11/14/2016

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1

Integrating Current & Novel Treatment Strategies for the Management of CRPC

Charles J Ryan, MDThomas Perkins Distinguished Professor of Medicine and Urology

Helen Diller Family Comprehensive Cancer CenterUniversity of California, San Francisco

UCSF

Progress in Metastatic Prostate Cancer

Survival

PalliationMitoxantrone

Zoledronic acid

Docetaxel

Denosumab

Sipuleucel-T

Cabazitaxel

Abiraterone

Enzalutamide

Radium-223

Samarium-153 Strontium-89

1992 1996 2000 2004 2008 2012

FDA Approvals in Castration-Resistant Prostate Cancer

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Available Treatment Agents forAdvanced Prostate Cancer 

Local therapy

Androgen deprivation therapy (ADT)

Therapies after ADT

Death

ADT

supportive care (egdenosumab/bisphosphonates)

mCRPCpost-

docetaxel

mCRPCsymptomatic

mCRPCmildly

symptomatic

mCRPCasymptomatic

(failed ADT)

Hormonesensitive

Sipuleucel-T

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Radium 223

EnzalutamideADT + Docetaxelin high-volume

disease?

1. How do we define Castration Resistant Prostate Cancer?

5

Testosterone 500 ng/mL

50 ng/mL

Castration Therapy

PSA

Castration Resistance

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?

5

Testosterone 500 ng/mL

50 ng/mL

Castration Therapy

PSA

Castration Resistance

+ = Lethal Prostate cancer

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What’s the Prognosis?

CRPC Chemo-naïve Prognostic Nomogram

Wide Range….

Halabi et al JCO 2014

5

Perisistent AR Signaling Pathway is the Pivotal Target of CRPC treatment

Anantharaman A, Friedlander TW. Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review. Urol Oncol. 2015 Dec 16.

Depiction of mechanisms of resistance to androgen deprivation therapy: • AR amplification• increased intratumoralandrogen synthesis

• hypersensitivity of AR• mutations of AR• alternative splicing of AR to constitutively active splice variants.

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Mechanism #1

UCSF

Immunotherapy

Provenge: Background

s

0

5

10

15

20

PS

A (

ng/m

L)

-10 0 10 20 30

Week

Sip-T

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

Antigen-loaded precursor APC

Precursor APC Maturing antigen-

loaded APC

In vivo T cell activation

T cells attack tumor cells

Infuse patient

APC8015

Antigen Processing

Antigen Loading

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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

†

• Primary endpoint: Overall survival1,2

• Secondary endpoint: Objective disease progression2

†

Adverse event PROVENGE (n=338)

Control (n=168)

All Grades (%)

Grades 3–5 (%)

All Grades (%)

Grades 3–5 (%)

Chills 54.1 1.2 12.5 0

Fever (pyrexia) 29.3 0.3 13.7 1.8

Headache 16.0 0.3 4.8 0

Influenza‐like illness 9.8 0 3.6 0

Myalgia 9.8 0.6 4.8 0

Hypertension 7.4 0.6 3.0 0

Hyperhidrosis 5.3 0 0.6 0

Groin pain 5.0 0 2.4 0

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

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Mechanism #2

UCSF

Targeting Persistent AR signaling

The Human Endocrine System Drives Prostate Cancer Growth

Hypothalamus (Brain)

LHRH

Pituitary Gland

FSH, LH

Testicles

Testosterone

DHT

PROSTATE CANCER CELLS

Adrenal gland

Antiandrogens: Casodex FlutamideNilutamide, Enzalutamide,Apalutamide

orchiectomy

LHRH agonists(Lupron, Zoladex)

Estrogen

Abiraterone

Abiraterone

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Model of AR Amplification as Mechanism of Resistance to Androgen Deprivation Therapy

Chen et al., 2004 Nature Medicine

3BHSD1 3BHSD2

UGT2B15 UGT2B17

SRD5A1 SRD5A2

AKR1C3 17BHSD3

CYP17A

P=0.0013 P=0.0031

P=0.0050 P=0.0004

P=0.0026 P<0.0001

P=0.0005 - 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091

BP CP METS BP CP METS

- 25 - 20 - 15 - 10 - 5 0 BP CP METS BP CP METS

5 - 20 - 15 - 10 - 5 0

BP CP METS BP CP METS

- 20 - 15 - 10 - 5 0 5 BP CP METS BP CP METS

- 25 - 20 - 15 - 10 - 5 0 BP CP METS

- 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091 BP CP METS BP CP METS

- - - - - - - 10 -

- - - -

- - - - -

1. Transcripts encoding steroidogenic enzymes are detected within tumor

2. Tumor androgens in CRPC metastases from anorchid patients exceed levels in prostate cancer tissues from eugonadal subjects

3. These may be particularly relevant for tumors with overexpressed AR

AR targeting:Abiraterone – Intracrine AndrogensEnzalutamide – AR amplification

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

CRPC samples have robust AR expression Mohler et al

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3BHSD1 3BHSD2

UGT2B15 UGT2B17

SRD5A1 SRD5A2

AKR1C3 17BHSD3

CYP17A

P=0.0013 P=0.0031

P=0.0050 P=0.0004

P=0.0026 P<0.0001

P=0.0005 - 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091

BP CP METS BP CP METS

- 25 - 20 - 15 - 10 - 5 0 BP CP METS BP CP METS

5 - 20 - 15 - 10 - 5 0

BP CP METS BP CP METS

- 20 - 15 - 10 - 5 0 5 BP CP METS BP CP METS

- 25 - 20 - 15 - 10 - 5 0 BP CP METS

- 25 - 20 - 15 - 10 - 5 0 P<0.0001 P=0.0091 BP CP METS BP CP METS

- - - - - - - 10 -

- - - -

- - - - -

Prostate Cancer can make its own androgens

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

Mostaghel et al. Urol Oncol 2009; 27(3): 251‐257

DHT, dihydrotestosterone; T, testosterone

The level of androgen in the tumor tissue

Serum testosterone  castration stage cannot completely eradicate androgens in PC environment

There are enough androgens within the tumor tissue to activate AR 

Testosterone Levels Within Metastases From the Castrate Men Exceeded Serum Levels

tAR

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11-deoxycortisol x 5 Cortisol x 2

DHEA-S < 15 μg/dLLLQ

HypokalemiaHypertensionFluid overloadRenin suppression

ACTH x 5

Abiraterone

Pregnenolone x 20Deoxycorticosterone x 60Corticosterone x 2Aldosterone

Negative feedback

Androstenedione Testosterone 1-2 ng/dL

17α-hydroxpregnenolone

Enzalutamide (Xtandi)

• 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

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

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Hormonally Driven ResistancePre‐Receptor (Ligand) and Receptor Events

Ryan, Tindall Journal of Clinical Oncology 2011

Pre‐Receptor Events:

Adrenal Androgen ProductionAnd Polymorphisms

IntracrineAndrogen Production

Receptor events:

AR Amplification and Mutation

AR Splice Variants

Two very active agents

Radiographic Progression-Free Survival (Months) 0 3 6 9 12 15 18 21

Rad

iog

rap

hic

Pro

gre

ssio

n-F

ree

Su

rviv

al (

%)

60

50

40

30

20

10

0

90

80

70

100

Enzalutamide Placebo

Hazard Ratio: 0.186 (95% CI: 0.15, 0.23) P<0.0001

Enzalutamide 872

Placebo 845 863 835

850

781

824

744

797

701

745

644

566

484

395

328

244

213

128

102

33

27

2

2

0

0

Duration of Overall Survival (Months)

Su

rviv

al (

%)

60

50

40

30

20

10

0

90

80

70

100

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

Enzalutamide Placebo

Hazard Ratio: 0.706 (95% CI: 0.60,0.84) P<0.0001

Patients at Risk

Patients still alive at data cut off Enzalutamide: 72%; Placebo: 63%

Abiraterone/Pred vs Prednisone Enzalutamide Vs Placebo

Ryan et al NEJM 2013, Lancet Onc 201                                                            Beer et al NEJM 2014

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Progress for Most ( 69% of patients respond to abiraterone)

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• 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 D

ecli

ne

Fro

m B

asel

ine

(%)

-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.

Time to All Landmarks Favored Abiraterone…for the population as a whole

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

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…But not a home run for  all

Ryan et al Proc ASCO 2013

A patient who does not respond to abiraterone has rPFSand OS no different from Tax 327 data of a decade ago.

• Kaplan‐Meier estimates of OS and HRs (relative to the good prognosis category) were determined

Who “Does Best” with Abiraterone/Enzalutamide?

Baseline risk factor p Value Hazard

ratio

BPI (2-3 vs 0-1) < 0.0001 1.71 (1.34-2.17)

LDH ( > ULN [234 IU/L] vs ≤ ULN) < 0.0001 2.03 (1.51-2.74)

ALP ( > ULN [131 IU/L] vs ≤ ULN) 0.0004 1.60 (1.23-2.08)

Bone metastases (≥ 10 vs < 10) < 0.0001 1.92 (1.49-2.47)

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Sequen cing: Retrospective Experience Abiraterone after  enzalutamide

Very Modest response 

Response to Abiraterone Therapy

Study N Sequence(order drugs administered)

PSA Response Enzalutamide 

Therapy(≥50%)

PSA Response(≥50%)

Median PFS Median OS

Ileana 2012 24 DocetaxelEnzalutamideAbiraterone

‐ 13% 2.4 months ‐

Noonan 2013

30 DocetaxelEnzalutamideAbiraterone

60% 3% 15.4 weeks 50.1 weeks

Loriot 2013 38 DocetaxelEnzalutamideAbiraterone

‐ 8% 2.7 months 7.2 months

HR=0.61 (95% CI: 0.43-0.87)p=0.0055

— abiraterone + prednisone (n=124)--- + prednisone (n=140)

Treatment with AA + P significantly prolonged OS to 53.6 months

placebo+prednison41.8m

COU-AA-302�randomized,�double-blind,�placebo-controlled�phase�III�clinical�study.�The�median�treatment�periodabiraterone�+�prednisone20.4m，placebo+prednisone11.2m（HR�0.41，95%CI�0.31-0.54，p<�0.0001）。

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Earlier Intervention for More Survival Benefits with 11.8 mo of OS Extended

Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11‐15 March 2016, Munich, Germany

2016 EAU COU-AA-302stratified analysis

Earlier Stage of Chemotherapy-naïve mCRPCsubjects:

[BPI] Short Form score 0-1

[PSA] < 80 ng/ml

[GS] Gleason score < 8

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Primary Resistance

CRPC

EnzalutamideOr Abiraterone

30% = Primary Resistance

Response

60+% = Acquired

Resistance:

Death Non-PC Cause

(?%) Resistance with Phenotypic Change:e.g. Neuro-endocrine

ASI= Androgen Synthesis InhibitorART = AR Targeted Therapy

Ryan Proc GU ASCO 2013

AR‐V7: AR SPLICE VARIANT “half AR” – Activated without Binding Androgen

Antonarakis ES. 2014 ASCO Annual Meeting. Abstract 5001.

NTD LBDHinge

CBP

DBD

CRPC contains variants which lack 

LBD

No current therapies can inhibit because they work 

through LBD

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AR Splice Variants (AR‐Vs)

AR-V13

AR-V1

AR-V2

AR-V3

AR-V4

AR-V5

AR-V6

AR-V7

AR-V8

AR-V9

AR-V12

AR-V14

AR-V10

AR-V11

31 7 82 4

66948516

6691451566905968

6694180566863249

66941675

5 6 9

6694352866944119

66931244

66931531

66942669

6694282666905852

66937320

66937464

CE4

6690084566900562

CE1

66909400

CE2

66912029

CE5

6691341266863098

1b

66915918

4155 nts

8753 nts

CE3

66763874

66766604

66788683

66788864

MTLGDNLPEQAAFWRHLHIFWDHVVKK stop

Transcripts Proteins

KALPDCERAASVHF stop

LFSINHT stop

SVQPITPDAMYL stop

1 2 3 CE1

1 2 3 CE13

1 2 CE13CE4

1 2 CE13CE43

1 2 CE23

1 2 CE23

1 2 CE33

1 2 3

1 2 CE53

1 2 93 4 8

1 2 93 4 5 6

1 2 93 4 5 6

MTLGAVVVSERILRVFGVSEWOP stop

MTLGAVVVSERILRVFGVSEWOP stop

RAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

MTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

MTLGD stop

MTLGAGSRVS stop

MTLGEKFRVGNCKHLKMTRP stop

MTLGGFDNLCELSS stop

1 2 3 MTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL stop

1 2 3 MTLGGKILFFLFLLLPLSPFSLIF stop

AR4

AR1/2/2b

AR1/2/3/2b

AR3

ARv567es

Alternative names AR-Vs

Transcriptional activity

Inactive

Conditional

Unknown

Constitutive

Constitutive

Unknown

Unknown

Constitutive

Unknown

Conditional

Constitutive

Unknown

Unknown

Unknown

7

AR: Xq11-12

69 nts

Liu LL et al, Oncogene 2013

ARV7More abundant than others:

Compatible with detection in clinical samples

Constitutively active:

Cannot be inhibited by LBD‐targeting drugs

Produces translated protein product:

Not affected by nonsense‐mediated mRNA decay

Expression increased (~20 fold) in CRPC

Prevalence of AR‐V7 in CRPC  (n=62)

• Pre‐Enza, Pre‐Abi :  11.6%

• Post‐Enza only :  25.0%

• Post‐Abi only :  51.2%

• Post‐Enza and Post‐Abi :  66.7%

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AR‐V7 and Resistance to Enzalutamide and Abiraterone in CRPC

PSA Responses According to AR‐V7 Status

Antonarakis ES, et al. N Engl J Med. 2014;371:1028‐38.

AR‐V7 positiveAR‐V7 negative

Enzalutamide‐Treated Patients

‐100

Best PSA

 Response, %

 chan

ge

100

50

‐50

†

*†

*†

* †

† †

†

†

† † †

†

†

††

† † †

† †

0

Abiraterone‐Treated Patients

‐100Best PSA

 Response, %

 chan

ge

100

50

‐50

* * **

†

†

†

†

0

AR‐V7 positiveAR‐V7 negative

The dotted line shows the threshold for defining a PSA response (≥50% reduction in PSA level from baseline).*Increase seen of > 100% in best PSA response. †Pa ents in the enzalutamide cohort who previously receivedabiraterone and patients in the abiraterone cohort who previously received enzalutamide.

Conversions of ARV-7

Nakazawa et al Ann Oncol 2015

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ARV7 ratio to flAR:ARV7 is a function of AR amplfication

Antonarakis NEJM 2014

Combination Phase III: Alliance: A031201 ‐ PI Michael Morris (accrued)

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

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Mechanism #3

UCSF

Targeting Bone Metastasis

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.

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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

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How to use radium?

• Chemo refusers?

• Frailer patients?

• Post chemo

• In combination

Mechanism #4

UCSF

Targeting Variant Histologies

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Treatment Mediated Selection Pressure: Neuro‐Endocrine Prostate Cancer as an example of phenotypic change

AR Driven  Adenocarcinoma

AR directed therapy 

“eliminates” Adenocarcinoma

Neuro‐endocrine/small cell predominant

mCRPC Tissue Collection: West Coast Dream Team Approach

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Histology of 124 Evaluable Biopsies<br />74 % were “pure” with a single histologic subtype (**isolated by LCM)<br />Remainder (26%) were comprised of mixed populations

Presented By Eric Small at 2015 ASCO Annual Meeting

Overall survival as function of biopsy pathology<br />Grouping IAC and SCNC

Presented By Eric Small at 2015 ASCO Annual Meeting

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Clinically “Anaplastic” Histologically“Small Cell “

Need to Reconcile clinical vs histological vs genomic

Genomic Target Present?

But the holy grail is the liquid biopsy

Scher et al Proc ASCO GU  2016

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Harnessing Multi‐platform informatics to discover  

Harnessing Multi‐platform informatics to discover  

NEXT Ideal: A marker that melds Predictive and prognostic

Prognostic“how sick is patient?”

LDHAlkPhosOpiates y/n?Visceral Disease

Predictive“Will drug work?”

– Does Prognostic trump Predictive?‐If a predictive pattern is identified in a patient will they still be able to receive the intervention?

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Mechanism #5

UCSF

Targeting DNA repair

BRCA and prostate cancer

• Germline BRCA 1,2  are rare in prostate cancer– present in 0.33‐5% 

• HOWEVER– Homologous DNA repair defects (HR) are common in prostate cancer

• Germline and somatic inactivating mutations in HR DNA repair genes collectively occur in up to 20%–25% of prostate cancers – CHEK2, BRIP1/FANCJ, SBS1, BRCA1 and ATM 

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Mateo J et al. N Engl J Med 2015;373:1697‐1708.

Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration‐Resistant Prostate Cancer.

Mateo J et al. N Engl J Med 2015;373:1697‐1708.

Antitumor Activity of Olaparib and Association with Defects in DNA‐Repair Genes, According to Biomarker Status.

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PARP inhibitors in development

Source: NIH Clinical Trials registry. www.ClinicalTrials.gov. ‐ See more at: http://www.onclive.com/publications/Oncology‐live/2015/June‐2015/parp‐inhibitors‐move‐into‐the‐limelight#sthash.X2Kqz6Ic.dpuf

Carboplatin also targets defective DNA repair

• Platinum based chemotherapy active

• Underutilized.

• May ‘double cover’ neuroendocrine and HRD tumors

• Generic, well tolerated

• Need trials!

54

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Hagel S et al, Ann Oncol 2016

Prior studies of platinum‐based therapy

Do we know how to select patients??

Mateo et al, NEJM 2015Lord and Ashworth, Nat Rev Cancer 2016

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Integrating Biology into CRPC Management

• AR signaling is the key to most CRPC

• Variant histologies also may be implicated. 

• DNA Repair defects are a ‘new’ 

• Tumor interrogation imperative to future therapy development