1

Castration Resistant Prostate Cancer

Charles J Ryan, MDAssociate Professor of Medicine and Urology

Helen Diller Family Comprehensive Cancer CenterUniversity of California, San Francisco

UCSF

1. How do we define Castration Resistant Prostate Cancer?

Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL)

2. What makes prostate cancer lethal and how do we assess prognosis in patients?

+ = Lethal Prostate cancer

Lethal Prostate Cancer = Castration Resistant AND Metastatic

“Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”

Nobel Lecture. Dec 13, 1966

Lymph Node

Bone Metastasis

Overview of Treatment Options for CRPC

Immunotherapy

Chemotherapy

mCRPC1st line

Chemotherapy

Androgen Synthesis Inhibitor

mCRPC postDocetaxel

Sipuleucel T (Prostvac Tricom- phIII)

Docetaxel

Abiraterone (Standard)

Abiraterone (Tak 700)

Cabazitaxel

mCRPCPre- Chemotherapy

Mitox-antrone

Androgen Deprivation

(LHRH)Leutinizing Hormone Releasing Hormone Agonists/ Antagonists

Sipuleucel T (Asymptomatic or

Minimally Symptomatic)

Non-metCRPC

Anti-Apoptosis

Tyrosine Kinase Inhibitor

Androgen Receptor

Antagonist

Radio-isotopes (Alpharadin) (Alpharadin)

(Cabozantanib)

OGX-011 +Docetaxel

Enzalutamide(Enzalutamide)

(ARN-509)

The Human Endocrine System Drives Prostate Cancer Growth

Hypothalamus (Brain)

LHRH

Pituitary Gland

FSH, LH

Testicles

Testosterone

DHT

PROSTATE CANCER CELLS

Adrenal gland

Ketoconazole

Antiandrogens: Casodex FlutamideNilutamide, MDV3100, ARN-509

orchiectomy

LHRH agonists(Lupron, Zoladex)

Estrogen

Abiraterone

TAK-700

New Treatments for Advanced Prostate Cancer

UCSF

Androgen Synthesis InhibitorsAR antagonists

Second line chemotherapyC-Met inhibitor (?)

Radio-isotopes

New Treatments for Advanced Prostate Cancer

UCSF

Targeting the T Cell

Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy

· Cytotoxic chemotherapy quickly debulks tumors– Resistance and tumor

regrowth may occur · Immunotherapy activates the

immune system– Clinical effect may take

time to develop– Responses may be

sustained due to immunologic memory

Time

Chemotherapy

Immunotherapy

Time ontreatment

Tum

or s

ize

Progression

Webster et al. J Clin Oncol. 2005;23:8262.

Provenge: Background

Small EJ et al., J Clin Oncol 18: 3894, 2000

Provenge: (second) Pivotal Trial Results

†Control was nonactivated, autologous, peripheral blood mononuclear cells.

Kantoff PW et al. N Engl J Med. 2010;363:411-422. UCSF

Adverse Events

Phase 3 design allowed for crossover from placebo to vaccine

Provenge: (second) Pivotal Trial Results: Peak effect at 3 years

Kantoff PW et al. N Engl J Med. 2010;363:411-422. UCSF

Sipuleucel-T in CRPC: How do we use it?

• Sipuleucel-T prolongs life in patients with asymptomatic met CRPC

• Sipuleucel-T is extremely well tolerated

• For use only in asymptomatic CRPC with no visceral mets

• Not remission inducing

• My bias – use it early before advancing to prednisone-containing regimens (abiraterone, docetaxel, cabazetaxel, mitoxantrone all require steroids)

UCSF

ProstVac-VF: Antigen-Specific Immunotherapy

Drake. Nat Rev Immunol. 2010;10(8):580-593.

ProstVac-VF: Phase 2 Trial

Asymptomatic or minimally symptomatic

mCRPC(N = 125)

ProstVac-VF TriCom + GM-

CSF (n = 84)

Empty vector + Placebo (n = 41)

PROGRESSION

SURVIVAL

Treated at physician’s discretion

Treated at physician’s discretion

Crossover

Kantoff et al. J Clin Oncol. 2010;28(5):1099-1105.

2:1

Overall survival.

Kantoff P W et al. JCO 2010;28:1099-1105

©2010 by American Society of Clinical Oncology

Prostvac randomized phase II – Overall Survival

New Treatments for Advanced Prostate Cancer

UCSF

CYP-17 Inhibitors

Matching Biology to Therapy along the Path to AR signaling

Androgen Production

AR Binding

Signaling Event Intervention

Conversion to DHT

Androgen Transport/

Circulation/Uptake

SCC InhibitorsCYP 17

Inihibitors

Block Transport

5-Alpha Reductase inhibitors

Ketoconazole -AbirateroneTak-700 Tok-001

Drugs

Dutasteride

MDV-3100ARN-509Tok-001

Novel AR Inhibitors

Pre

-Rec

epto

r R

ecep

tor

Intracrine Production

Polymorphisms

Amplified 5 Alpha Reductase

Amplified ARSplice Variant AR

Aberration

None

Prostate Cancer can make its own androgens

Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447-54

20

COU-AA-301: Abiraterone Acetate Improves Overall Survival in post chemotherapy mCRPC

HR = 0.646 (0.54-0.77)P < 0.0001

Abiraterone acetate: 14.8 months

Placebo: 10.9 months

0 100 200 300 400 500 600 7000

20

40

60

80

100

AAPlacebo

Su

rviv

al (

%)

Days From Randomization

AA 797 728 631 475 204 25 0

Placebo 398 352 296 180 69 8 1 UCSF

Overall Study Design of COU-AA-302

• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada

• Stratification 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

Efficacy end points

Placebo dailyPrednisone 5 mg BID

(Actual n = 542)

RANDOMIZED

1:1

• Progressive chemo-naïve mCRPC patients(Planned N = 1088)

• Asymptomatic or mildly symptomatic

Patients

Ryan et al Proc ASCO 2012

Treatment Arms Evenly MatchedAA + P

(n = 546)Placebo + P

(n = 542)

Median age, years (range) 71 (44-95) 70 (44-90)

Median time from initial diagnosis to first dose (years) 5.5 5.1

Median PSA (ng/mL) 42.0 37.7

Median testosterone (ng/dL) 4.0 4.0

Median alkaline phosphatase (IU/L) 93.0 90.0

Median hemoglobin (g/dL) 13.0 13.1

Median lactate dehydrogenase (IU/L) 187.0 184.0

Gleason score (≥8) at initial diagnosis 53.9% 50.0%

Extent of disease

Bone Metastases >10 bone lesions

Soft tissue or node

83%

48%

49.1%

80%

47%

50%

Pain (BPI Short Form)

0-1

2-3

66%

32%

64%

33%

Ryan et al Proc ASCO 2012

Statistically Significant Improvement in rPFS Primary 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 Proc ASCO 2012

Strong Trend in OS Primary End Point

Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008.

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)

33

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

Data cutoff 12/20/2011.

Ryan et al Proc ASCO 2012

Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone

25

• 29% of patients on the prednisone control arm had a decline in PSA by ≥ 50%• 69% of patients on the abiraterone arm had a decline in PSA by ≥ 50%

-25

Ma

xim

al

De

cli

ne

Fro

m B

as

eli

ne

(%

)

-50

-75

-100

0

25

50

75

100

Abiraterone + Prednisone Placebo + Prednisone

IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.

Serologic and Clinical ResponsesAA + P

(n = 546)Placebo + P

(n = 542) RR (95% CI) P Value

PSA decline ≥50% 62% 24% NA <0.0001

N=220 N=218

RECIST: Defined objective response

Complete response

Partial response

Stable disease

Progressive disease

36%

11%

25%

61%

2%

16%

4%

12%

69%

15%

2.273 (1.591, 3.247)

<0.0001

Ryan et al Proc ASCO 2012

Time to All Landmarks Favored Abiraterone

Baseline PSA

ProgressionTumor/Bone Progression

Pain

Death

Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.

Chemotherapy

ECOG PS Decline

Primary Endpoints: rPFS and OS

Secondary Endpoints

ECOG PS = Eastern Cooperative Oncology Group Performance Status.

24-48 months

p = 0.001p < 0.0001 p = 0.0053p < 0.0001

p < 0.0001 p = 0.0097

Ryan et al Proc ASCO 2012

Abiraterone(months)

Prednisone(months) P Value Hazard Ratio

(95% CI)

FACT-G 16.6 11.1 0.002 0.76(0.63-0.91)

PCS 11.1 5.8 < 0.001 0.70(0.60-0.83)

Physical well-being 14.8 11.1 0.002 0.76(0.64-0.90)

Functional well-being 13.3 8.4 0.001 0.76(0.64-0.90)

Emotional well-being 22.1 14.2 0.001 0.71 (0.59-0.87)

Social/Family well-being 18.4 16.6 0.528 0.94(0.78-1.14)

Median Times to Functional Status Degradation

Basche et al Proc ESMO 2012

Can we cure prostate cancer medically?

AA and LHRHa in Newly Diagnosed Intermediate and High Risk CaP Undergoing Radical Prostatectomy

Newly Diagnosed Intermediate and

High Risk CaP• Positive biopsies (≥ 3)• Gleason score ≥ 7 (4 + 3),

T3, PSA ≥ 20 ng/mL or• PSA velocity > 2 ng/mL/yr

12 weeks AA/ LHRHa/pred

Radical Prostatectomy

• Pathologic response• Prostate androgen levels• AR signaling

Confirm pathology

12 weeks LHRHa

Biopsy• Pathology• Prostate androgen

levels (primary aim)

• AR signaling

12 weeks AA/LHRHa/pred

5 mg qd

Supported by grants from Janssen R&D (formerly Ortho Biotech Oncology R&D [unit of Cougar Biotechnology]) and from a Prostate Cancer Foundation Challenge Award to Drs Balk and Nelson.

AA, abiraterone acetate; LHRHa, leuprolide acetate; pred, prednisone.

Taplin et al Proc ASCO 2012

Pathology Results12 weeks AA/

24 weeks LHRHa (n = 28)

24 weeks AA/24 weeks LHRHa

(n = 30)

Results n = 27 n = 29 p Value

pCR 1/27 (4%) 3/29 (10%) 0.6120

Near CR (tumor ≤ 5 mm) 3/27 (11%) 7/29 (24%) 0.2992

Total pCR/near pCR 4/27 (15%) 10/29 (34%) 0.0894

pT3 16/27 (59%) 14/29 (48%) -

Positive nodes 3/27 (11%) 8/29 (28%) -

Positive margins 5/27 (19%) 5/29 (17%) -

Taplin et al Proc ASCO 2012

Abiraterone in CRPC: How do we use it?

• Abiraterone prolongs life in patients with met CRPC pre and post chemotherapy

• Treatment delays the need for chemotherapy, time to pain, preserves QOL

• Can it be combined with other therapies? Should it be continued after disease progression?

• What are the mechanisms of resistance?– Pharmaco-kinetic? – Pharmaco-genomic?– Alternate signaling paths?– AR mediated progression?

UCSF

Enzalutamide

• Second-generation AR antagonist

• Binds AR more potently than does bicalutamide

• Not a partial agonist of AR

• Inhibits translocation of AR into nucleus and decreases AR binding to DNA

• Oral agent; 160 mg daily (seizures at higher doses)

• Compared with placebo in ongoing randomized phase 3 trial (post-chemotherapy, ketoconazole-naïve)

Tran et al. Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. Scher et al. Lancet. 2010;375(9724):1437-1446.

Enzalutamide (MDV3100)

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

• No demonstrated agonist effects in pre-clinical models.

Enzalutamide1

T

AR

T

Tumor Death

Cell nucleus

Inhibits Binding of Androgens to AR

Inhibits Nuclear Translocation of AR

Inhibits AssociationOf AR with DNA

AR

Cell cytoplasm

Tran et al. Science 2009;324:787–90.

2

3

35UCSF

Higher AR levels in CRPC tumors

AR expression in Bone Marrow Mets

Stanbrough et al Cancer Research 2006

Holzberlein et al Am J Pathology

At autopsy – 73% of 15 samples exhibit AR amplification.

Friedlander/Paris et al

CRPC samples have robust AR expression Mohler et al

MDV-3100Time to PSA Progression

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

MDV3100 160 mg once daily + prednisone 5 mg twice daily

Placebo once daily + prednisone 5 mg twice daily

RANDOMIZE

N = 1170

Men with docetaxel-pretreated mCRPC (keto-naïve)

2

1

Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010.

Primary objective: OS

Enzalutamide - AFFIRM

Kaplan–Meier Estimates of Primary and Secondary End Points in the Intention-to-

Treat Population.

Scher HI et al. N Engl J Med 2012. DOI: 10.1056/NEJMoa1207506

MDV3100: Phase 3 Trial (AFFIRM)

Combination Phase III: Alliance: A031201 - PI Michael Morris

Total of 616 deaths, log-rank statistic 90% power (one sided type I error rate of 0.025) to detect HR of 0.77 in favor of arm B

Stratification factor: prior chemo

Arm A:Enzalutamide

Arm B:

EnzalutamideAbirateronePrednisone

ARN-509 in Men with High Risk Non-Metastatic Castration-Resistant Prostate Cancer

Abstract 107237

Smith MR,1 Antonarakis ES,2 Ryan CJ,3 Berry W,4 Shore ND,5 Liu G,6 Alumkal J,7 Higano C,8 Chow Maneval E,9 Rathkopf DE10

1 Massachusetts General Hospital and the Harvard Medical School, Boston, MA; 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; 3UCSF Helen Diller Family Comprehensive Cancer

Center, San Francisco, CA; 4 Cancer Centers of North Carolina, Raleigh, NC; 5Carolina Urologic Research Center, Myrtle Beach, SC; 6University of Wisconsin Carbone Cancer Center, Madison, WI; 7Oregon Health & Science

University Knight Cancer Institute, Portland, OR; 8Seattle Cancer Care Alliance and the University of Washington, Seattle, WA; 9Aragon Pharmaceuticals, San Diego, CA; 10Sidney Kimmel Center for Prostate and Urologic Cancers,

Memorial Sloan-Kettering Cancer Center, New York, NY

Background ARN-509 is a potent and selective antagonist of the androgen

receptor (AR) that is being developed for the treatment of men with castration-resistant prostate cancer (CRPC)

ARN-509 inhibits AR nuclear translocation and DNA binding to androgen response elements

In contrast to bicalutamide, ARN-509 shows no significant

agonist properties in the context

* Clegg N et al., Cancer Res 2012; 72:1-10

In murine tumor models of CRPC, ARN-509 showed dose-dependent tumor regressions superior to bicalutamide

ARN -509 - Phase II Design

Here we report preliminary results for the cohort of high risk non-metastatic (M0) CRPC patients

47 patients were enrolled between Nov 2011 and Jun 2012

Data cut-off 10 Jan 2013

Patients received ARN-509 at 240 mg/day on a continuous 28-day dosing cycle

PSA assessments performed every month

Tumor assessments performed every 4 months

Post-Abi Metastatic

CRPC patients 1º Endpoint: 12-week PSA response2º Endpoints: Time to PSA Progression, safety

Tx-Naïve Metastatic

(n = 90)

Non-Metastatic (M0)

Smith MR, Proc GU ASCO 2013

ARN-509 - PSA Response

-100

-75

-50

-25

0

25

50

75

100

% C

hang

e in

PS

A f

rom

bas

elin

e

-100

-75

-50

-25

0

25

50

75

100

At 12 Weeks

At 24 Weeks

Smith MR, Proc GU ASCO 2013

Cabozantanib –cMET + VEGFr inhibitor

Smith et al JCO 2012

Cabozantanib –cMET + VEGFr inhibitor

Smith et al JCO 2012

Cabozantanib –cMET + VEGFr inhibitor

Smith et al JCO 2012

Cabozantanib –cMET + VEGFr inhibitor

http://www.cometclinicaltrials.com/index.html

New Treatments for Advanced Prostate Cancer

UCSF

Chemotherapy

Tax 327 Primary Objective: Overall Survival

OS Docetaxel: 18.2 p = 0.03

Mitoxantrone: 16.4 – –

Months

Prob

abil

ity

of S

urvi

ving

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

UCSF

Docetaxel Cabazitaxel (XRP6258)

(C45H57NO14)Cabazitaxel is a 7,10 dimethoxy analogue of docetaxel

Two Different Chemical Entities

Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance. Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com.

(C43H53NO14)Docetaxel is an esterified product

of 10-deacetyl baccatin III

The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients with metastatic CRPC previously treated with docetaxel (De Bono et al)

Primary objective: Overall survival

Secondary objectives: PFS (tumor progression, pain progression, PSA progression, or death from any cause), response rate, safety

Mitoxantrone 12 mg/m² q 3 wk+ prednisone for 10 courses (MP,

n=377)

Cabazitaxel 25 mg/m² q 3 wk+ prednisone for 10 courses (CBZP,

n=378)Men with metastatic CRPC progressing during and after

docetaxel(N=755)

RANDOMIZE

UCSF

Primary Endpoint (Overall Survival) Met

Time (months)

Pro

por

tion

of

OS

(%

)100

80

60

40

20

00 6 12 18 24 30

MP CBZP

Median OS (months) 12.7 15.1

Hazard ratio 0.72

95% CI 0.61–0.84

P-value <.0001

CensoredMPCBZP

Combined medianfollow-up: 13.7 months

UCSF

Summary of Hematologic AEs53

Hematologic AEsa JEVTANA® 25 mg/m² q 3 wk+ prednisone 10 mg qd (n=371)

mitoxantrone 12 mg/m² q 3 wk+ prednisone 10 mg qd (n=371)

Grade 1–4, n (%) Grade 3–4, n (%) Grade 1–4, n (%) Grade 3–4, n (%)Neutropeniab 347 (94%) 303 (82%) 325 (87%) 215 (58%)Febrile neutropenia 27 (7%) 27 (7%) 5 (1%) 5 (1%)Anemiab 361 (98%) 39 (11%) 302 (82%) 18 (5%)Leukopeniab 355 (96%) 253 (69%) 343 (93%) 157 (42%)Thrombocytopeniab 176 (48%) 15 (4%) 160 (43%) 6 (2%)

a In ≥5% of patients.b Based on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370).

JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.Data on file. Clinical study report/EFC6193 (TROPIC).

• Protocol did not permit primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) at cycle 1

Chemotherapy: How do we use it?

1. Palliation

2. Rapid progression/ Symptoms/ Need for ‘debulking’

3. Intermittent vs Continuous

4. Special populations - Anaplastic, Small cell etc

UCSF

New Treatments for Advanced Prostate Cancer

UCSF

Radium 223

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

Ra

Ca

Radium-223 Targets Bone Metastases

• Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1

– Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue

Range of alpha-particle

Radium-223

Bone surface

1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

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

• 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

Planned follow-up is 3 years

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 = 541Median OS: 14.0 months

Placebo, n = 268Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-0.875

P = 0.00185

SRE Prevention – Denosumab and Zoledronic acid both approved.

Fizazi et al, 2011.

Overarching Principles of CRPC management

• No Standards of care exist on how to manage patients without radiographic evidence of metastases.

• Maintain ADT in all patients (LHRH agonists/antagonist or orchiectomy)• Allowing asymptomatic mCRPC to go untreated until symptoms develop

is no longer advised given the efficacy and tolerability of new agents.• Consider bone targeted therapy in patients at risk for skeletal

combinations.• Consider that progression can be ‘mixed’ or in a focal site despite

systemic control of disease – focal sites of progression can be treated with radiation therapy.

• Molecularly driven treatment selection is being developed and enrollment in clinical trials that test this is ideal.