New horizons in Prostate Cancer Treatment in Prostate Cancer – Taxotere An old dog with new tricks...

New horizons in ProstateCancer Treatment

Expanding options, extendingsurvival, and improving quality of

life

Chip ReningerHematology and Oncology

Consultants of Pa

September 2015

Outline

1. Expanding Treatment Options for metastatic Prostate Cancer for hormone sensitive disease and castrate resistant disease

2. Evolving Biology of CRPC

3. Taxotere emeging role in f irst line treatment of HSMPC/high risk local disease

4. Novel Agents for the treatment of CRPC

Immunotherapies

Sipuleucel-T

Androgen Biosynthesis Inhibitors (ABI’s)/novel anti-androgens

Abiraterone, Enzalutamide (MDV-3100)

Cytotoxics

Cabazitaxel

Bone\micro-environment directed therapies

Radium 223/Xofigo

5. “Picking the right treatment for the right patients at the right time”

Hematology & OncologyConsultants of PA

2

Castration resistant:deaths from disease

Diagnoses

Rising PSA

3Clinical

Metastases:Castrate1st Line

DocetaxelStandard

2Clinical

Metastases:Castrate

Pre-

ClinicallyLocalizedDisease

1Rising PSA:

Castrate

ClinicalMetastases:

Non-Castrate

4Clinical

Metastases:Castrate2nd Line

No Standard

With detectable metastases:deaths from cancer exceed

that from other causes

28,660186,320

Non-CastrateAndrogen depletion /

blockade (bicalutamide)

Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification


3

Typical Timing of AvailableTreatments


4

Systemic Medical Treatmentsof Prostate Cancer


5

Disease States and PossibleTreatment in Prostate Cancer

Localized Disease Confned to the Prostatenewly diagnosed- surgery/RT +/-hormones +/- chemotx

Localized Disease with spread to adjancentorgans or pelvic lymph nodes – RT+hormones +/- Chemotx

Biochemical(psa) recurrence after surgery -+/- salvage radiation +/-hormones

Biochemical(psa) recurrence afterRadiation- +/- salvage surgery +/-hormones

Newly diagnosed prostate cancer withmetastatic disease outside the pelvis-hormones + chemotx

Biochemical progression with or withoutmetastatic disease after initial hormonetherapy- additional hormonal tx in the formof androgen receptor blocker (casodex)

Biochemical and/or metastatic disease afterstandard hormone treatment so calledcastrate resistant disease – newer hormonalagents (Zytiga/Xtandi), chemotx (taxotere,Jevtana), immunotherapy (Provenge), boneseeking radioisotopes (xofgo)


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Typical Tiiming of AvailableTreatments


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First Line Hormone Sensitive disease- -The Basics of Hormone Therapy

GNRHanalogs(lupron)And GNRHantagonists(frmagon)

Casodex –binds to ARto blocktestosteroneaffects


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Understanding the Biology of CRPCDriver Pathways of Dependency of PC

Tomlins, S. A. Eur Urol 2009Taylor, B et al, Cancer Cell 2010

Kong D. Cancer Sci 2008Jenkins, R. B. Cancer Res 1997

Khor, L. Y. Clin Cancer Res 2007

Androgen Receptor (AR) 55% 100%

PTEN loss 25%80%

PI3K/Akt, Ras/Raf, RB 42%100%

TMPRSS2-ETS fusion 50%33%

Genetic variants of androgen transporter genes

Primary Mets

Prostate Cancer: “Adapting” to castrate environment

ALTERN.SPLICING

ABERRANTMODIFICATION

• GF, cytokines• Src

Sumo

AC

P

COFACTORPERTURBATION

• CoAct gain• CoR loss/dismissal

CoACT

INTRACRINEANDROGENSYNTHESIS

T

MUTATION• gain of function

AR

selectivepressure

Hormone Therapy

adaptation

RECURRENT TUMOR DEVELOPMENTCRPC

RESTORED AR ACTIVITY(rising PSA)

>30% CRPC

ARDEREGULATION

• amplification• overexpression

Penning & Knudsen2010Hematology & Oncology

Consultants of PA10

Chemotherapy in Prostate Cancer – Taxotere

An old dog with new tricks

Taxotere approvedin CRPC

only tx shown toimprove survivalafter failure on gnrhanalog and casodex

Modest beneft of 2.5months over standardtreatment withmedian survival of 19mos vs 16.5 monthswith standard of care

Taxotere improvedsurvival in:

2014: Newlydiagnosed “highvolume” metastaticdisease incombination withhormones vshormones alone(SOC)at the time ofdiagnoses. 13 monthsimprovement inoverall survival from3.5 yrs to 4.75 yrs

2015: improvedsurvival in all menwith newlydiagnosed metastaticprostate cancer

2015:possible survivalbeneft in men withlocalized high riskcancer in 2 trials

2004 2014/ 2015


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“Traditional” use of chemotherapy for CRPC

Presented By Ian Tannock at 2015 ASCO Annual Meeting

Chemotherapy in Prostate Cancer Castrate Resistant DiseaseTaxotere 2004

Castrate Resistant Disease


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Chemotherapy in Prostate Cancer Hormone Sensitive Metastatic

–Taxotere - 2014


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<br />Role of chemotherapy for hormone-naïve PC<br />


Taxotere: New Standard in Hormone Naïve Metastaticdisease , high Volume disease - 2014


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High risk local and metastatic diseaseTaxotere 2015


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Taxotere- STAMPEDE-2015


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Taxotere- STAMPEDE-2015


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Taxotere 2015 – high risk locallyadvanced RTOG 0521


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19



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Role of chemotherapy for localized high-riskPC (M0) after radiation therapy

Presented By Ian Tannock at 2015 ASCO Annual MeetingHematology & OncologyConsultants of PA

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Forest plot for Failure-Free Survival in men with M0 disease (thanks to Dr. Eitan Amir)


Chemotherapy in Prostate CancerTaxotere: Possible option in localizeddisease


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For the frst time an improvement in overallsurvival observed with adjuvant chemotherapyfor localized high risk hormone sensitiveprostate cancer

The effect and role of Docetaxel in hormonesensitive prostate cancer is consistent with andsupported by other studies such as chaartedand stampede

This analysis is early and additional follow upis needed in both stampede and RTOG0521

Conclusions


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Metastatic Castrate ResistantDisease- asymptomatic or minimally

symptomatic chemotherapy naive Observation

Antiandrogenwithdrawal

Ketoconazole

Taxotere andprednisone*

Immunotherapy

Provenge (Sipuleucel-T)*

Hormone

Abiraterone (Zytiga)and Prednisone*

Enzalutamide(Xtandi)*

Chemotx

Cabiztaxel (Jevtana)*

Bone SeekingRadioisotopes

Radium-223(xofgo)*

Prior to 2010 After 2010

*Overallsurvival inRCT


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Immunotherapy Approaches in PC

§ Active immunotherapy

v tumor associated antigen is directly targeted by loading in thatantigen in APC or into vaccine vector at protein or DNA level

v Antigen specifc immunotherapy

§Sipuleucel-T

§Poxvirus-based vectors

§DNA based vaccines

§ Passive immunotherapy

v Antibodies to specifc receptors/antigens

§Prostate Specifc Membrane Antigen (PSMA)

§ Immune Checkpoint Inhibitors

v Strategies to maintain activated tumor specifc T-cells by neutralizingco-inhibitory receptors

v Anti-cytotoxic T lymphocyte protein 4 (CTLA 4)

§ Ipilumimab, tremelimumab

v Anti- program death 1 (PD-1)(PDL-1)

§ MDX-1106


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Patient’s white bloodcells harvested

Short-term culture with protein“cassette”

Shipping

Cells infused back intopatient (IV)

GM-CSFProstatic acid

phosphatase

Active Cellular Immunotherapy(Sipuleucel-T)


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Provenge (sipuleucel–t)

Median survivalbeneft

Survival above thecontrol group

Can be given with otherhormonal therapies andwell tolerated


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Targeting the AndrogenPathway

Androgen Biosynthesis Inhibitors

*Abiraterone Acetate

TAK 700

VN/124-1 (TOK-001)

Novel Anti-Androgens

*Enzalutamide

RD 162

EPI-001 (AR N-Terminal)

SNARE-1 (selective nuclear receptor exporter-1)

* FDA approvedHematology & OncologyConsultants of PA

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Hormonal TherapyZYTIGA (abiraterone acetate)

Abiraterone acetate(ZYTIGA®)

converted in the body toabiraterone, an androgenbiosynthesis inhibitor,that inhibits an enzymevital to producingtestoterone(androgens).

enzyme is expressed intesticular, adrenal, andprostatic tumor tissuesand is required forandrogen biosynthesis.Hematology & Oncology

Consultants of PA31

Zytiga in chemotx non naïvepts-

COU-AA-301 Study Design

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

Stratifcation according to

ECOG performance status (0-1 vs 2)

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

Prior chemotherapy (1 vs 2)

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

Abiraterone 1000 mg dailyPrednisone 5 mg BID

n=797

Primary end point

• OS (25% improvement; HR0.8)

Secondary endpoints (ITT)

• TTPP

• PFS

• PSA response

Effcacy endpoints (ITT)

Placebo dailyPrednisone 5 mg BID

n=398

RANDOMIZED

2:1

• 1195 patients withprogressive mCRPC

• Failed 1 or2 chemotherapyregimens, one ofwhich containeddocetaxel

Patients

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

deBono N Engl J Med. 2011 May 26;364(21):1995-2005Hematology & OncologyConsultants of PA

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COU-AA-301: Abiraterone AcetateImproves 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

Ov

eral

l S

urv

ival

, %

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

deBono N Engl J Med. 2011 May 26;364(21):1995-2005Hematology & Oncology Consultants of PA 33

Overall Study Design of COU-AA-302

Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at151 sites in 12 countries; USA, Europe, Australia, Canada

Stratifcation by ECOG performance status 0 vs 1

AA 1000 mg dailyPrednisone 5 mg BID

(Actual n = 546)

Co-Primary:• rPFS by central review• OS

Secondary:• Time to opiate use

(cancer-related pain)• Time to initiation of

chemotherapy• Time to ECOG-PS

deterioration• TTPP

Effcacy end points

Placebo dailyPrednisone 5 mg BID

(Actual n = 542)

RANDOMIZED

1:1

• Progressive chemo-naïve mCRPCpatients(Planned N = 1088)

• Asymptomatic ormildly symptomatic

Patients

Ryan et al. ASCO 2012 Hematology & Oncology Consultants ofPA

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Statistically Significant Improvement in rPFSPrimary End Point

NR, not reached; PL, placebo.Data cutoff 12/20/2010.

100

80

60

40

20

0

0

Pro

gre

ssio

n-F

ree

(%)

3 6 9 15 1812

546542

489400

340204

16490

123

00

AAPL

4630

Time to Progression or Death (Months)

AA + PPL + P

AA + P (median, mos): NR

PL + P (median, mos): 8.3

HR (95% CI): 0.43 (0.35-0.52)

P value: < 0.0001

Ryan et al. ASCO 2012 Hematology & Oncology Consultants of PA 35

Strong Trend in OS Primary EndPoint

546542

538534

482465

452437

2725

00

524509

503493

02

120106

258237

412387

100

80

60

40

20

0

0

Su

rviv

al (

%)

3 12 15 27

Time to Death (Months)

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AA + PPL + P

6 9 30242118

AAPL

AA + P (median, mos): NR

PL + P (median, mos): 27.2

HR (95% CI): 0.75 (0.61-0.93)

P value: 0.0097

Updated GU ASCO 2013: Rathkopf et al. Abstract # 5-r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001- OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) p= 0.0151Hematology & Oncology

Consultants of PA36

Xtandi MOA


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AFFIRM: Phase 3 Trial of Enzalutamidevs Placebo in Post-Chemotherapy

Castration-Resistant Prostate Cancer(CRPC)

RANDOMIZED

2:1

Primary

Endpoint:Overall Survival

Enzalutamide 160 mg daily

n = 800

Placebon = 399

PatientPopulation:

1199 patients withprogressive CRPC

* Failed docetaxel chemotherapy

*Glucocorticoids were not required but allowed


Tran et al. Science 2009;324:787–90. 38

AFFIRM: Clinical Outcomes

Variable Enzalutamide

(800 pts.)

Placebo(399 pts.)

HazardRatio

P -value

OS(months)

18.4 13.6 0.631 <0.0001

PSAprogression(months)

8.3 3.0 0.218 <0.0001

rPFS(months)

8.3 2.9 0.404 <0.0001

1st SRE(months)

16.7 13.3 0.621 <0.0001

CR + PR 28.9% 3.8% - <0.0001

FACT-P 43.3% 17.8% - <0.0001

De Bono et al. ASCO 2012Hematology & Oncology Consultants ofPA

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Enzalutamide in chemotx naïvepatients

Hematology & Oncology Consultants ofPA

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Xtandi-Prior to chemotx incastrate resistant Prostate

cancer

Hematology & Oncology Consultantsof PA

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Alpha Beta

Relative particle mass 7000 1

Initial energy (MeV) 3-8 0.01-2.5

Range in tissue (µm) 40-90 50-5000

LET (KeV/µm) 60-230 0.015-0.4

Charge +2 -1

Ion pairs/µm 2000-7000 5-20

DNA hits to kill cell 1-5 100-1000

Radium-223 (XOFIGO)

• Based on alpha emitter Radium-223• ideal half-life of 11.4 days• Excreted via small bowel• Safe and easy to produce, deliver and handle

Range of alpha-particle

Radium-223

Encouraging Phase II results Hematology & OncologyConsultants of PA

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TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) +Best standard of care

Placebo (saline) + Best standard of care

RANDOMISED

2:1

N = 922

PATIENTS

• Confirmedsymptomatic

CRPC• ≥ 2 bonemetastases

• No knownvisceral

metastases• Post-docetaxel

or unfit fordocetaxel

ALSYMPCA (ALpharadin in SYMptomaticProstate CAncer) Phase III Study Design

• Total ALP: < 220 U/L vs ≥ 220

U/L• Bisphosphonate use:

Yes vs No• Prior docetaxel:

Yes vs No

STRATIFICATION

Planned follow-up is 3 years


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Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA Overall Survival

0

10

20

30

40

50

60

70

80

90

100

%Radium-223, n = 541

Median OS: 14.0 months

Placebo, n = 268Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-0.875

P = 0.00185

EORTC 2011Hematology & OncologyConsultants of PA

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Xofigo -Prior to chemotx incastrate resistant Prostate

cancerBeforeXofgo

AfterXofgo


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Metastatic castrate resistantprostate cancer after progression on

Taxotere – Jevtana(Cabazitaxel) Microtubulestabilizer

Developed indocetaxel-resistantprostate cancer celllines

a favorablepharmacokinetic andsafety profile

decreased propensityfor P-glycoprotein(Pgp)-mediated drugresistance.

inhibited cell growthin a wide range ofhuman cancer celllines, includingtumor modelsexpressing Pgp.


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Support Medications not shownto improve survival but reduce

complications of disease Bone Building Drugs

Zometa

Xgeva(denosumab)

Drugs for Man fashes

SSRI

gabapentin


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New treatments on the Horizon

Hormonal therapy

Targeted therapy Dasatinib, Cabozantinib, Custirsen, Tasquinimod

Immunotherapy CHECKPOINT INHIBITORS

ANTI-CTLA4 IMMUNOTHERAPY: IPILIMUMAB

anti pd1, anti pdl1

, Immunostimulatory monoclonal antibodies

VACCINE, ,

PROSTVAC-VFHematology & OncologyConsultants of PA

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Conclusion

5 new agents since 2015 approved formetastatic castrate resistant prostate cancer allof which have been shown to improve survival

2004 median survival from 17 to 20 months withtaxotere

2015 median survival has increased to between 3-4years

More therapies are on the way, cost will be an issue,fnding targets that are indicators for response aredesperately needed

Getting closer to disease state that we can control,immunotherapy may allow us to get long termremission in some pts

Combination therapy and moving treatment up inthe disease will likely be benefcial, expense/targets


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New horizons in Prostate Cancer Treatment in Prostate Cancer – Taxotere An old dog with new tricks...

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