10/17/2014

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Optimal Management of

Castration Resistant Prostate Cancer (CRPC) in 2014

15th Annual Advances in Oncology

October 10-11, 2014

Primo N. Lara, Jr., MD Professor of Medicine

UC Davis School of Medicine

Disclosures

Consultant: Janssen Pharmaceuticals, Clovis Oncology, US Diagnostic Services, Astex Therapeutics, Exelixis, Immunogen, Pfizer, Teva,

Medivation, Halozyme, Novartis Grant/Research Support: Millennium, Polaris, Oncogenex, GlaxoSmithKline,

Genentech, Aragon Pharmaceuticals, Janssen Biotech, Inc.

The presentation (does not include) discussion of the use of product(s) for

which they are not labeled (e.g., off label use) is still investigational.

Acknowledgement Daniel Petrylak MD (Yale University) for allowing me to

“borrow” some of his slides!

CRPC therapy by state: 2010

Zoledronic acid with CRPC (metastatic disease)

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel

chemotherapy

Secondary

hormonal Rx Docetaxel

Mitoxantrone Best supportive care

not known 3 months not known

Survival

benefit

2010

CRPC therapy by state: 2014

Abiraterone or Cabazitaxel acetate

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel

chemotherapy

Secondary

hormonal Rx Docetaxel

not known 3 months not known

Sipuleucel-T Docetaxel

4 months 3 months 4 months 2.5 months

Denosumab or Zoledronic acid (bone metastatic disease)

Survival

benefit

Survival

benefit

Mitoxantrone

Best supportive care 2010

2014

Enzalutamide – 4.8 months

Rad223 – 3.1 months

Enzalutamide – 2.2 months

Abiraterone – 5.2 months

Rad223 – 4.6 months

Development of CRPC

ALTERN.

SPLICING

ABERRANT

MODIFICATION

•GF, cytokines •Src

Sumo

AC

P

COFACTOR

PERTURBATION

•CoAct gain •CoR loss/dismissal

CoACT

INTRACRINE

ANDROGEN

SYNTHESIS

T

MUTATION •gain of function

AR

selective

pressure

Hormone Therapy

adaptation

CRPC

RESTORED AR ACTIVITY

(rising PSA)

RECURRENT TUMOR DEVELOPMENT

>30% CRPC

AR

DEREGULATION

•amplification •overexpression

Penning and Knudsen. Trends Endocrinol Metab. 2010;21(5):315-24.

Classes of Agents in CRPC

• Immunotherapeutic

– Sipuleucel T

• Androgen-receptor targeted

– Enzalutamide, Abiraterone , ?Docetaxel

• Cytotoxic

– Docetaxel, Cabazitaxel

• Radioisotope

– Radium 223

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Abiraterone Acetate: Androgen Biosynthesis Inhibitor

Pregnenolone

DHEA Androstenedione Testosterone DHT

17OH- Pregnenolone

Cortisol

Aldosterone

Androgens

Cholesterol

Abiraterone

Abiraterone

COU 301: Abiraterone vs. Placebo in post-docetaxel setting

2 prior chemo OS: 14.0 months abiraterone acetate vs 10.3 months placebo1 1 prior chemo OS: 15.4 months abiraterone acetate vs 11.5 months placebo1

Updated results: 4.6-month difference in median survival with abiraterone acetate2

Placebo Abiraterone

Acetate Median OS (months) 10.9 14.8 Hazard Ratio 0.65 95% CI 0.54-0.77 P value <0.001

Placebo

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Ove

rall

Su

rviv

al

(%)

Days from Randomization

Abiraterone Acetate

Median OS Δ: 3.9 months 35.4% reduction in risk of death

1. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 2. Fizazi K, et al. European Multidisciplinary Cancer Congress; 2011. Abstract 7000.

Ryan, NEJM 2013

Enzalutamide

• Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway

• No demonstrated agonist effects in pre-clinical models

Tran C et al. Science 2009;324:787-790.

T

T

AR

Nucleus

Enzalutamide Inhibits Binding of Androgens to AR

Inhibits Nuclear Translocation of AR

Inhibits Association Of AR with DNA

Tumor Death

AR

Cytoplasm

X

X

X

Enzalutamide vs. Placebo: Post-Docetaxel

Scher HI, et al. N Engl J Med. 2013; 367:1187-1197

Median OS Δ: 4.8 months 37% reduction in risk of death

Enzalutamide Placebo

Median Overall Survival (months)

18.4 13.6

Hazard ratio 0.63 95% CI 0.53, 0.75 P value < 0.001

Enzalutamide vs. Placebo in Post-Docetaxel Setting

Beer T, et al. NEJM 2014.

Median OS: Enzalutamide, 32.4 Months; Placebo, 30.2 months

Enzalutamide

Placebo

100

90

80

70

60

50

40

30

20

10

0

Hazard Ratio: 0.706

(95% CI: 0.60, 0.84)

P < 0.0001

Duration of Overall Survival (Months)

Su

rviv

al (%

)

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

Patients still alive at data cut off

Enzalutamide: 72%; Placebo: 63%

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NCI Alliance Trial A031201: Enzalutamide +/- Abiraterone Acetate

Phase III Trial in Chemonaïve mCRPC

Phase 3 multicenter, randomized study conducted through the NCI’s National Clinical Trials Network (NCTN)

1:1

N = 1224 • Progressive

chemonaïve mCRPC patients

• Asymptomatic or mildly symptomatic

• PS 0-1

Enzalutamide 160 mg QD

Enzalutamide 160 mg QD Abiraterone Acetate 1000 mg QD

Prednisone 5 mg BID

Primary Endpoint: • Overall survival

Secondary: • PFS • Radiographic PFS • PSA response • Objective response • Toxicity

UCDCC#243: Enzalutamide + Metformin Trial (PI: CP Evans)

SCREENING

Day -28 to -1

Patients with

progressive

CRPC, prior

chemotherapy

allowed¥,

ECOG 0-2,

serum

testosterone

must be at

castrate levels

(< 50 ng/dL)

within 14 days

prior to

registration

Meta-

static

Soft

Tissue or

Bone

Biopsy¥

“3+3”

DOSE

ESCALATION

DLT with expanded

cohort of 6 patients

(Maximum of 24

patients with up to

18 of the patients at

MTD expansion)

PROGRESSION*

(measured by

PSA and

radiographic

disease

progression for

soft tissue and

bone disease)

*optional

metastatic soft

tissue or bone

biopsy

(only if consent is

obtained)

End of Treatment

Initiation of cytotoxic or

investigational therapy

Intolerable adverse event

Any seizure

Creatinine, LFTs, ANC, or

platelet values that mandate

discontinuation

Gross noncompliance or

violation

PFS endpoint reached: treatment

may continue if not starting cytotoxic or

investigational therapy

Confirmed PSA progression

Confirmed bone disease

progression on Week 13 bone scan

Bone disease progression

on Week ≥ 25 bone scan

Soft tissue disease progression

on CT scan or MRI

FOLLOW-UP

Every 4 weeks

after progression

or discontinuation

of treatment

(total 12 weeks)

* Discontinuation

due to DLT,

continue to follow

every 4 weeks

until AE is stable

or resolved.

¥ CRPC patients who have been treated with docetaxel chemotherapy (and abiraterone pre-chemotherapy is

acceptable) will have a radiographic metastatic soft tissue or bone biopsy, which is mandatory at screening and

optional at progression. Abiraterone may have only been given pre-chemotherapy.

Androgen Receptor Splice Variants

Some variants still constitutively active as transcription factor despite lack of LBD

AR Splice Variant Mediated Resistance

Nelson, NEJM 2014

Antoranakis, NEJM 2014

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4

6 injections at 4-week intervals

Radium-223 dichloride (50 kBq/kg) +

best standard of care†

Placebo (saline) + best standard of care†

•Total ALP: < 220 U/L vs. ≥ 220 U/L •Bisphosphonate use: Yes vs. No •Prior docetaxel: Yes vs. No

•Confirmed Symptomatic CRPC

•≥2 bone metastases

•No known visceral metastases

•Post-docetaxel or unfit for docetaxel*

Radium 223 Phase III Study Design1

Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

*Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable †Best standard of care defined as a routine standard of care at each center, eg. local external beam radiotherapy, corticosteroids, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole

PATIENTS STRATIFICATION

R

A

N

D

O

M

I

Z

E 2:1

N=921

TREATMENT PHASE

>100 centers in 19 countries Planned follow-up is 3 years

Radium-223 dichloride (n = 614)

Placebo (n = 307)

Median OS (months)

14.9 11.3

HR 0.695

95% CI 0.581–0.832

P value 0.00007

Radium 223: Overall Survival

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

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

0

10

20

30

40

50

60

70

80

90

100

Pa

tien

ts (

%)

Treatment Radium-223 dichloride Placebo

3.6 month OS benefit

Reference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

Ran

do

miz

e

Mitoxantrone 12 mg/m2

Prednisone 10 mg q day

Q 21 days up to 10 cycles

Docetaxel 75 mg/m2

Prednisone 10 mg q day

Q 21 days up to 10 cycles

Docetaxel 30 mg/m2/wk

Prednisone 10 mg q day

5 on; 1 off x 6 cycles N=1006

TAX 3271

SWOG 99162

Random

ize

Mitoxantrone 12 mg/m2

Prednisone 5 mg bid

Q 21 days

Docetaxel 60 mg/m2 d 2

Estramustine 280 mg d1-5*

Dexamethasone 20 mg, tid d 1 & 2

N=770

*Warfarin and aspirin

Pivotal Docetaxel CRPC Trials

1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.

0%

20%

40%

60%

80%

100%

0 12 24 36 48 Months

D+E

M+P

# at

Risk

338

336

# of

Deaths

217

235

Median in Months

18

16

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

S9916: Overall Survival

Docetaxel q 3 wk

Weekly Docetaxel

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Phase III Trials of Docetaxel Combinations in CRPC

Docetaxel/Pred vs

Docetaxel Combined

With:

Status Results

DN-101 Terminated early Negative

GVAX Terminated early Negative

Bevacizumab Completed Negative

VEGF-Trap Completed Negative

Atrasentan Completed Negative

ZD4054 Completed Negative

Dasatinib Completed Negative

Lenalidomide Completed Negative

Custersin (OGX-011) Completed Negative

To date, no combination improves on docetaxel and pred

Cabazitaxel vs. Mitoxantrone in Post-Docetaxel CRPC Setting

MP 377 300 188 67 11 1

CBZP 378 321 231 90 28 4 Number

at risk

Proportion of OS (%)

80

60

40

20

0

100

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

15.1 12.7 Median OS (months)

0.59–0.83 95% CI

<.0001 P-value

0.70 Hazard Ratio

CBZP MP

E3805 – CHAARTED

Chemotherapy in Hormone Sensitive Prostate Cancer

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 maximum

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

Sweeney, ASCO 2014

N = 790

High Extent: > 4 bone mets, visceral mets

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

ba

bility

Presented by: Christopher J. Sweeney, MBBS

HR=0.61 (0.47-0.80) p=0.0003

Median OS:

ADT + D: 57.6 months

ADT alone: 44.0 months

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

ba

bility

OS by extent of metastatic disease at start of ADT

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

Presented by: Christopher J. Sweeney, MBBS

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

Conclusions

• Taxanes are active against prostate cancer – Docetaxel SOC in “high-volume” metastatic HSPC and CRPC

– Cabazitaxel improves OS in post-docetaxel CRPC setting

• AR-targeted therapies (Enzalutamide, Abiraterone) improve survival – Resistance mechanisms include selection of AR-splice variants

• Radium 223 and Sipuleucel-T improve survival in select CRPC subsets

• Optimal sequence of therapies is undefined