castration-resistant prostate cancer: are we done with hormone therapy?

Are We Done with Hormone Therapy?

Gerhardt A6ard MD MRCP PhD Cancer Research UK Clinician ScienAst The InsAtute of Cancer Research and

the Royal Marsden NHS FoundaAon Trust

Financial disclosure

•  Abiraterone was developed at The InsAtute of Cancer Research and is licensed to Cougar Biotechnology/J&J. The ICR also has a commercial interest in the development of inhibitors of PI3K, AKT and HSP90.

•  I am included in The ICR co-‐inventors’ reward scheme of abiraterone.

•  I receive research funding from Astra Zeneca and Genentech.

•  I have received honoraria, lecture fees and travel support from Sanofi, Janssen, Veridex, Ipsen, NovarAs, Millenium PharmaceuAcals, Ventana/Roche.

Survival of paAents with CRPC is improving

Omlin/Pezaro Eur Urol, 2013

•  259 chemo-‐ naïve paAents

•  median OS of 30.6 months (95% CI 27.6 – 36.5)

•  Treated between 2003 and 2011 in one insAtuAon

Ø  Old prognos:c nomograms under-‐es:mate median survival

ExciAng Ames for CRPC

*Denotes products that are not approved for use; approval dates are an esAmate only

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Abiraterone

Cabazitaxel

Sipuleucel-‐T

Docetaxel

Mitoxantrone (1996)

Androgen-‐deprivaFon therapies

EstramusFne (1981)

Enzalutamide

CabozanFnib*

Prostvac VF*

Ipilimumab*

Tasquinimod*

CusFrsen*

Radium-‐223*

Orteronel*

ExciAng Ames for CRPC – and the AR takes center stage

*Denotes products that are not approved for use; approval dates are an esAmate only

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Abiraterone

Cabazitaxel

Sipuleucel-‐T

Docetaxel

Mitoxantrone (1996)


EstramusFne (1981)

Enzalutamide

CabozanFnib*

Prostvac VF*

Ipilimumab*

Tasquinimod*

CusFrsen*

Radium-‐223*

Orteronel*

Treatments in development for CRPC

*Not approved for use; approval dates are an esAmate only

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Abiraterone

Cabazitaxel

Sipuleucel-‐T

Docetaxel

Mitoxantrone (1996)


EstramusFne (1981)

CabozanFnib*

Prostvac VF*

Ipilimumab*

Tasquinimod*

CusFrsen*

Radium-‐223*

Orteronel* Galeterone*

ARN-‐509*

OGX-‐047*

OMD-‐201*

PARPi*

Enzalutamide

Challenges we face as physicians treaAng CRPC

•  Is there a role for sequencing 2nd and 3rd generaAon AR targeAng drugs?

•  Is there a role for combinaAons of AR targeAng drugs?

•  How do we select paAents for one drug versus another?

•  Which drug/class of agents do we prioriAse for combinaAon studies?

A@ard and de Bono, Clin Cancer Res, 2011

Ø A significant number of paAents with castraAon-‐resistant prostate cancer have disease that remains driven by ligand acAvaAon of the androgen receptor

Abiraterone: CYP17A1 inhibitor Updated Analysis (775 Events)

•  Median duraAon of follow-‐up: 20.2 months •  Median duraAon of treatment: AA, 8 months vs placebo, 4 months

Median OS Benefit: 4.6 Months

de Bono et al, NEJM 2011

Ø Abiraterone inhibits adrenal CYP17A1 and causes significant suppression of serum androgens and estrogens

Ø Tumor CYP17A1-‐dependent synthesis of steroidogenic ligands has been demonstrated in preclinical models but remains unproven in paAents (albeit supported by strong circumstanAal data)

Enzalutamide: new generaAon AR antagonist

Scher H et al, NEJM 2012 1

Surv

ival

(%)

100

80

60

MDV3100 800 775 701 627 400 211 72 7 0Placebo 399 376 317 263 167 81 33 3 0

MDV3100: 18.3 months (95% CI: 17.3, NYR)

Placebo: 13.6 months (95% CI: 11.3, 15.8)

HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death

40

20

00 3 6 9

Duration of Overall Survival, Months12 15 18 21 24

Median OS Benefit: 4.8 Months

Disease progression in prostate cancer

Chemotherapy

Tumor volum

e & acFvity

NOTE: This diagram represents typical disease progression. Some paAents are metastaAc at diagnosis and are thus sAll castraAon sensiAve.

Abiraterone & enzalutamide Abiraterone

PREVAIL ongoing

Abiraterone doubled time to rPFS in chemotherapy-naïve mCRPC

IA3 data. rPFS assessed by investigator review at prespecified IA.

100

80

60

40

20

0 0

Sub

ject

s W

ithou

t Pro

gres

sion

or

Dea

th (%

)

6 12 18 30 36 24

546 542

389 244

240 133

157 78

20 7

0 0

Abiraterone Prednisone

117 45

Months From Randomization


Abiraterone (median, mos): 16.5

Prednisone (median, mos): 8.3

HR (95% CI): 0.53 (0.45-‐0.62)

p Value: < 0.0001

15 9 3 21 27 33

485 406

311 176

195 99

131 62

66 20

4 0

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

OS favors abiraterone pre-chemotherapy

IA3 data. aPrespecified significance level by O’Brien-Fleming Boundary = 0.0035.

100

80

60

40

20

0

Sub

ject

s W

ithou

t Dea

th (%

)

6 12 18 30 36 24

546 542

524 508

482 465

421 400

68 67

0 0


333 283

Months From Randomization


Abiraterone (median, mos): 35.3

Prednisone (median, mos): 30.1

HR (95% CI): 0.79 (0.66-‐0.95)

p Valuea: 0.0151

15 9 3 21 27 33

538 534

503 492

452 437

393 361

175 153

15 9

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

0

The challenge of demonstrating an OS benefit in pre-chemotherapy pts

aFirst patient crossover after unblinding on 7 May 2012. IA3 data clinical cut-of f date on 22 May 2012. bPrior to unblinding (eg. not per protocol). IA3 data.

Abiraterone (n = 419)

n (%)

Prednisone (n = 482)

n (%) No. with selected subsequent therapy for mCRPCa 274 (65) 347 (72)

Docetaxel 239 (57) 304 (63)

Cabazitaxel 60 (14) 70 (15)

Ketoconazole 39 (9) 63 (13)

Abirateroneb 38 (9) 78 (16)

Sipuleucel-T 33 (8) 28 (6)

Ryan et al NEJM 2012

Ø However, although >90% of paAents respond to castraAon, the response rate to subsequent AR targeAng is up to 50-‐60%

PSA declines with abiraterone (or enzalutamide)

What is the evidence to support conAnued targeAng of the AR?

•  Hypothesis 1: AR/steroid receptor signaling remains important in a significant proporAon of paAents progressing on abi/enza

•  PSA rising at progression in a significant number of paAents Ø  Is this AR driven?

•  Responses with repeated targeAng of AR •  AR shows conAnued nuclear expression in a proporAon of paAents

Combined Image

DAPI AR Pan-‐CK

Ki-‐67 CD45

Nuclear expression of AR in a paAent progressing on abiraterone

Combined

TargeAng the AR in abi/enza resistant CRPC

•  Hypothesis 2: CYP17A1 inhibiAon without concomitant exogenous glucocorAcoids will improve efficacy in addiAon to reducing toxicity

Mechanism of acAon of abiraterone in humans

pregnenolone progesterone 11-‐DOC corAcosterone aldosterone

17α-‐OH-‐preg 17α-‐OH-‐prog

corAsol corAsone

5α-‐pregnane-‐ 17α-‐ol-‐3,20-‐dione

5α-‐pregnane-‐ 3α,17α-‐diol-‐20-‐one

DHEA

DHEA-‐S

androstenedione

testo 5α-‐DHT androstanediol androsterone

CYP17A1 17α-‐hydroxylase

CYP17A1 C17,20-‐lyase CYP17A1

C17,20-‐lyase

A@ard et al, J Clin Oncol 2008; A@ard et al, JCEM 2012

Mechanism of acAon of abiraterone in humans



corAsol corAsone



DHEA

DHEA-‐S

androstenedione




C17,20-‐lyase



corAsol corAsone



DHEA

DHEA-‐S

androstenedione




C17,20-‐lyase

ACTH

hypokalemia

hypertension fluid overload

Suppression of Renin

AddiAon of exogenous glucocorAcoids suppresses the ACTH drive



corAsol corAsone



DHEA

DHEA-‐S

androstenedione




C17,20-‐lyase

…although someAmes incompletely

…are long-‐term steroids detrimental in a propor:on of pa:ents?

VT-‐464: can complete & irreversible C17,20-‐lyase inhibiAon be achieved

without corAsol suppression?

Compound Human CYP17 Lyase IC50 (mM)

Human CYP17 Hydroxylase

IC50 (mM)

Human CYP17 Lyase/Hydroxylase

Selectivity

VT-464 0.069 0.670 9.7

Abiraterone 0.015 0.0025 0.17

0

10

20

30

Abiraterone VT-‐464 Vehicle

ng/m

l

Pregnenolone

0 5 10

ng/m

l

DeoxycorFcosterone

0

10

20

30

40


ng/m

l

Progesterone

0

200

400


ng/m

l

CorFcosterone

Eisner et al, ENDO 2012

VT-‐464 is almost 60-‐fold more lyase-‐selecAve than abiraterone.

VT-‐464: can complete & irreversible C17,20-‐lyase inhibiAon be achieved

without corAsol suppression? Phase 1/2 study underway in chemotherapy-‐naïve CRPC paAents: •  Exogeneous glucocorAcoids not required to date •  Dose-‐related decreases in androgens observed with no

impact on corAsol, pregnenolone, progesterone or corAcosterone levels

•  PSA responses observed in current dose cohort (one confirmed response @ 12 weeks with 92% decrease from baseline)

•  Safety and tolerability acceptable to date

A6ard, PCF Annual retreat Oct 2012, Oral PresentaAon Royal Marsden/University of Athens/St Gallen


•  Hypothesis 3: LBD targeAng using structurally different AR antagonists/ with funcAonally disAnct properAes (AR degradaAon?)/ lower drug brain levels will prove effecAve

•  (or new AR targe:ng drugs can be posi:oned differently)

•  ARN-‐509

ODM-‐201: significant acAvity (pre-‐abiraterone/enzalutamide)

Massard et al, ESMO 2012

Sequencing of MDV3100 followed by abiraterone

MDV3100 abiraterone

Bianchini et al, ESMO 2012

Sequencing of MDV3100 followed by abiraterone

Bianchini et al, ESMO 2012

PSA declines on docetaxel aver abiraterone -‐ clinical evidence for cross-‐

resistance?

Mezynski, Annals of oncol, 2012

Pa:ents who were resistant to abiraterone also proved resistant to docetaxel


•  Hypothesis 4: Re-‐acAvaAon of AR occurs through LBD-‐independent mechanisms –  Repeated LBD targeAng will prove ineffecAve in the majority of paAents

•  Do AR splice variants cause resistance?

Can HSP90 inhibiAon reverse abiraterone resistance by impacAng AR stability?

Centenera et al, Clin Cancer Res 2012

Ø Two-‐part Phase I/II study of AT13387 alone or in combinaAon with abiraterone Ø Accrual ongoing Ø Mul:ple CRPC biopsies, CTC studies

OGX-‐427 – targeAng HSP27


Ø  Hypothesis 5: EvaluaAon of an unselected

paAent populaAon will be unsuccessful

Ø  AcAvity in treatment-‐naïve CRPC but can a survival advantage be achieved post abi/enza?

AR-‐independent disease progression •  75 year old previously progressed on castraAon, bicalutamide, dexamethasone –  Started abiraterone and prednisone in Jan 2010 –  Baseline PSA 50ng/dl –  Good PSA response (nadir: 6.7, July 2010)

March 2011 June 1 Sep 15 Nov 8 Dec 10 11 18 18 11

Biopsied x2

AR IHC ERG IHC ERG FISH

Pre-‐treatment biopsy

Tumor biopsy whilst responding to treatment New liver metastasis

CirculaAng tumor cells N=36

How can we select paAents?

Ø  Response rates to abiraterone are equivalent in PTEN loss and PTEN normal paAents

ERG Rearranged ERG Normal Total

No 20 42 62

90% decline 12 3 15

32 45 77

P=0.001


No 12 27 39

50% decline 20 18 38

Total 32 45 77

P=0.07


No 12 27 62

50% -89% 8 15 38

90% decline 12 3 15

32 45 77

P=0.007

ERG and magnitude of PSA

decline with abiraterone

Attard et al, Cancer Res 2009

Will paAents with AR negaAve CTC prove unresponsive to treatment?

•  AR expression levels and subcellular localizaAon can be quanAtated on each CTC

Composite DAPI CK CD45 AR

Composite DAPI CK CD45 AR

Nuclear AR localizaFon

Cytoplasmic AR localizaFon

CD45 DAPI CK AR

CD45 DAPI CK AR

In collaboraAon with Epic Sciences – posters presented by Dena Marrinucci and Ryan Di6amore

Hit the AR as hard as possible in AR-‐driven prostate cancer

•  Hypothesis 6: Can we improve the efficacy of AR targeAng by combining CYP17A1 inhibitors with AR antagonists?

Hit the AR as hard as possible in AR-‐driven prostate cancer

•  Hypothesis 6: Can we improve the efficacy of AR targeAng by combining CYP17A1 inhibitors with AR antagonists?

•  Does abiraterone achieve a truly ligand free state?

Residual urinary androgens and estrogens in paAents treated with abiraterone

A@ard et al, JCEM 2012 N=24

Can resistance occur through selecAon of AR mutaAons acAvated by exogenous glucocorAcoids given with abiraterone?

T877A L701H AR found in MDA Pca 2b cells

Richards et al, Cancer Res 2012 Zhao et al, Nature Med 2000

Ø Abiraterone is a weak AR antagonist in addiAon to a potent CYP17A1 inhibitor

Ø Uncertain relevance in paAents Ø Could explain some of the acAvity reported in preclinical models

Abiraterone inhibits growth of AR+ cancer cells grown in normal medium

Ø  How much of this effect is AR antagonism versus CYP17A1 inhibiAon?

Richards et al, Cancer Res 2012

Abiraterone inhibits R1881 sAmulated ARR3-‐luciferase acAvity

Ø  No acAvaAon observed with previously described AR mutaAons

Ø AddiAon of an anA-‐androgen to abiraterone could reverse resistance (or increase response rate)

Ø AddiAon of an anA-‐androgen to abiraterone could reverse resistance (or increase response rate)

Ø Is there any benefit to adding a CYP17A1 inhibitor to an anA-‐androgen?

AR inhibiAon by MDV3100 is associated with an increase in androgen biosynthesis

T Ch

ange in Bon

e Marrow A

spira

te(%

)

-‐100 -‐90 -‐75 -‐50 -‐30 0 25 50 75 100

37 pa:ents 33 pa:ents T Ch

ange in Blood

(%)

-‐100 -‐90 -‐75 -‐50 -‐30 0 25 50 75 100

Efstathiou et al. J Clin Oncol 2011; 29(Suppl)

Bone Marrow Blood

Blood Testosterone

0.00 0.05 0.10 0.15 0.20 0.25

Week 8

Concen

traF

on

(ng/mL)

Pretreatment

Bone Marrow Testosterone

0.00 0.05 0.10 0.15 0.20 0.25 0.30

Week 8

Concen

traF

on

(ng/mL)

End of Study Pretreatment

Sustained depleAon of testosterone following abiraterone

End of Study

Efstathiou et al. J Clin Oncol 2012

Increased hormone levels reduce inhibiAon of AR acAvity by MDV3100

Richards et al, Cancer Res 2012

ADT + zoledronic acid + docetaxel

ADT + docetaxel

ADT-alone

ADT + zoledronic acid

ADT + celecoxib

ADT + zoledronic acid + celecoxib

STAMPEDE study evaluaAng AR targeAng in hormone therapy-‐naïve paAents

A

B

C

D

E

Past accrual Possible future accrual Follow-up

F

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ADT + abi G

ADT + M1/RT H

ADT + enza+abi J

Challenges we face as physicians treaAng CRPC

•  Is there a role for sequencing 2nd and 3rd generaAon AR targeAng drugs? YES BUT IDEALLY IN SELECTED PATIENTS

•  Is there a role for combinaAons of AR targeAng drugs? EVALUATION WARRANTED

•  How do we select paAents for one drug versus another? MILLION DOLLAR QUESTION

•  Which drug/class of agents do we prioriAse for combinaAon studies? INHIBITORS OF PI3K/AKT….

A@ard and de Bono, Clin Cancer Res, 2011

Acknowledgements RMH/ICR Prostate Targeted Therapy Group Johann de Bono, Alison Reid, David Olmos Carmel Pezaro, Debbie Mukherjee, Dile6a Bianchini, Jo Hunt, Liz Sheridan Gal Maier, Bindu Baikady, Ajit Sarvadikar

The ICR Alan Ashworth, Paul Workman, Elaine Barrie

RMH Academic Urology Unit

David Dearnaley, Chris Parker

RMH Academic Biochemistry M Dowse6, L Folkerd

University of Birmingham Wiebke Arlt, Angela Taylor

The ICR Cancer Biomarkers Team Roberta Ferraldeschi, Penny Flohr, Suzanne Carreira, Juliet Richards, Ai Chiin Lim, Anna Wingate, Jane Goodall, Ruth Riisnaes, Susana Miranda, Ines Figuereido, Karolina Nowakowska, Mateus Crespo, Somi Hedayat

University of Michigan Rich Auchus

Epic Sciences

Dena Marrinucci and Ryan Di6amore

J&J/Cougar Biotechnology

Arturo Molina, Thian Kheoh

The paFents and their families

castration-resistant prostate cancer: are we done with hormone therapy?

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