Daniel P. Petrylak, MD Professor of Medicine and Urology

Smilow Cancer Center

Yale University Medical Center

New Haven, Connecticut

How Far Have We Come

in Managing CRPC?

Sequencing Castration-Resistant Prostate Cancer (CRPC) Therapy–2010

Zoledronic acid with CRPC (metastatic disease)

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel (D)

chemotherapy

Secondary

hormonal

treatment

Docetaxel Mitoxantrone best supportive care

not known 3 months not known

Survival

benefit

Enzalutamide – 2.2 months

Abiraterone – 5.2 months

Ra 223 – 4.6 months

Sequencing CRPC Therapy–2015

Abiraterone or Cabazitaxel acetate (AA)

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel

chemotherapy

Secondary

hormonal

treatment

Docetaxel

not known 3 months not known

Sipuleucel-T Docetaxel

4 months 3 months 4 months 2.5 months

Denosumab or Zoledronic acid with CRPC (metastatic disease)

Survival

benefit

Survival

benefit

Mitoxantrone

best supportive care 2010

2014

Enzalutamide – 4.8 months

Ra 223 – 3.1 months

Classes of Agents

• Immunotherapeutic

– Sipuleucel T

• Hormonal

– Enzalutamide, abiraterone , ?docetaxel

• Cytotoxic

– Docetaxel, cabazitaxel

• DNA damage

– Ra 223

How Do We Sequence These Agents?

• Clinical characteristics

– Symptomatic vs asymptomatic

– Visceral vs non visceral

– Pre vs post docetaxel

• Biological markers

– Androgen receptor

– TRPMSS2-ERG

Immunotherapy

IMPACT Overall Survival (OS): ITT Population

Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422.

P =.032 (Cox model)

HR = 0.775 [95% CI: 0.614, 0.979]

Median Survival Benefit = 4.1 months

Sipuleucel-T (n = 341)

Median Survival: 25.8 months

Placebo (n = 171)

Median Survival: 21.7 months

Hormonal Therapy

Development of Castrate-Resistant Prostate Cancer

THERAPEUTIC FAILURE

AR CRPC

development

RESTORED AR ACTIVITY

(rising PCa)

DHT DHT

AR CoACT

Alternative

splicing

Aberrant

modification

-growth factor,

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

Knudsen KE, et al. Trends Endocrinol Metab. 2010;21(5):315-324.

AR, androgen receptor; AC, acetylation; P, phosphorylation; Sumo, sumoylation; CoAct, coactivators;

CoR, corepressors; T, testosterone; PSA, prostate specific antigen)

Abiraterone Acetate: Androgen Biosynthesis Inhibitor

Pregnenolone

DHEA Androstenedione Testosterone DHT

17-OH-

Pregnenolone Cortisol

Aldosterone

Androgens

Cholesterol

Abiraterone

Abiraterone

DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone

COU 301: Overall Survival

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 <.001

Placebo

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Overa

ll S

urv

ival

(%)

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. Presented at: European

Multidisciplinary Cancer Congress; September 23-27, 2011; Stockholm, Sweden. Abstract 7000.

COU 302: Abiraterone Acetate Phase III Trial in Chemonaïve mCRPC

• Phase III multicenter, randomized, double-blind,

placebo-controlled study conducted at 151 sites

in 12 countries; USA, Europe, Australia, Canada

• Stratification by ECOG PS 0 vs 1

1:1

N = 1088

•Progressive chemo

naïve metastatic

CRPC patients

•Asymptomatic or

mildly symptomatic

Abiraterone acetate

1000 mg daily

Prednisone 5 mg bid

n = 546

Placebo daily

Prednisone 5 mg bid

n = 542

Primary endpoints:

• Radiographic progression-

free survival (rPFS) by

central review

• OS

Secondary:

• Time to opiate use

(cancer-related pain)

• Time to initiation of

chemotherapy

• Time to ECOG PS

deterioration

• Time to PSA progression

Ryan CJ, et al. Lancet Oncol. 2015;16(2):152-160. Saad F, et al. Presented at: American Urological

Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 713.

ECOG PS, Eastern Cooperative Oncology Group performance status

Statistically Significant Improvement Over Placebo in rPFS and All Secondary Endpoints

Patient reported outcomes favored AA + prednisone vs placebo + prednisone

Full data to be reported *Prespecified alpha level 0.0035

Note: All secondary end points remain significant after adjusting for multiplicity testing

Outcome

AA + prednisone

Median, months

Placebo + prednisone

Median, months HR (95% CI) P value

rPFS 16.5 8.3 0.53 (0.45, 0.62) <.0001

OS 35.3 30.1 0.79 (0.66, 0.96) .0151 *

Time to opiate use

(cancer related pain) Not reached 23.7 0.71 (0.59, 0.85) .0002

Time to chemo initiation 26.5 16.8 0.61 (0.51, 0.72) <.0001

Time to ECOG PS

deterioration 12.3 10.9 0.83 (0.72, 0.94) .0052

Time to PSA progression 11.1 5.6 0.50 (0.43, 0.58) <.0001

Ryan CJ, et al. Lancet Oncol. 2015;16(2):152-160. Saad F, et al. Presented at: American Urological

Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 713.

Final Overall Survival Analysis of COU-AA-302, a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-

Resistant Prostate Cancer Patients Without Prior Chemotherapy

• Median follow-up of 49.2 months

• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)

100

80

60

40

20

0

0

Ove

rall

Su

rviv

al,

%

9 21 30 48 60 39

546

542

525

509

422

401

296

261

59

42

0

0

Abiraterone

Prednisone

202

148

Time to Death, Months 24 12 3 36 45 54

538

534

453

438

359

322

189

132

15

10

HR (95% CI): 0.81 (0.70-0.93)

P value: .0033

Prednisone, 30.3 months

Abiraterone, 34.7 months

6 15 18 27 33 42 51 57

0

1

118

84

218

176

504

493

483

466

394

363

330

292

273

227

235

201

Ryan CJ, et al. Lancet Oncol. 2015;16(2):152-160. Saad F, et al. Presented at: American Urological

Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 713.

Enzalutamide

• Oral drug rationally

designed to target AR

signaling, impacting

multiple steps in AR

signaling pathway

• No demonstrated agonist

effects in preclinical

models

Tran C, et al. Science. 2009;324(5958):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 Prolonged Survival, Reducing Risk of Death

Scher HI, et al. N Engl J Med. 2013; 367(13):1187-1197.

Median OS Δ: 4.8 months

37% reduction in risk of death

Enzalutamide Placebo

Median OS,

months 18.4 13.6

Hazard ratio 0.63

95% CI 0.53, 0.75

P value <.001

100

90

80

70

50

40

30

20

60

10

0

0 3 6 9 12 15 18 21 24

Duration of Overall Survival, Months

Su

rviv

al, %

Primary endpoint: OS and PFS

Enzalutamide 160mg QD

Placebo QD

PREVAIL Phase III Trial of Enzalutamide in Asymptomatic or Mildly Symptomatic

Metastatic CRPC Prechemotherapy

R

A

N

D

O

M

I

Z

E

1:1

mCRPC

asymptomatic or

mildly

symptomatic

patients

<4 BPI

(n = 1680)

Fully accrued

National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/results?term=NCT01212991.

Accessed: May 27, 2015.

PREVAIL: Overall Survival

Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

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 <.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%

AR-V7, the most important AR transcriptional variant, is

expressed at detectable levels of circulating tumor cells

in a significant proportion of CRPC patients

AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer

Outcome AR-V7[–] → AR-V7[–]

(n = 36)

AR-V7[–] → AR-V7[+]

(n = 6)

AR-V7[+]→ AR-V7[+]

(n = 16)

PSA response 68%

(95%CI, 52%-81%)

17%

(95%CI, 4%-58%)

0%

(95%CI, 0%-19%)

PSA PFS 6.1 months

(95%CI, 5.9 months-NR)

3.0 months

(95%CI, 2.3months-NR)

1.4 months

(95%CI, 0.9-2.6 months)

PFS 6.5 months

(95%CI, 6.1 months-NR)

3.2 months

(95%CI, 3.1 months-NR)

2.1 months

(95%CI, 1.9-3.1 months)

Antonarakis E, et al. N Engl J Med. 2014;371:1028-1038.

What About Corticosteroids (CS)?

Advantages and Disadvantages of Corticosteroid Therapy in

Prostate Cancer

• Advantages

‒ Independent antitumor activity

‒ Palliation of pain

• Disadvantages

‒ Antagonism with

immunotherapeuticagents

‒ ?Marks for worse prognosis

AFFIRM: Phase III randomized study of enzalutamide versus placebo

in patients with metastatic CRPC post-docetaxel (N = 1199)

• CS use was allowed but not required

Analysis: Effect of baseline CS use on outcomes

• 30% of patients on CS at study entry

• Patients on CS had poor prognostic features compared other patients

• Multivariate analysis incorporating known prognostic factors was

carried out

Conclusion: CS use at baseline increased risk of death and

progression independent of other prognostic factors

• Overall survival, HR (95% CI) = 0.54 (0.45, 0.64)

(- CS use vs + CS use, P<.0001)

CS and Prostate Cancer: AFFIRM Data

Chemotherapy

10th Anniversary of Docetaxel Plenary Presentations

Chemotherapy

• Formerly reserved for patients who are

– Symptomatic

– Rapidly progressive

– Visceral disease

• Now should be considered for patients

with extensive disease at the initiation of

androgen blockade

TAX-327 and SWOG 9916: Overall Survival

The standard of care for CRPC changed from mitoxantrone/prednisone to

docetaxel/prednisone based on TAX-327 and SWOG 9916 studies1,2

SWOG 99-16: Docetaxel/estramustine

improved median survival by 2 months

vs mitoxantrone/prednisone2

TAX-327: Docetaxel improved survival and rates

of response in terms of pain, PSA level, and

quality of life vs mitoxantrone/prednisone1

100

80

60

40

20

0

OS

, %

Months

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

Docetaxel

q3w

Weekly

docetaxel

Mitoxantrone

100

80

60

40

20

0

OS

, %

P = .02

Months

48 0 12 36 24

Docetaxel + estramustine

(217 deaths; median: 17.5 months)

Mitoxantrone

+ prednisone

(235 deaths; median:

15.6 months)

OS, overall survival

1. Tannock TF, et al. N Engl J Med. 2004;351(15):1502-1512. 2. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520.

Delay in Chemotherapy Initiation Due to Newly Approved Hormonal Agents

• COUGAR 302: Abiraterone/prednisone vs

placebo/prednisone

– Delay 8.6 months

• PREVAIL: Enzalutamide vs Placebo

– Delay 17.2 months

Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. Beer T, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA1.

E3805–CHAARTED Treatment

STRATIFICATION

Extent of metastases

-High vs Low

Age

≥70 vs <70 years old

ECOG PS

- 0-1 vs 2

CAB> 30 days

-Yes vs No

SRE prevention

-Yes vs No

Prior adjuvant ADT ≤12 vs >12 months

Randomize

ARM A:

ADT + docetaxel

75mg/m2 every

21 days for

maximum 6 cycles

ARM B:

ADT (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

Chemo 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

N = 790

Sweeney C, et al. J Clin Oncol. 2014;32(5s): Abstract LBA2.

CAB, combined androgen blockade; SRE, skeletal-related event; ADT, androgen deprivation therapy;

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 =.0003

Median OS:

ADT + docetaxel: 57.6 months

ADT alone: 44.0 months

Sweeney C, et al. J Clin Oncol. 2014;32(5s): Abstract LBA2.

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

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

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

improvement in median OS 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 =.0006

HR =.60 (0.45-0.81)

Median OS:

ADT + docetaxel: 49.2 months

ADT alone: 32.2 months

P = .1398

HR =.63 (0.34-1.17)

Median OS:

ADT + docetaxel: Not reached

ADT alone: Not reached

Sweeney C, et al. J Clin Oncol. 2014;32(5s): Abstract LBA2.

Pro

ba

bilit

y

Pro

ba

bilit

y

OS, Months OS, Months

Androgen Deprivation +/-

Docetaxel: GETUG-AFU 15

Median

survival (months)

ADT: 54.2 (50.8-69.1)

ADT + D: 58.9 (42.2-NR)

Biochemical PFS,

and clinical PFS

were improved in

the docetaxel arm

Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

Phase III Trials of Docetaxel Combinations

Docetaxel/prednisone

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 prednisone

TROPIC: Phase III Registration Study 146 Sites in 26 Countries

Primary endpoint: OS

Secondary endpoints: 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 factors ECOG PS (0, 1 vs 2) Measurable vs non measurable disease

Metastatic CRPC patients who progressed during and after treatment with a docetaxel-based regimen

(N = 755)

Primary Endpoint: Overall Survival (ITT Analysis)

MP 377 300 188 67 11 1

CP 378 321 231 90 28 4

Number at risk

Pro

po

rtio

n o

f O

S (

%) 80

60

40

20

0

100

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

de Bono JS, et al. Lancet. 2010;376(9747):1147-1154.

Mitoxantrone

+ prednisone

(MP)

Cabazitaxel +

prednisone

(CP)

Median

OS, months

12.7 15.1

HR 0.70

95% CI 0.59–0.83

P value <.0001

Ongoing Trials

• FIRSTANA

– Docetaxel 75 mg/m2

– Cabazitaxel 25 mg/m2

– Cabazitaxel 20 mg/m2

• PROSELICA

– Cabazitaxel 25 mg/m2

– Cabazitaxel 20 mg/m2

Bone Targeted Agents

*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 (eg, stilbestrol), estramustine, or ketaconazole

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

Z

E

D

2:1

N = 921

PATIENTS

• Confirmed

symptomatic

CRPC

• ≥ 2 bone

metastases

• No known

visceral

metastases

• Post-

docetaxel or

unfit for

docetaxel*

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

Clinicaltrials.gov identifier: NCT00699751

• Total ALP:

<220 U/L vs ≥220 U/L

• Bisphosphonate use:

Yes vs No

• Prior docetaxel:

Yes vs No

STRATIFICATION

Parker C, et al. N Engl J Med. 2013;369(3):213-223.

ALSYMPCA: Overall Survival

Radium 223

Median OS: 14.9 months

Placebo

Median OS: 11.3 months

HR = 0.70

95% CI, 0.58, 0.83

P<.001

Months 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

%

Parker C, et al. N Engl J Med. 2013;369(3):213-223.

Have We Optimized Androgen

Receptor Pathway Targeted

Therapy?

Karim Fizazi, MD, PhD

The Rebirth of Bone-Targeted

Therapy for Metastatic CRPC

Neal D. Shore, MD, FACS