how far have we come in managing crpc? · crpc development restored ar activity (rising pca) dhtdht...

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



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



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


3.2 months


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


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


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


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


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


• PROSELICA



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

how far have we come in managing crpc? · crpc development restored ar activity (rising pca) dhtdht...

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