): 1.16 (1.12 – 1.21)• MI HR: 0.91 (0.84 – 1.00)MI HR: 0.91 (0.84 – 1.00)

– US claims basedUS claims based• Incident DM HR: 1.36 Incident DM HR: 1.36 (Lage, et al; Urology, 2007)(Lage, et al; Urology, 2007)

• Incident DM HR: 1.44 (p<0.001), MI HR: 1.11 (p=0.03)Incident DM HR: 1.44 (p<0.001), MI HR: 1.11 (p=0.03)

• Adjuvant ADT (RTOG 85-31) Adjuvant ADT (RTOG 85-31) (Efstatstiou, JCO, 2009)(Efstatstiou, JCO, 2009)

– Median 8.1 yr follow upMedian 8.1 yr follow up– No increased risk MI/sudden deathNo increased risk MI/sudden death

Intermittent ADT As a New Drug Screen

• Drug x vs. placebo during “off” periodDrug x vs. placebo during “off” period

• Need to monitor testosterone and DHT Need to monitor testosterone and DHT recoveryrecovery

• Drugs in studyDrugs in study– Thalidomide – no major effect Thalidomide – no major effect (Figg, ASCO 2008)(Figg, ASCO 2008)

– Pazopanib (VEGFR/PDGFR TKI) Pazopanib (VEGFR/PDGFR TKI) • Closed, too toxicClosed, too toxic

– Dutasteride (5-Dutasteride (5- reductase inhibitor) reductase inhibitor)• UC/NU SPORE clinical trial and othersUC/NU SPORE clinical trial and others

Castrate Resistant Disease

• Not really “hormone refractory”Not really “hormone refractory”• AR still a relevant targetAR still a relevant target• Other potential targetsOther potential targets

– Immune systemImmune system– DNA and DNA repairDNA and DNA repair

• Mechanisms of castrate resistanceMechanisms of castrate resistance– AR amplificationAR amplification– AR mutationAR mutation– AR modificationAR modification– Ligand availabilityLigand availability– AR interactionsAR interactions

What we know…

• Prostate cancer requires AR signaling for development Prostate cancer requires AR signaling for development and sustenance.and sustenance.

• AR activation is required throughout the natural history AR activation is required throughout the natural history of prostate cancer.of prostate cancer.

• AR activation in CRPC occurs via many mechanisms.AR activation in CRPC occurs via many mechanisms.

• Successful blockade of the receptor pathways will Successful blockade of the receptor pathways will confer greater therapeutic control on metastatic prostate confer greater therapeutic control on metastatic prostate cancer.cancer.

Testosterone

• Actually a growth inhibitory and Actually a growth inhibitory and differentiating agent in normal prostatedifferentiating agent in normal prostate

• Cells adapted to androgen depleted Cells adapted to androgen depleted environmentenvironment– AR upregulationAR upregulation– Growth inhibited by androgenGrowth inhibited by androgen– Tumor shrinkage in xenograft modelsTumor shrinkage in xenograft models

• Randomized phase II trial initiatedRandomized phase II trial initiated

Abiraterone Phase II

Pre-Chemo

Post-Chemo

Attard JCO 2009

Ryan ASCO 2009

Danila ASCO 2009

Reid ASCO 2009

COU-AA-301 Study Design

• Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)study (147 sites in 13 countries; USA, Europe, Australia, Canada)

• Stratification according to Stratification according to – ECOG performance status (0-1 vs 2)ECOG performance status (0-1 vs 2)

– Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present]) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present])

– Prior chemotherapy (1 vs 2)Prior chemotherapy (1 vs 2)

– Type of progression (PSA only vs radiographic progression with or without PSA Type of progression (PSA only vs radiographic progression with or without PSA progression)progression)

Abiraterone 1000 mg dailyPrednisone 5 mg BID

n=797

Primary end point

• OS (25% improvement; HR 0.8)

Secondary endpoints (ITT)

• TTPP

• PFS

• PSA response

Efficacy endpoints (ITT)

Placebo dailyPrednisone 5 mg BID

n=398

RANDOMIZED

2:1

• 1195 patients with progressive mCRPC

• Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel

Patients

Abbreviations: BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer.Source: Clinicaltrials.gov identifier: NCT00638690.

COU-AA-301 Patient Disposition

Abiraterone (n=797)

Placebo (n=398)

Subjects treated 791 394

Median number of cycles of therapy (range) 8 (1-21) 4 (1-21)

Treatment ongoing, n (%) 222 (28.1) 54 (13.7)

Treatment discontinued, n (%) 569 (71.9) 340 (86.3)

COU-AA-301 Baseline Demographics

Abiraterone(n=797)

Placebo (n=398)

Total (n=1195)

Median age, years (range)

69.0 (42-95)

69.0 (39-90)

69.0(39-95)

Race, %

White 93.3 92.7 93.1

Black 3.5 3.8 3.6

Asian 1.4 2.3 1.7

ECOG PS 2, % 10.7 11.1 10.8

Significant pain present, % 44.3 44.0 44.2

2 Prior chemotherapies, % 28.2 28.4 28.3

COU-AA-301 Baseline Disease Characteristics

Abiraterone (n=797)

Placebo (n=398)

Primary site of disease, %

Bone 89.2 90.4

Node 45.4 41.5

Liver 11.3 7.6

Lung 13.0 11.4

COU-AA-301: Abiraterone Acetate Improves OS in mCRPC

HR=0.646 (0.54-0.77) P <0.0001

Placebo: 10.9 months (95% CI: 10.2, 12.0)

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Ove

rall

Su

rviv

al,

%

Days from Randomization

Abiraterone: 14.8 months (95% CI: 14.1, 15.4)

1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo

Abiraterone 797 728 631 475 204 25 0

Placebo 398 352 296 180 69 8 1

Survival Benefit Consistently Observed Across Patient Subgroups

Variable Subgroup N HR 95% CI

All subjects All 1195 0.66 0.56-0.79

Baseline ECOG 0-1 1068 0.64 0.53-0.78

2 127 0.81 0.53-1.24

Baseline BPI <4 659 0.64 0.50-0.82

4 536 0.68 0.53-0.85

No. of prior chemo regimens 1 833 0.63 0.51-0.78

2 362 0.74 0.55-0.99

Type of progression PSA only 363 0.59 0.42-0.82

Radiographic 832 0.69 0.56-0.84

Baseline PSA above median YES 591 0.65 0.52-0.81

Visceral disease at entry YES 709 0.60 0.48-0.74

Baseline LDH above median YES 581 0.71 0.58-0.88

Baseline ALK-P above median YES 587 0.60 0.48-0.74

Region North America 652 0.64 0.51-0.80

Other 543 0.69 0.54-0.90

0.5 0.75 1 1.5Favors

AbirateroneFavors

PlaceboAbbreviations: HR=hazard ratio; ALK-P=alkaline phosphatase.

COU-AA-301: Secondary End Points Achieved Statistical Significance

Abiraterone(n=797)

Placebo (n=398)

HR(95% CI)

P Value

TTPP, mo 10.2 6.6 0.58

(0.46, 0.73) <0.0001

rPFS, mo 5.6 3.60.67

(0.59, 0.78)<0.0001

PSA response rate (>50% reduction), %

Total 38.0 10.1 <0.0001

COU-AA-301: Summary of AEs

Abiraterone(n=791)

Placebo (n=394)

All Grades Grades 3/4 All Grades Grades 3/4

All treatment-emergent AEs, % 98.9 54.5 99.0 58.4

Serious AEs, % 37.5 32.1 41.4 35.3

AEs leading to discontinuation, % 18.7 10.5 22.8 13.5

Deaths within 30 days of last dose, %

10.5 13.2

Underlying disease 7.5 9.9

Other specified cause 2.9 3.3

Drug-related AEs 0 0

COU-AA-301: AEs of Special Interest

AE, %

Abiraterone(n=791)

Placebo (n=394)

All Grades Grades 3/4 All Grades Grades 3/4

Fluid retention 30.5 2.3 22.3 1.0

Hypokalemia 17.1 3.8 8.4 0.8

LFT abnormalities 10.4 3.5 8.1 3.0

Hypertension 9.7 1.3 7.9 0.3

Cardiac disorders 13.3 4.1 10.4 2.3

Novel More Potent AR Antagonists• BMS-641988 (development discontinued)BMS-641988 (development discontinued)

• MDV3100MDV3100– Phase I/II trialPhase I/II trial– Phase III trial initiated (docetaxel refractory)Phase III trial initiated (docetaxel refractory)

Scher, et al, ASCO 2009

60 mg (n=22)

150 mg (n=23)

240 mg (n=28)

2 pt off study <12 wk

3 pt off study <12 wk

7 pt off study <12 wk

Castrate Resistant Disease Non-Hormonal Treatment Options

• Good prognosis (asymptomatic, “low Good prognosis (asymptomatic, “low volume”)volume”)– Standard docetaxel chemotherapyStandard docetaxel chemotherapy– ? Immunotherapy (Provenge? Immunotherapy (Provenge, sipuleucel-T), sipuleucel-T)– Investigational therapyInvestigational therapy

• Poor prognosisPoor prognosis– Standard docetaxel chemotherapy Standard docetaxel chemotherapy – Standard cabazitaxelStandard cabazitaxel– Investigational chemotherapy combinationsInvestigational chemotherapy combinations

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Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion

Protein

APC takes up the antigen

Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC)

Fully activated, the APC is now sipuleucel-T

The precise mechanism of sipuleucel-T in prostate cancer has not been established.

Antigen is processed and presented on surface of the APC INFUSE PATIENT

T-cells proliferate and attack cancer cells

sipuleucel-T activates T-cells in the body

Active T-cell

Inactive T-cell

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Sipuleucel-T: Logistics of Therapy

Day 1Leukapheresis

Day 2-3sipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Central Processing Doctor’s Office

COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4

4646

Randomized Phase 3 IMPACT Trial

(IMmunotherapy Prostate AdenoCarcinoma (IMmunotherapy Prostate AdenoCarcinoma Treatment)Treatment)

Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer (N=512)

Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer (N=512) Placebo

Q 2 weeks x 3Placebo Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

2:1

Treated at Physician Discretion and/or Salvage Protocol

Treated at Physician Discretion and/or Salvage Protocol

Treated at Physician Discretion

Treated at Physician Discretion

Primary Endpoint: Overall SurvivalSecondary Endpoint: Objective Disease Progression

PROGRESSION

PROGRESSION

SURVIVAL

SURVIVAL

4747

IMPACT Overall SurvivalFinal Analysis (349 events)

36.5 mo median f/u HR = 0.759 (95% CI: 0.606, 0.951)p = 0.017 (Cox model)

Sipuleucel-T (n = 341)Median Survival: 25.8 mo.36 mo. survival: 32.1%

Placebo (n = 171)Median Survival: 21.7 mo.36 mo. survival: 23.0%

No. at Risk

Sipuleucel-T 341 274 142 56 18 3

Placebo 171 123 59 22 5 2

4848

Adverse Events More Commonly1 Reported in Sipuleucel-T Group

Preferred TermSipuleucel-T

N = 338%

PlaceboN = 168

%Chills 54.1 12.5Pyrexia 29.3 13.7Headache 16.0 4.8Influenza-Like Illness 9.8 3.6Myalgia 9.8 4.8Hypertension 7.4 3.0Hyperhidrosis 5.3 0.6Groin Pain 5.0 2.4

1 Reported by ≥ 5% of sipuleucel-T patients and having a ≥ 2-fold difference from placebo.The majority of the most common AEs were mild or moderate in severity.

Safety results obtained from primary analysis did not substantively change with additional data obtained after study closure.

Challenges• Why no effect on prostate cancer progression?Why no effect on prostate cancer progression?

– Ability to measure disease progression sucksAbility to measure disease progression sucks– Something “bad” happened in control groupSomething “bad” happened in control group– Something “good” happened in treated group that is Something “good” happened in treated group that is

unrelated to cancerunrelated to cancer– Important: no effect on symptomsImportant: no effect on symptoms

• CostCost– $93,000 not include all apheresis and infusion costs$93,000 not include all apheresis and infusion costs

• LogisticsLogistics– Limited apheresis capacityLimited apheresis capacity– Limited processing capacityLimited processing capacity

Other Immune Therapy Approaches

• Anti-CTLA4: IpilimumabAnti-CTLA4: Ipilimumab– ““Turn off the brake”Turn off the brake”

• Potential for severe auto-immune diseasePotential for severe auto-immune disease

• Auto-immune diarrheaAuto-immune diarrhea

• Anti-tumor activity in phase II trialsAnti-tumor activity in phase II trials

– Castrate/Docetaxel resistant pts:Castrate/Docetaxel resistant pts:• Phase II External beam RT ± ipilimumabPhase II External beam RT ± ipilimumab

• Based on possible immune enhancing effects of RTBased on possible immune enhancing effects of RT

– Castrate resistant pre-chemo pts:Castrate resistant pre-chemo pts:• Placebo vs IpilimumabPlacebo vs Ipilimumab

Other Immune Therapy Approaches (2)

• A true vaccine: PSA-TRICOMA true vaccine: PSA-TRICOM– ““Prime” and “boost” vaccinationsPrime” and “boost” vaccinations– Castrate/Docetaxel resistant patientsCastrate/Docetaxel resistant patients– Quadramet ± PSA-TRICOMQuadramet ± PSA-TRICOM

How do we Measure “Immune Activation”

• Ongoing blood collection study to:Ongoing blood collection study to:– Analytically validate HMBG1 in serum as Analytically validate HMBG1 in serum as

marker of “danger signal”marker of “danger signal”– Analyze serum antibodies to identify new Analyze serum antibodies to identify new

immune targetsimmune targets– Store serum for evaluating other possible Store serum for evaluating other possible

biomarkersbiomarkers

5353

CABAZITAXEL PHASE III

Primary endpoint: OSSecondary endpoints: Progression-freesurvival (PFS), response rate, and safety

Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles

(n=378)

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=377)*Oral prednisone/prednisolone: 10 mg daily.

Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease

mCRPC patients who progressed during and after treatment with a docetaxel-based

regimen (N=755)

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Summary of Demographics and Patient Characteristics

MP (n=377) CBZP (n=378)

Age Median (years) 67.0 68.0≥65 (%) 57.0 64.9

ECOG PS (%)0, 1 91.2 92.62 8.8 7.4

PSA (ng/mL)Median 127.5 143.9

Measurability of disease (%)Measurable disease 54.1 53.2Non-measurable disease 45.9 46.8

Disease Site (%)Bone 87.0 80.2Lymph node 44.8 45.0Visceral 24.9 24.9

PSA: Prostate-specific antigen.

5555

Primary Endpoint: Overall Survival

MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4

Numberat risk

Proportionof OS (%)

80

60

40

20

0

100

0 months 6 months 12 months 18 months 24 months 30 months

15.112.7Median OS (months)

0.59–0.8395% CI

<.0001P-value

0.70Hazard Ratio

CBZPMP

5656

Most Frequent Grade ≥3 Treatment-Emergent AEs*

MP (n=371) CBZP (n=371)

All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%)

Any adverse event 88.4 39.4 95.7 57.4

Febrile neutropenia 1.3 1.3 7.5 7.5

Diarrhea 10.5 0.3 46.6 6.2

Fatigue 27.5 3 36.7 4.9

Asthenia 12.4 2.4 20.5 4.6

Back pain 12.1 3 16.2 3.8

Nausea 22.9 0.3 34.2 1.9

Vomiting 10.2 0 22.6 1.9

Hematuria 3.8 0.5 16.7 1.9

Abdominal pain 3.5 0 11.6 1.9

*Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

5757

Total Deaths During Study Safety Population

MP (n=371) CBZP (n=371)

Total deaths during study 275 (74.1%) 227 (61.2%)

Due to progression 253 (68.2%) 197 (53.1%)

Due to AEs 7 (1.9%) 18 (4.9%)

Due to other reasons 15 (4.0%) 12 (3.2%)

XL184

• MET/VEGF pathway targetedMET/VEGF pathway targeted

• Dramatic changes in bone scanDramatic changes in bone scan

• Clinical implications to be determinedClinical implications to be determined

Conclusions• Advanced prostate cancer pts can have a long Advanced prostate cancer pts can have a long

historyhistory– Opportunity for multiple therapiesOpportunity for multiple therapies– Toxicities and quality of life importantToxicities and quality of life important– Issues of co-morbid disease and agingIssues of co-morbid disease and aging

• Philosophy of chronic d. managementPhilosophy of chronic d. management

• Androgen receptor pathway targeting is keyAndrogen receptor pathway targeting is key

• DNA targeted chemotherapy plays a roleDNA targeted chemotherapy plays a role

• Immunotherapy may play a roleImmunotherapy may play a role

• New therapies need to be identifiedNew therapies need to be identified