Treatment options for

mCRPC in 2015

Guidelines?

Treatment Algorithm?

Christos N. Papandreou, M.D., Ph.D.University of Thessaly

School of Μedicine

March 2015

DISCLOSURES

• Invited speaker / Advisory boards / Grants

– Amgen

– Astellas

– Bayer

– Bristol

– Janssen

– Novartis

– Roche

– Sanofi

Prostate cancer disease continuum

Tumourvolume

Time

Castration

Docetaxel/chemotherapy

Localtherapy*

Metastatic

Symptoms

Castration-resistant

Non-metastatic

Asymptomatic

Hormone-sensitive

2nd-line hormonal therapies

BicalutamideFlutamideNilutamide

Death

AbirateroneCabazitaxelEnzalutamideAlpharadine

*e.g. Radiotherapy

Continued AR signalling

Kohli & Tindall. Mayo Clin Proc 2010;85:77–86.AR, androgen receptor

Abiraterone

CRPC – Definition

European Association of Urology (EAU)

Castrate-resistant prostate cancer

Serum castration levels of testosterone <50 ng/dL or <1.7 nmol/L

Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over

the nadir, with a PSA >2 ng/mL

Anti-androgen withdrawal for at least 4 weeksa

PSA progression despite secondary hormonal manipulations

or

Progression of osseous lesions: progression or appearance of two or more lesions

on bone scan or soft tissue lesions using the Response Evaluation Criteria In Solid

Tumours (RECIST) criteria and with nodes ≥2 cm in diameter

aEither anti-androgen withdrawal or one secondary hormonal manipulation completed

Cytokines, RTKs,

Microtubule bindingSteroids

AR gene located on

X chromosome

AR protein has 3 main

regions:

N-terminal domain

(NTD) which contains

the activation function

Central DNA binding

domain (DBD)

C-terminal ligand binding

domain (LBD) where

testosterone and DHT

bind

The human AR gene, transcript and protein

Hu R et al. Expert Rev Endocrinol Metab. 2010 Sep;5(5):753-76

(CAG repeats)

Pienta KJ et al. Clin Cancer Res 2006;12:1665-1671; Debes JD NEJM 2004; 351: 1488-90

1. T prod - Amplification AR

2. Mutations AR – AR SVR

3. Outlow pathway

4. Bypass pathway

5. Co-activiators

6. Stem cell regeneration

Mechanisms of disease progression in CRPC

Bcl

Bcl BclBcl

Bcl

Bcl

4

Bcl-2 overexpression

Androgen

production

ARSV

bicalutamide resistance

High concentrationsof androgens in tumour(both primary1-2 & mets3) microenvironment

Origin: adrenal gland & prostate cancer cells1-3

Genetic polymorphismsin androgen conversionand transportation4

DHT synthesis maybypass testosteronein driving CRPC5

1Nishiyama et al. Clin Cancer Res 2004; 10: 7121-262Titus MA et al. Clin Cancer Res 2005; 11: 4653-57

3Montgomery RB et al. Cancer Res 2008;68:4447-544Yang M et al.J Clin Oncol 2011; 29:2565-73

5Chang K-H et al. PNAS 2011;108: 13728–33

Persistent androgens in tumours (1)

AR splice variants (ARv)

Ligand bindingdomain is lacking

Not expected to associatewith cytoplasmicchaperones

May contribute to development of CRPC

ARv isoforms are constitutively active, promoting tumor cellgrowth independent of ligand

May contribute to resistance to Enz and Abi

Dehm SM et al. Cancer Res 2008; 68: 5469–77Hu R et al. Cancer Res 2009; 69:16-22

Watson et al. PNAS 2010; 107: 16759-65Ryan CJ & Tindall DJ; J Clin Oncol 2011; 29: 3651-58

Therapeutic strategies targeting

AR signaling pathway

Docetaxel inhibits PSA expression inhuman prostate tumors

Control Docetaxel treatment

Control Docetaxel

Significant reduction

in PSA expression

in prostate tumors

of patients treated

with docetaxel0

20

40

60

80

100

120

140

PSA

Exp

ress

ion

*

*p < 0.01

Zhu et al. Cancer Res, 70:7992,2010

Abiraterone: CYP17 blockade inhibits

androgen synthesis

Fizazi. ECCO-ESMO 2009; Teaching Lecture

abiraterone

Abiraterone acetate

Phase III post-chemo study design

Phase 3 multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)

Abiraterone 1000mg daily

Prednisone 5mg BID

n=797

Primary end point:

• OS (25% improvement;

HR 0.8)

Secondary end points:

• TTPP

• rPFS

• PSA response

Efficacy end points (ITT)

Placebo daily

Prednisone 5mg BID

n=398

RANDOMIZED

2:1

• 1195 patients with

progressive mCRPC

• Failed 1 or 2

chemotherapy regimens,

1 of which contained

docetaxel

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

COU-AA-301

14.8 months vs 10.9 months

Hazard ratio, 0.65;

95% CI, 0.54 to 0.77; P<0.001

N Engl J Med 2011;364:1995-2005

Median follow-up of 12.8 months

3.9-month benefit in OS

15.8 months vs 11.2 months

Final analysis

Survival benefit 4.6 months

The Lancet 13, Issue 10, 2012, 958–95

Abiraterone Acetate: OS Benefit Post-Chemotherapy

N Engl J Med 2011;364:1995-2005

N Engl J Med 2011;364:1995-2005

French ATU: Poor response to abiraterone

in patients with high Gleason score

Abiraterone French ATU program

(post-docetaxel setting)

408 mCRPC patients enrolled in 19 centers

Gleason 8-10: 51.2% at diagnosis

Independent predictive factors of poor

response to Abiraterone:

Gleason score 8-10

Number of chemotherapy lines (>1)

Azria D et al. J Clin Oncol 2012;30 (Suppl 5):abstract 149

Ph III trial of Abiraterone in asymptomatic or mildly

symptomatic mCRPC Pre-chemotherapy

Abiraterone acetate

1000 mg daily

Placebo daily

50% improvement in radiologic progression-free survival and 25%

improvement in overall survivalPrimary endpoint:

• 1000 patients with

asymptomatic or

mildly symptomatic

metastatic CRPC

• Chemotherapy naïve

• Randomized 1:1

• Stratified by: ECOG

performance status

(0 vs. 1)

T

R

E

A

T

U

N

T

I

L

P

R

O

G

R

E

S

S

I

O

N

Prednisone 5mg twice daily

Prednisone 5mg twice daily

COU-AA-302

No visceral mets

EPI-001

Inhibits transactivationof the N-terminal domain

Differs from anti-androgens which targetC-terminal ligand bindingdomain

Can potentially escape several mechanismsof castration resistance

Not yet clinically tested

Andersen RJ. Cancer cell 2010; Cancer Cell 17, 535–546

DHT

NUCLEUSCYTOPLASM

TDHEA

AR

EPI-001

MDV3100 (Enzalutamide)

Affects multiple steps in androgen signaling Inhibits binding of androgens to AR C-terminal

domain

Inhibits nuclear translocation of AR

Inhibits association of AR with DNA

Chen, et al. Lancet 2009, 10: 981–91

Scher H et al. ASCO GU 2012: J Clin Oncol 2012, 30;(suppl 5): abstr LBA1

Eplerenone activates mutant AR

Exogenous corticoids activate mutant AR in CRPC patients treated with abiraterone

Spironolactone binds and activates wild-type and mutant AR

Mutant AR activation by eplerenone inhibitedby abiraterone or bicalutamide, but most effectively by Enzalutamide (MDV3100)

Richards J et al. Cancer Res 2012; 72; 2176–82

31

Study design AFFIRM is a Phase 3, randomised, double-blind, placebo-controlled trial

Recruitment in 156 centres from 15 countries between September 2009 and November 2010

The AFFIRM trial design incorporated the recommendations of the Prostate Cancer Clinical Trials Working Group 2

Exclusion criteria included: Severe concurrent disease, infection or comorbidity, brain metastases, history of another malignancy

within previous 5 years, treatment with androgen receptor antagonists, 5-alpha reductase inhibitors, oestrogens or

chemotherapy, within 4 weeks of enrolment. Corticosteroids were not required but allowed.

CRPC=castration-resistant prostate cancer; OS=overall survival.

Scher HI, et al. N Eng J Med 2012;367:1187–97.

RANDOMISED

2:1

Patients:

• 1199 patients with

progressive CRPC

• 1–2 prior chemotherapy

regimens (≥1 docetaxel)

Primary endpoint:

• OS

Enzalutamide

160 mg daily

n=800

Placebo

n=399

Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).

AFFIRM: Overall survival

3 6 9 18 21 2415

100

80

60

40

20

0

0

Surv

ival

(%

)

Duration of overall survival (months)

12

775 701 627 72 7 0211800 400Enzalutamide, n =

376 317 263 33 3 081399 167Placebo, n =

Placebo: 13.6 months(95% CI: 11.3–15.8)

Enzalutamide: 18.4 months(95% CI: 17.3–NYR)

HR = 0.63 (95%CI: 0.53–0.75); p<0.00137% reduction in risk of death

4.8 month difference in median overall survival

CI, confidence interval; HR, hazard ratio; NYR, not yet reached

No at risk:

{27%}

AFFIRM: Enzalutamide improved outcomes in patients with liver and

lung metastases compared with placebo

Efficacy outcome

Liver mCRPC Lung mCRPC

Enzalutamide

(n=92)

Placebo

(n=34)

Enzalutamide

(n=122)

Placebo

(n=59)

OS, months (95% CI) 9.0 (6.4–10.7) 5.7 (4.2–9.5) 16.5 (12.5–NM) 10.4 (8.1–NM)

HR0.697

(95% CI: 0.436–1.114)

0.760

(95% CI: 0.493–1.172)

rPFS, months (95% CI) 2.9 (2.8–4.9) 2.8 (2.7–3.2) 5.6 (5.3–8.2) 2.8 (2.7–2.9)

HR0.645

(95% CI: 0.413–1.008)

0.427

(95% CI: 0.298–0.612)

Confirmed PSA

response,* % (95% CI)

35.1

(24.4–47.1)

4.8

(0.1–23.8)

52.8

(42.9–62.5)

4.3

(0.5–14.5)

Objective response,† %

(95% CI)

14.9

(8.2–24.2)

3.3

(0.1–17.2)

29.3

(20.6–39.3)

4.9

(0.6–16.5)

*A confirmed PSA response reflected a 50% decline from baseline.

†Objective response defined as complete or partial soft tissue response per RECIST 1.1 (Response Evaluation Criteria In

Solid Tumors).

CI=confidence interval; HR=hazard ratio; mCRPC=metastatic castration-resistant prostate cancer; NM=not met; OS=overall survival;

PSA=prostate-specific antigen; rPFS=radiographic progression-free survival.

Loriot Y, et al. Presented at ASCO 2013; Poster presentation 5065.

35

AFFIRM: Significantly fewer patients experienced pain progression

with enzalutamide than with placebo

Enzalutamide Placebo

Number of evaluable patients 625 259

n (%) with pain progression 174 (28%) 101 (39%)

95% CI 24.4–31.5% 33.0–45.2%

p value 0.0018

CI=confidence interval.

Fizazi K, et al. Presented at ESMO 2012; Oral presentation 896O.

Definition: Any increase in the mean pain score at Week 13 compared with baseline

as assessed by pain diaries

To be evaluable: Valid pain diary entries for ≥4 out of 7 days at baseline run-in period

and 7 days preceding Week 13 visit

AEs, n (%)

Total events (all grades) Grade ≥3 events

Enzalutamide

(n=800)

Placebo

(n=399)

Enzalutamide

(n=800)

Placebo

(n=399)

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

Diarrhoea 171 (21) 70 (18) 9 (1) 1 (<1)

Hot flush 162 (20) 41 (10) 0 0

Musculoskeletal pain 109 (14) 40 (10) 8 (1) 1 (<1)

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

36

AFFIRM: Most common AEs with enzalutamide*

*Included in this category are adverse events that occurred in >10% of patients in the enzalutamide group and that

occurred

in the enzalutamide group at a rate that was at least 2% higher than that in the placebo group.

AE=adverse event.

Scher HI, et al. N Engl J Med 2012;367:1187–97.

Enzalutamide substantially displaced FDHT binding at all

doses, with a maximum effect at 150 mg

Finding suggests androgen receptor binding by

enzalutamide might be saturated at plasma

concentrations of 5-15 mcg/ml

At baseline and 4 weeks post-enzalutamide

treatment, PET scans showed a reduction in

FDHT* accumulation in tumour within the

vertebrae

*FDHT: 16-18F-fluoro-5-dihydrotestosterone

Scher HI, et al. Lancet. 375:1437, 2010.

4 weeks post-enzalutamide therapy

Baseline

Phase I/II study: Androgen receptor inhibition by FDHT PET imaging

CTCs

Discordant FDG-PET / FDHT-PET

FDHT response does not predict

FDG response !

38

Enzalutamide in chemotherapy-naïve

mCRPC patients: Study design PREVAIL is a Phase 3 randomised, double-blind, placebo-controlled trial

evaluating the safety and efficacy of enzalutamide in chemotherapy-naïve patients with mCRPC

*Patient scored less than four on BPI-SF-Q3.

Recruitment in 207 centres from 22 countries across four continents between September 2010 and September 2012.

ADT=androgen-deprivation therapy; BPI-SF=Brief Pain Inventory-Short Form; ECOG PS=Eastern Cooperative Oncology Group

performance status; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; QD=once daily;

rPFS=radiographic progression-free survival; T=testosterone.

Beer TM, et al. N Engl J Med 2014;371:424–33.

RANDOMISED

1:1

Patients:

•1717 patients with

mCRPC

•Chemotherapy-naïve

•Asymptomatic/

mildly symptomatic*

•ECOG PS 0–1

•PSA progression,

rPFS progression or

both in bone or soft

tissue on ADT

•Serum T ≤50 ng/dL

•Steroids allowed but

not required

•Ongoing ADT

Co-primary endpoints:

• OS

• rPFS

Secondary endpoints:

• PSA response

• Soft-tissue response

• Time to:

– Initiation of

chemotherapy

– First SRE

– PSA progression

Enzalutamide

160 mg QD

n=872

Placebo QD

n=845

4% of men were on steroids in

each treatment arm prior to

study entry

100

80

60

40

20

0

40

Enzalutamide significantly reduced the risk of radio-graphic

progression or death in both patient groups

*Non-visceral subgroup patients presented with only bone or nodal disease at screening; †Visceral subgroup patients

presented with lung and/or liver disease at screening.

CI=confidence interval; HR=hazard ratio; NYR=not yet reached; rPFS=radiographic progression-free survival.

Evans CP, et al. AUA 2014; Oral presentation PI-05.

rPF

S (

%)

0 3 6 9 12 15 18 21

Time to event (months)

Non-visceral Subgroup

HR=0.175

(95% CI: 0.14–0.22)

P<0.0001

Enzalutamide 735 465 235 114 29 3 1 0

Placebo 700 269 71 17 4 0 0 0

Placebo:

4.0 months

(95% CI: 3.7–5.4)

Enzalutamide: 14.1 months

(95% CI: 13.8–NYR)

0 3 6 9 12 15 18

100

80

60

40

20

0

97 49 21 14 5 2 0

101 36 8 3 1 0 0

Visceral Subgroup

rPF

S (

%)

Time to event (months)

Placebo:

3.6 months

(95% CI: 3.3–5.5)

Enzalutamide: NYR

(95% CI: 10.9–NYR)

HR=0.283

(95% CI: 0.16–0.49)

P<0.0001

41

Enzalutamide significantly improved the risk of death in patients

without visceral metastases

*Non-visceral subgroup patients presented with only bone or nodal disease at screening; †Visceral subgroup patients

presented with lung and/or liver disease at screening.

CI=confidence interval; HR=hazard ratio; NYR=not yet reached.

Evans CP, et al. AUA 2014; Oral presentation PI-05.

100

80

60

40

20

0

Ove

rall

su

rviv

al

(%)

0 3 6 9 12 15 18 21 24 27 30 33 36

Time to event (months)

HR=0.692

(95% CI: 0.57–0.83)

P=0.0001

Enzalutamide 774 771 763 741 714 669 510 360 219 112 27 2 0

Placebo 739 731 690 661 624 577 430 287 186 87 22 1 0

Placebo:

30.2 months

(95% CI: 28.0–NYR)

Enzalutamide: NYR

(95% CI: 31.5–NYR)

Non-visceral Subgroup

98 92 87 83 83 76 56 35 25 16 6 0 0

106 104 91 83 77 67 54 41 27 15 5 1 0

0 3 6 9 12 15 18 21 24 27 30 33 36

100

80

60

40

20

0

Ove

rall

su

rviv

al

(%)

Visceral Subgroup

Placebo:

22.8 months

(95% CI: 16.9–NYR)

Enzalutamide: 27.8

(95% CI: 20.9–NYR)

HR=0.822

(95% CI: 0.55–1.23)

P=0.343

Time to event (months)

42

Survival benefit was observed across all

patient subgroups analysed

Date of analysis: 16 September 2013.

CI=confidence interval; ECOG=European Cooperative Oncology Group; HR=hazard ratio.

Beer TM, et al. N Engl J Med 2014;371:424–33. Suppl appendix.

Subgroup

Number of patientsenzalutamide/

placebo

HRfor death(95% CI)

All patients 872/845 0.71 (0.60–0.84)

ECOG performance status=0 584/585 0.70 (0.56–0.87)

ECOG performance status=1 288/260 0.69 (0.53–0.90)

Age <75 555/553 0.77 (0.62–0.96)

Age ≥75 317/292 0.60 (0.47–0.79)

Geographic region – North America 218/208 0.83 (0.60–1.16)

Geographic region – Europe 465/446 0.68 (0.54–0.86)

Geographic region – Rest of world 189/191 0.62 (0.42–0.92)

Visceral disease (lung and/or liver) –Yes 98/106 0.82 (0.55–1.23)

Visceral disease (lung and/or liver) – No 774/739 0.69 (0.57–0.83)

0 0.5 1.0 1.5

Favours

enzalutamide

Favours

placebo

CHEMOTHERAPY IN mCRPC

Prednisone +/- Mitoxantrone

Ανακούφιση

από πόνο

Διάρκεια

ανακούφισης

Απάντηση

PSA

Διάμεση

επιβίωση

(μήνες)

M+P 29% 43 εβδομάδες 33% 12

P 12% 18 εβδομάδες 22% 11.3

P=.01 P<.001 NS NS

Tannock IF, et al., J Clin Oncol 14(6): 1756-64, 1996

Docetaxel / Estramustine vs Mitoxantrone / Prednisone

Petrylak DP, et al: NEJM 351:1513-20, 2004

Tannock IF, et al: NEJM 351:1502-12, 2004

Docetaxel / Prednisone vs Mitoxantrone / Prednisone

TAX 327

Median OS Δ: 2.9 mo

30% crossover

only 3% NF

TAX 327 OS

Tannock et al, N Engl J Med 2004; 351: 1502-1512

Impact of pain on OS in TAX 327

Docetaxel q3w

(n = 335)

Docetaxel qw

(n = 334)

Mitoxantrone

(n = 337)

No pain

n 183 183 184

Median survival 23.0 21.1 19.8

Hazard ratio 0.73 0.95

p value 0.009 0.65

Pain

n 152 151 153

Median survival 14.9 15.1 12.8

Hazard ratio 0.85 0.8

p value 0.17 0.068

Berthold DR, et al. J Clin Oncol 2008;26:242–45

However, asymptomatic Pts with adverse prognostic factors

may require prompt initiation of chemotherapy

Variable

Multivariate HR

95% CI P-Value

Liver metastases 1.63 1.07-2.50 0.023 Number of metastatic sites (>2 vs <2) 1.58 1.19-2.09 0.001

Pain at Baseline 1.46 1.21-1.76 <0.0001 Performance Status

(<70 vs >80)

1.42

1.08-1.85

0.011 Progression Type: Measurable disease

Bone scan progression

1.40 1.28

1.13-1.76 1.05-1.55

0.002 0.014

Baseline PSA Doubling Time (<55 days vs. >55 days)

1.20

1.001-1.44

0.048

Baseline log PSA (for every unit rise in log(PSA) in ng/dl)

1.17

1.10-1.24

<0.0001

Tumor Grade: (Gleason >8 or WHO 3-4 vs Gleason <7 or WHO 2-3)

1.18

0.98-1.41

0.076

Alkaline phosphatase (log scale) (per log unit rise, IU/L)

1.26

1.14-1.38

<0.001

Hemoglobin (per unit rise, g/dl)

0.91

0.85-0.97

0.006

Multivariate analysis (N= 635)

2nd line Chemo in mCRPC?

Symptomatic patients

Asymptomatic with Rapid Progression

Neuroendocrine / anaplastic phenotypre

Docetaxel Cabazitaxel

O OO

O

OCOCH3

OCOC6H

5

HOH

O

O

OH

NH

O

O

CH3

CH3

OH OOH

O

OCOCH3

OCOC6H

5

HOH

O

O

OH

NH

O

OO

Semisynthetic taxane selected to overcome emergence of taxane resistance1

Preclinical data1

As potent as docetaxel against sensitive cell lines and tumor models

Active against tumor cells/models resistant to currently available taxanes

Poor mdr substrate -- BBB penetration

Clinical data2

Neutropenia was the DLT in phase I trials

Antitumor activity in mCRPC, including docetaxel-resistant disease1. Attard G et al. Pathol Biol (Paris). 2006;54(2):72-84; Pivot X et al. Ann Oncol. 2008;19(9):1547-1552.

2. Mita AC et al. Clin Can Res. 2009;15(2):723-730.

(C45H57NO14)

7,10 dimethoxy analogue of docetaxel

(C43H53NO14)

Docetaxel : esterified product of 10-deacetyl baccatin III

1o Endpoint: Overall Survival (ITT analysis)

Mitoxantrone 377 300 188 67 11 1Cabazitaxel 378 321 231 90 28 4

De Bono JS et al. Lancet. 2010;376:1147-154.

100

90

0 6 12 18 24 30

Months

Probability of

Overall

Survival (%)

80

70

60

50

40

30

20

10Mitoxantrone

0

Number at risk

Cabazitaxel Mitoxantrone

Median OS (months) 15.1 12.7

Hazard ratio 0.70

95% CI 0.59-0.83

P value 0.0001

Cabazitaxel

(ITT analysis)

Factor

Patient

NumberHazard Ratio

(95%CI)

ITT population; all patients 755 0.70 (0.59-0.83)

ECOG status 0, 1 694 0.68 (0.57-0.82)

ECOG status 2 61 0.81 (0.48-1.38)

Measurable disease: no 350 0.72 (0.55-0.93)

Measurable disease: yes 405 0.68 (0.54-0.85)

No. of prior chemo: 1 528 0.67 (0.55-0.83)

No. of prior chemo: ≥2 227 0.75 (0.55-1.02)

Age <65 y 295 0.81 (0.61-1.08)

Age ≥65 y 460 0.62 (0.50-0.78)

Pain at baseline: no 314 0.57 (0.43-0.77)

Pain at baseline: yes 310 0.76 (0.59-0.98)

TROPIC: Overall Survival Subgroup Analysis

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

0 0.5 1 1.5 2

Favors CBZ Favors M

TROPIC: Progression-Free Survival

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

Cabazitaxel

100

90

0 6 9 1815 21

Months

Probability of

Progression-Free

Survival (%)

80

70

60

50

40

30

20

10

Cabazitaxel

0

Number at risk

Mitoxantrone 377 115 27 9 6 2452378 168 52 15 4 0090

3 12

Cabazitaxel Mitoxantrone

Median PFS (months) 2.8 1.4

Hazard ratio 0.74

95% CI 0.64-0.86

P value 0.0001

Mitoxantrone

TROPIC: Hematologic Adverse Events

Cabazitaxel (n=371)

Mitoxantrone (n=371)

All Grades

n (%)

Grade 3

n (%)

All Grades

n (%)

Grade 3

n (%)

Neutropenia 347 (94) 303 (82) 325 (88) 215(58)

Febrile neutropenia – 28 (8) – 5 (1)

Leukopenia 355 (96) 253 (68) 34 (92) 157 (42)

Anemia 361 (97) 39 (11) 30 (281) 18 (5)

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

58% grade ≥3 neutropenia in mitoxantrone arm of the TROPIC study vs 22% in mitoxantrone arm of TAX 327

Prophylactic use of G-CSF was permitted except for Cycle 1 of treatment at the discretion of the investigator

Data for hematologic adverse events were based on laboratory assessments

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

Tannock IF et al, on behalf of the TAX 327 Investigators. N Engl J Med. 2004;351:1502-1512.

Chemo-tx in Hormone-naïve

high risk mPCa ?

Presented by: Christopher J. Sweeney, MBBS, ASCO 2014

E3805 – CHAARTED Treatment

STRATIFICATION

Extent of Mets

-High vs Low

Age

≥70 vs < 70yo

ECOG PS

- 0-1 vs 2

CAB> 30 days

-Yes vs No

SRE Prevention

-Yes vs No

Prior Adjuvant ADT

≤12 vs > 12 months

R

A

N

D

O

M

I

Z

E

ARM A:

ADT + Docetaxel

75mg/m2 every 21

days for up to 6

cycles

ARM B:

ADT (androgen

deprivation therapy

alone)

Evaluate

every 3 weeks

while

receiving

docetaxel and

at week 24

then every 12

weeks

Evaluate

every 12

weeks

Follow for time

to progression

and overall

survival

Chemotherapy

at investigator’s

discretion at

progression

ADT allowed up to 120 days prior to randomization.

Intermittent ADT dosing was not allowed

Standard dexamethasone premedication but no daily

prednisone

High volume: visceral metastases and/or >4 bone metastases

(at least 1 beyond pelvis and vertebral column)

Presented by: Christopher J. Sweeney, MBBS, ASCO 2014

Primary endpoint: Overall survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)

0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTAL

A 397 101 296 57.6B 393 136 257 44.0

Pro

bability

HR=0.61 (0.47-0.80) p=0.0003

Median OS:

ADT + D: 57.6 months

ADT alone: 44.0 months

N=790

PS: 0-2

f/up: 29mos

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)

0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTAL

A 134 19 115 .B 142 26 116 .

Pro

bability

Presented by: Christopher J. Sweeney, MBBS, ASCO 2014

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)

0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTAL

A 263 82 181 49.2B 251 110 141 32.2

Pro

ba

bility

OS by extent of metastatic disease at start of ADT

In patients with high volume metastatic disease, there is a 17 month improvement in median

overall survival from 32.2 months to 49.2 months

We projected 33 months in ADT alone arm with collaboration of SWOG9346 team

High volume Low volume

p=0.0006

HR=0.60 (0.45-0.81)

Median OS:

ADT + D: 49.2 months

ADT alone: 32.2 months

p=0.1398

HR=0.63 (0.34-1.17)

Median OS:

ADT + D: Not reached

ADT alone: Not reached

f/up: 29mos

Presented by: Christopher J. Sweeney, MBBS, ASCO 2014

ADT + Docetaxel benefited all

subgroups

25% of High Volume : visceral

Comments

Strength: number of High Volume pts (514, 65%)

too selected? 125/514 (24%) HV pts with visceral

Insufficient evidence to recommend that low-volume patients with

castration-sensitive disease undergo early docetaxel therapy

f/up: 29 mos

There is a need to optimize the distinction between those who benefit from

chemotherapy and those who do not.

High volume: liver, lung, extensive / lytic bone, other, early non-

responders ?

OSTEOTROPIC

RADIOPHARMACEUTICALS

Radium-223 Targets Bone Metastases

Radium-223 acts

as a calcium

mimic

Naturally targets

new bone growth

in and around

bone metastases

Radium-223 is

excreted by the

small intestine

Ca

Sr

Ba

Ra

ALSYMPCA (ALpharadin in SYMptomatic

Prostate CAncer) Phase III Study Design

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg)

+ Best standard of care

Placebo (saline)

+ Best standard of care

R

A

N

D

O

M

I

S

E

D

2:1

N = 921

PATIENTS

• Confirmed

symptomatic

CRPC

• ≥ 2 bone

metastases

• No known

visceral

metastases

• Post-

docetaxel or

unfit for

docetaxel

Planned follow-up is 3 years

• Total ALP:

< 220 U/L vs ≥ 220 U/L

• Bisphosphonate use:

Yes vs No

• Prior docetaxel:

Yes vs No

STRATIFICATION

Clinicaltrials.gov identifier: NCT00699751

Month 0 3 6 9 12 15 18 21 24 27 30

Radium-

223

614 487 332 193 125 62 31 8 8 1 0

Placebo 307 207 108 51 33 17 8 6 3 1 0

ALSYMPCA Updated Analysis

Time To First SRE*

HR = 0.64 95% CI, 0.52, 0.78

P < 0.0001

Radium-223, n = 614

Median: 12.2 months

Placebo, n = 307

Median: 6.7 months

0

10

20

30

40

50

60

70

80

90

100

%

*Provisional data

ALSYMPCA Updated Analysis

Overall Survival

Radium-223, n = 614

Median OS: 14.9 months

Placebo, n = 307

Median OS: 11.3 months

HR = 0.69595% CI, 0.581, 0.832

P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium-

223614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo307 288 228 157 103 67 39 24 14 7 4 2 1 0

0

10

20

30

40

50

60

70

80

90

100

%

ALSYMPCA Updated Analysis

Survival Benefit Across Patient Subgroups

2015

Abiraterone

Enzalutamide

in 2015

GUIDELINES ???

Guidelines are only relevant

to diseases and NOT to

patients; especially to A

particular patient

Short response (<1 year) to 1st-line ADT

Lack of undetectable PSA with 1st ADT

High Gleason score (8-10)

Short PSA doubling time (< 4-6 mo)

Visceral metastases

Predominantly lytic bone mets

Disproportionally low PSA to tumor burden

Presence of B symptoms (PS: co-morb vs dz!!)

PD on chemo-tx CEA or NSE (in the absence of other causes)

Decision tree

75

Indication for immediate chemotherapy

(Docetaxel Cabazitaxel or Pt-based)

There might be only one chance !!!

Predictors of very poor or No response to hormonal therapy

(including abiraterone/enzalutamide)

Think of

ANAPLASTIC

PCa

SUGGESTIONS...

mCSPC or mCRPC

Anaplastic Features

Yes (20%)

Docetaxel

Cabazitaxel

Paclitaxel ±Carboplatin

Mitoxantrone

Vinorelbine

EP

No (80%)

GoodPS

Chemo naïve

Indolent PD

Enzalutamide

Abiraterone*

Alpharadine*

Rapid PD

Docetaxel

Enzalutamide

Abiraterone

Post 1st line chemo

Indolent PD

Enzalutamide

Abiraterone

Alpharadine*

Rapid PD

Cabazitaxel

Enzalutamide

Abiraterone

Poor PS

Disease related

Chemo naïve

Docetaxel

Enzalutamide

Abiraterone*

Post 1st line chemo

Cabazitaxel(mitoxantrone

vinorelbine) Enzalutamide

Abiraterone

Alpharadine*

Comorbidity related

Chemo naïve

Enzalutamide

Abiraterone*

Alpharadine*

Post 1st line chemo

Enzalutamide

Abiraterone

(2nd line chemo)

Alpharadine*

* without visceral mets

mCSPC or mCRPC

Anaplastic Features

Yes (20%)

Docetaxel

Cabazitaxel

Paclitaxel ±Carboplatin

Mitoxantrone

Vinorelbine

EP

No (80%)

GoodPS

Chemo naïve

Indolent PD

Enzalutamide

Abiraterone*

Alpharadine*

Rapid PD

Docetaxel

Enzalutamide

Abiraterone

Post 1st line chemo

Indolent PD

Enzalutamide

Abiraterone

Alpharadine*

Rapid PD

Cabazitaxel

Enzalutamide

Abiraterone

Poor PS

Disease related

Chemo naïve

Docetaxel

Enzalutamide

Abiraterone*

Post 1st line chemo

Cabazitaxel(mitoxantrone

vinorelbine) Enzalutamide

Abiraterone

Alpharadine*

Comorbidity related

Chemo naïve

Enzalutamide

Abiraterone*

Alpharadine*

Post 1st line chemo

Enzalutamide

Abiraterone

(2nd line chemo)

Alpharadine*

* without visceral mets

FUTURE…

F-DHT scan

vs

Choline scan

Hypothesis

Detection of AR-V7 in CTC samples

from patients with mCRPC may predict

resistance to enzalutamide and abiraterone.

Antonarakis ES, ASCO 2014, A 5001

Design: Prospective Biomarker Study

30 men (in each group) with CRPC who were about to

begin treatment w/ enzalutamide or abiraterone

85% Power to detect a difference in PSA response

rates from 10% (in AR-V7[+] men) to 60% (in AR-V7[–]

men), using a 2-sided a=0.10

CTC samples were collected at 3 time points: Baseline/pretreatment

At time of Response to enzalutamide/abiraterone

At time of Resistance to enzalutamide/abiraterone

Antonarakis ES, ASCO 2014, A 5001

Outcome Measures

PSA response rate (≥50% PSA decline)

PSA progression-free survival (modified PCWG2)

Progression-free survival (modified PCWG2)

Overall survival (premature)

Antonarakis ES, ASCO 2014, A 5001

Outcomes: AR-V7 “conversions”

Outcome AR-V7[–] → AR-

V7[–] (n=36)

AR-V7[–] → AR-

V7[+] (n=6)

AR-V7[+] → AR-

V7[+] (n=16)

PSA Response68%

(95%CI, 52 –

81%)

17%

(95%CI, 4 – 58%)

0%

(95%CI, 0 – 19%)

PSA Progression-Free

Survival

6.1 months

(95%CI, 5.9 mo –

NR)

3.0 months

(95%CI, 2.3 mo –

NR)

1.4 months

(95%CI, 0.9 – 2.6

mo)

Progression-Free

Survival

6.5 months

(95%CI, 6.1 mo –

NR)

3.2 months

(95%CI, 3.1 mo –

NR)

2.1 months

(95%CI, 1.9 – 3.1

mo)Antonarakis ES, ASCO 2014, A 5001

Clinical Phenotypes

Scintigraphic Phenotypes (PET-CTs: FDG vs FDHT vs Choline)

IHC Phenotypes

CTCs Phenotype/Genotype

Molecular Pheno-/Geno-type ???