Management of mCRPC: Hormonal therapy and treatment ...gpgu.org/wp-content/uploads/2018/03/27-Bertrand-Tombal.pdf · Urologie Management of mCRPC: Hormonal therapy and treatment sequence

Urologie

Management of mCRPC:

Hormonal therapy and treatment sequence for

CRPC

Professor Bertrand Tombal, MD, PhD

Cliniques universitaires Saint-Luc

Université catholique de Louvain

Brussels, Belgium

Urologie

Credentials and conflict of interests

Professor and Chairman, Division of Urology, Cliniques

universitaires Saint Luc, Brussels, BE

President of European Organization Of Research and

Treatment of Cancer (EORTC)

PI of Prevail, 9785-CL-0321, and EORTC GUCG 1333

Investigator and paid advisor for Amgen, Astellas, Bayer

Pfizer, Ferring, Janssen, Sanofi Aventis

This meeting is organized and funded by Astellas Pharma

SRL

SmPC is available at the promotional booth or Astellas

employees.

This presentation has been prepared by and reflects the

personal view of Bertrand TOMBAL

XTA/17/0096/SEEd; for healthcare professionals only; date of preparation: 10/2017.

Urologie

The advanced PCa landscape in 2016

± 2-4 years

M1 HNPC

RX

progr.SRE

PAIN

PSA

progr.

± 7-15 years

High-risk

localized PCaSRE

PAIN

Local T/

RX

progr.

PSA

progr.

ADT

T/ treatment; ADT: androgen deprivation therapy; HNPC: hormone-naïve prostate cancer; PCa: prostate cancer;

PSA: prostate-specific antigen; RX progr.: radiological progression; SRE: skeletal-related events

Mottet N et al. EAU guidelines on prostate cancer, update 2015; http://uroweb.org/guideline/prostate-cancer/

(accessed March 2016); Vale CL et al. Lancet Oncol 2016;17:243-46

± ADT ± MTT

Salvage

Local T/

mCRPC

± ADT

PSA

progr.PSA

progr.

M0 CRPC

ADT

Urologie

CRPC portfolio in 2017

1. Fizazi K et al. Lancet Oncol 2012;13:983-92; 2. Ryan C et al. Lancet Oncol 2015;16:152-60; 3. Scher HI et al. N Engl J Med

2012;367:1187-97; 4. Beer C et al. N Engl J Med 2014;371:424-33; 5. Tannock IF et al. N Eng J Med 2004;2351:1502-12; 6. de

Bono JS et al. Lancet 2010;76: 1147-54; 7. Kantoff PW et al. N Engl J Med 2010;363:411-22; 8. Parker et al. N Engl J Med

2013;369:213-23

Relative reduction

in

risk of death, %

HR

(95% CI; P value)

Abiraterone/P vs. placebo/P (post-DOC)1 260.74

(0.64–0.86; P<0.001)

Abiraterone/P vs. placebo/P (pre-DOC)2 190.81

(0.70–0.93; P=0.003)

Enzalutamide vs. placebo (post-DOC)3 370.63

(0.53–0.75; P<0.001)

Enzalutamide vs. placebo (pre-DOC)4 230.71

(0.60–0.84; P=0.001)

DOC (q3w)/P vs. mitoxantrone/P5 240.76

(0.62–0.94; P=0.009)

Cabazitaxel/P vs. mitoxantrone/P (post-DOC)6 300.70

(0.59–0.83; P<0.0001)

Sipuleucel-T vs. placebo (pre-DOC)7 220.78

(0.62–0.98; P=0.03)

Radium-223 vs. placebo (post-DOC or DOC

unfit)8 300.70

(0.58–0.83; P<0.0001)

CRPC: castration-resistant prostate cancer; DOC: docetaxel; P: prednisone; q3w: every 3 weeks

Urologie

32,5

0

20

40

60

80

100

120

10 12 14 16 18 20 22 24 26 28

PS

A (

ng/m

l)

Months post RT

EBRT: external beam radiation therapy; ADT: androgen deprivation therapy, Images provided by B.Tombal &

F.Lecouvet , Clinique Universitaires Saint-Luc, Belgium

Case 1: 71 y.o. EBRT + 2 years ADT for locally-advanced PCa (T3b,

Gleason 8 (5+3), PSA 47 ng/ml, NO, MO), testosterone 43 ng/dl, PSA

doubling time 7 months

Months post initiation of ADT

following RP

Hot spot,

negative X-Rays

Urologie

When do you recommend initiating additional treatment for M0

CRPC patients (negative imaging, rising PSA, outside of clinical

trials) apart from maintaining ADT?

Gillessen S et al. Annals of Oncology 2015; 26: 1589–1604

Urologie

If you recommend treatment for M0 CRPC, what is your preferred

treatment option for M0 CRPC patients (negative imaging, rising PSA,

outside of clinical trials) apart from maintaining ADT?

Gillessen S et al. Annals of Oncology 2015; 26: 1589–1604

Urologie

Trial Drug N InclusionExpected

completion

Prosper(1) Enzalutamide 1560PSA DT

< 10 months08/2015

Spartan(2) ARN-509 1200PSA DT

< 10 months2016

Aramis(3) ODM-201 1500

PSA DT

< 10 months 2018

(1) NCT02003924; (2) NCT01946204; (3) NCT02200614

Randomized placebo- controlled trials in M0 CRPC

Primary endpoint: metastases free

survival (MFS).

Urologie• https://www.jnj.com/media-center/press-releases/janssen-submits-new-drug-application-to-us-fda-for-apalutamide-arn-

509-to-treat-men-with-non-metastatic-castration-resistant-prostate-cancer

• https://www.pfizer.com/news/press-release/press-release-

detail/pfizer_and_astellas_announce_positive_top_line_results_from_phase_3_prosper_trial_of_xtandi_enzalutamide_in

_patients_with_non_metastatic_castration_resistant_prostate_cancer

Urologie

32,5

49

64

0

20

40

60

80

100

120

10 12 14 16 18 20 22 24 26 28 32 34

PS

A (

ng/m

l)

Months post RT

EBRT: external beam radiation therapy; ADT: androgen deprivation therapy, Images provided by B.Tombal &

F.Lecouvet , Clinique Universitaires Saint-Luc, Belgium

Case 1. y.o. EBRT + 2 years ADT for locally-advanced PCa (T3b,

Gleason 8 (5+3), PSA 47 ng/ml, NO, MO), testosterone 43 ng/dl, PSA

doubling time 7 months

Months post initiation of ADT

following RP

Urologie

Mottet N et al. European Association of Urology Prostate Cancer Guidelines. https://uroweb.org/guideline/prostate-cancer.

Docetaxel is not registered for that indication in Romania

EAU Prostate Cancer Guidelines

Summary of Evidence LE

No definitive strategy regarding first treatment choice (which

drug/drug family first) can be devised.4

No clear-cut recommendation can be made for the most effective

drug for secondary treatment (i.e. hormone therapy, chemotherapy

or radium-223) as no clear predictive factors exist.

3

Recommendations LE GR

Ensure that testosterone levels are confirmed to be < 50

ng/mL4 A

Counsel, manage and treat patients with metastatic (m)CRPC

in a multidisciplinary team.3 A

Treat patients with mCRPC with life prolonging agents.

Base the choice of first line treatment on the performance

status, symptoms, comorbidities, location and extent of

disease (alphabetical order: abiraterone, docetaxel,

enzalutamide, radium-223, sipuleucel-T).

1b A

https://uroweb.org/guideline/prostate-cancer

Urologie

Case 2: 71; 10/2009: acromio-clavicular pain; PSA >2500 ng/ml, ALP 450

UI/L, Gleason 7

Images copyrighted to CUSL, Brussels (BE0416.885.016) ALP: alkaline phosphatase; PSA: prostate-specific antigen

The historical standard of care is

androgen deprivation therapy

Additional treatment to be

discussed:

Docetaxel

Other to come ?

Urologie

Images copyrighted to CUSL, Brussels (BE0416.885.016)

10/2009 07/2010


UI/L, Gleason 7

Androgen deprivation therapy (ADT) started, pain disappears after 7 days.

Urologie

0

100

200

300

400

500

600

700

800

O-0

9

J-1

0

A-1

0

J-1

0

O-1

0

J-1

1

A-1

1

J-1

1

O-1

1

J-1

2

A-1

2

J-1

2

O-1

2

J-1

3

A-1

3

J-1

3

O-1

3

J-1

4

PSA (ngL/ml)

Al.P (UI/L)


UI/L, Gleason 7

ADT stopped after 2 years and then restarted

Urologie

Tombal B et al. Eur J Cancer 2011;47:S179-88

The androgen receptor (AR)

is the main driver of

the adaptation mechanisms

Urologie

“Historical” second line hormonal agents

Drug RefPatients

(n)

N°

Trials

% PSA

Response

(range)

Duration

(months)

Bicalutamide (150 mg qd ) 1-4 31-52 4 14 - 45 4

Flutamide (250 mg tid) 5 101 1 23 4,2

Nilutamide (200 or 300 mg

qd)6-7 14-28 2 29-50 7-11

Ketoconazole (200- 400 mg

tid) + cortisone ± AAW8-13 28-128 6 27-63 3.5 -20

DES (1-3 mg) 14-15 21-42 2 24-43 NA-2.8

% PSA response: % of patients achieving 50% decrease in PSA; AAW = anti-

androgen withdrawal

1) JCO 1997 15(8):2928-38; 2) J Urol. 1998 159(1):149-53; 3) Urology 2001 58(1):53-8; 4) Urology. 2010

76(5):1189-93; 5) JCO 2001 19(1):62-71; 6) J Urol. 2003 169(5):1742-4; 7) Urology 2001 58(6):1016-20; 8) J Urol.

1997 157(4):1204-7; 9) Cancer 1997 80(9):1755-9; 10) JCO 2004 22(6):1025-33; 11) J Urol. 2002 168(2):542-5;

12) Urol Oncol. 2001 6(3):111-115; 13) Clin Cancer Res. 2009 15(22):7099-105; 14) JCO 2004 22(18):3705-12; 15)

Urology. 1998 52(2):257-60

Urologie

Molecular biology of CRPC

Imamura et al. International Journal of Urology (2016) 23, 654--665

Enzalutamide(Apalutamide)

(Darolutamide)Enzalutamide(Apalutamide)

(Darolutamide)

Abiraterone

Urologie

De Bono et al. N Engl J Med 2011;364:1995-2005.

HR 0.646 0.54 – 0.77

P < 0.0001

Mode of action of new AR pathways inhitor lead to increase in overall

survival in post-docetaxel setting, thus demonstrating the depency of

mCRPC on the AR

Overall Survival abiraterone + prednisone vs. prednisone (COU-AA_301)

OS 95%CI

Abiraterone

/P14.8 14.1-15.5

Placebo/P 10.9 10.2-12

Urologie

19H.I. Scher, NEJM 2012 Sep 27;367(13):1187-97.

OS 95%CI

Enzalutamid

e18.4 17.3-NYR

Placebo 13.6 11.3-15-6

Mode of action of new AR pathways inhitor lead to increase in overall

survival in post-docetaxel setting, thus demonstrating the depency of

mCRPC on the AR

Overall Survival enzalutamide vs. placebo post-docetaxel (AFFIRM)

Urologie

0

100

200

300

400

500

600

700

800

O-0

9

J-1

0

A-1

0

J-1

0

O-1

0

J-1

1

A-1

1

J-1

1

O-1

1

J-1

2

A-1

2

J-1

2

O-1

2

J-1

3

A-1

3

J-1

3

O-1

3

J-1

4

PSA (ngL/ml)

Al.P (UI/L)


UI/L, Gleason 7

Degarelix stopped after 2 years and then restarted

Urologie

The management of mCRPC before abiraterone and

enzalutamide

CRPC survival

M0

Radiographic

progression

Chemo-based

treatment3

Symptoms

Urologie

22Graph and table are updated results from J Clin Oncol 26:242-245. 2008

Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for

Advanced Prostate Cancer.

Tannock IF et al. N Engl J Med 2004;351:1502-12

Urologie

Disease Burden Median SurvivalChemotherapy

Indicated

Rising PSA only ~4 years ? No

Asymptomatic

metastases

(limited)

~18 to 24 months Individualize

Asymptomatic

metastases

(extensive)

~18 months Yes

Symptomatic

metastases

~9 to 16 monthsYes

Calabrò F, Sternberg CN., Eur Urol. 2007 Jan;51(1):17-26 ,

modified

When Should Chemotherapy be Started?

Urologie

Efficacy vs. sequencing

N Engl J Med. 2012 Sep 27;367(13):1187-97

• Efficacy trial: evaluating the benefit of Enzalutamide when the rest has failed

Urologie

• Efficacy trial: evaluating the benefit of Enzalutamide when the rest has failed

Efficacy vs. sequencing

N Engl J Med. 2012 Sep 27;367(13):1187-97

• Sequencing trial: opposing a new approach, immediate enzalutamide, to the older one, wait and give chemotherapy

Urologie

COU-AA-302 and PREVAIL are sequencing Trial

Advanced

PCa

Random

isation

SOCmCRPC

SOC: standard of care (ADT ± local T)

ARpI: AR pathways inhibitors abiraterone or enzalutamide

Docetaxel

AAO: all available options

ARpI AAO

Docetaxel

Tumour load

Pain, QoL deterioration, SRE,

fatigue….

Historical reference

arm

Investigational arm

SOCmCRPC

ARpI

Docetaxel

AAO

Urologie

Impact of PREVAIL and COU-AA-302 on the modern CRPC

landscape

CRPC survival

M0

Radiographic

progression

Enzalutamide2

Abiraterone1

CRPC: castration-resistant prostate cancer

Ryan CJ, et al. N Engl J Med 2013;368:138–48.

Basch E, et al. Lancet Oncol. 2013 Nov;14(12):1193-9..

Chemo-based

treatment

Symptoms

Urologie

Abiraterone (COU-AA-302)

Important secondary endpoints

Abi/Pred Pred. Δ p

Time to chemotherapy 25.2 16.8 17.2 < 0.001

Time to PSA progression (months) 11.1 5.6 8.4 < 0.001

Time to SRE < 0.001

Time to time to opiate use NR 23.3

Median time to progression of mean pain

intensity(1) 26.7 18.4 0.049

Time to HRQoL degradation (months)(2) 12.7 8.3 0.03

PSA response > 50% (%) 62 24

Objective response (% 36 16 < 0.001

1. Median time to progression of pain interference

2. Median time to functional status deterioration (FACT-P total score)



Urologie

Enzalutamide (PREVAIL):

Important secondary endpoints

Enzalutamide Placebo ∆ P

Time to chemotherapy (mo) 28.0 10.8 17.2 <0.001

Time to PSA progression (mo) 11.2 2.8 8.4 <0.001

Median time to 1st SRE (mo) 31.1 31.3 <0.001

SRE at first analysis (%) 32% 37% 0.74 <0.001

Time to pain (mo)1 NR yet

Time to HRQoL degradation

(FACT-P) (mo)² 11.3 5.6 5.7 <0.0001

PSA response >50% (%) 78 3.5 <0.001

Objective response (%) 58.8 5 <0.001

Beer TM et al. N Engl J Med 2014;371:424-33; Loriot Y et al. Lancet Oncol 2015;16:509-21

1Median time to progression of pain interference; ²Time to deterioration in HRQoL based on FACT-P total score. FACT-

P: Functional Assessment of Cancer Therapy – Prostate; HRQoL: health-related quality of life; SRE: skeletal-related

event

Urologie

40

18

4548

38

55

23

13

27

33

22

34

0

10

20

30

40

50

60

Total Physical WBSocial/family WBEmotional WB Functional WB PCa subscale

Pa

tie

nts

sh

ow

ing

im

pro

ve

me

nt

in F

AC

T-P

(%

)Enzalutamide efficacy: QoL (PREVAIL)

Loriot Y et al. Lancet Oncol 2015;16:509-21

P<0.0001

EnzalutamidePlacebo

P=0.001

8

P<0.0001P<0.0001

P<0.000

1

P<0.00

01

Improvement is defined by a score increase of:

10 (Total score); 4 (Social/family WB); 3 (Physical, emotional and functional WB and PCa

subscale)

WB: wellbeing

Urologie

Adjusted mean (95% CI) change in FACT-P PCa subscale

Loriot Y et al. Lancet Oncol 2015;16:509-21

Urologie


Advanced

PCa

Random

isation

SOCmCRPC



Docetaxel


ARpI AAO

Docetaxel

Tumour load


fatigue….


arm

Investigational arm

SOCmCRPC

ARpI

Docetaxel

AAO

Urologie

The impact of PREVAIL and COU-AA-302 in the modern

mCRPC landscape

1. Ryan et al. Lancet Oncol 2015;16:152-60; 2. Beer TM et al. N Engl J Med 2014;371:424-

33

Abiraterone

N (%)

Prednisone

N (%)

Subsequent

therapy for

mCRPC

365 (67) 435 (80)

Abiraterone 69 (13) 238 (44)

Cabazitaxel 100 (18) 105 (19)

Docetaxel 311 (57) 331 (61)

Enzalutamide 87 (16) 54 (10)

Ketoconazole 42 (8) 68 (13)

Radium-223 20 (4) 7 (1)

Sipuleucel-T 45 (8) 32 (6)

Enzalutamide

N (%)

Placebo

N (%)

Subsequent

therapy for

mCRPC

457 (52.4)685

(81.1)

Docetaxel 358 (41.1)504

(59.6)

Abiraterone 256 (29.4)417

(49.3)

Cabazitaxel 79 (9.1)149

(17.6)

Enzalutamide 21 (2.4)249

(29.5)

Sipuleucel-T 17 (1.9) 11 (1.3)

Radium-223 16 (1.8) 22 (2.6)

Urologie


Advanced

PCa

Random

isation

SOCmCRPC



Docetaxel


ARpI AAO

Docetaxel

Tumour load


fatigue….


arm

Investigational arm

SOCmCRPC

ARpI

Docetaxel

AAO

Urologie

The impact of PREVAIL and COU-AA-302 in the modern

mCRPC landscape

1. Ryan et al. Lancet Oncol 2015;16:152-60; 2. Beer TM et al. N Engl J Med 2014;371:424-33

Improvement in

OS (median)

HR

(95% CI; P-value)

Abiraterone/P vs.

placebo/P (COU-AA-302)1

4.4 mo0.81

(0.70-0.93; P <0.001)

Enzalutamide vs. placebo

(PREVAIL) 2 4 mo0.77

(0.67-0.8; P =0.0002)

The benefit is for the sequence not for

simply the drug.

Urologie

The Standard treatments sequence in 2017

CRPC survival

M0

Radiographic

progression

Enzalutamide2

Abiraterone1

CRPC: castration-resistant prostate cancer



docetaxel

Symptoms

Enzalutamide

Abiraterone

Cabazitaxel

Bone targeted therapies, including RA223

Urologie

First line treatment of early mCRPC: The

view from the experts of APCC

86

6

08

Abiraterone orenzalutamideCabazitaxel

Docetaxel

Radium 223

Sipuleucel-T90

22

6

What is your preferred

first-line mCRPC

treatment option:

Asymptomatic men who did

not receive docetaxel in the

HNPC setting

Gillessen S, Eur Urol. 2017 Jun 24. pii: S0302-2838(17)30497-9.

Asymptomatic men who did

receive docetaxel in the

HNPC setting

Urologie

ADT + docetaxel has supplanted ADT as upfront

systemic treatment.

Enzalutamide or Abiraterone are the reference

treatments of early mCRPC.

How early is early?



Urologie

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline

Disease for Enzalutamide-treated Men with Chemotherapy-naïve

Metastatic Castration-resistant Prostate Cancer.

CI = confidence interval; HR = hazard ratio; mets = metastases; NYR = not yet reached.

Evans CP et al. Eur Urol. 2016 Mar 19. pii: S0302-2838(16)00274-8.

Kaplan–Meier estimates of OS by number of bone metastases at

screening (<4 vs I4).

Urologie




Kaplan–Meier estimates of OS in the non-visceral and visceral

subgroups.



Urologie






Urologie


systemic treatment.



How early is early?

Is there still a role for hormonal

therapies without proven

benefit ?



Urologie

Use of first generation second line hormone

therapies in Prevail and COU-AA-302

CRPC survival

M0

Radiographic

progression

Enzalutamide1

Abiraterone2

Study % patient having received

antiandrogen prior to entering the

trial

COU-AA-

302(1)

100% (compulsory per protocol)

PREVAIL(2) 65%

(1) Ryan CJ, et al. N Engl J Med 2013;368:138–48 (appendix); (2) Beer TM, NEJM

2014;371:424-33 (appendix)

Second line

hormonal

manipulations?

Urologie

Urologie


systemic treatment.



How early is early?

Is there still a role for hormonal

therapies without proven benefit ?

Is it abiraterone or enzalutamide, or

both one after the other ?



Urologie

Administration and Side Effect profile and relative

contra-indications of Zytiga®

Abiraterone:

4 250 mg tablets without food (No food should be eaten for at least 2

hours before and for 1 hour after). Swallow whole. With prednisone 5 mg

BID

Control hypertension and correct hypokalemia before and during

treatment. Monitor blood pressure, serum potassium, and symptoms of

fluid retention at least monthly. Measure ALT and AST) and bilirubin levels

prior to starting treatment with ZYTIGA®, every two weeks for the first

three months of treatment, and monthly thereafter.

Side-effect of interest: hypertension, hypokalemia, fluid retention, liver

enzyme

Relatives contra-indications: patients with a history of cardiovascular

disease or with medical conditions that might be compromised by

increases in blood pressure, hypokalemia, or fluid retention. YP2D6

substrates with a narrow therapeutic index.Zytiga ® Summary of Product Characteristics (SmP) accessed on Nov 1, 2017 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/002321/WC500112858.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002321/WC500112858.pdf

Urologie

Administration and Side Effect profile and relative

contra-indications of Xtandi ®

Enzalutamide

Four 40 mg capsules (160 mg) orally with or without food.

No additional tests, except if is co-administered with

warfarin (CYP2C9 substrate), conduct additional INR

monitoring.

Side-effect of interest: fatigue, HTA, arthralgia,

Relatives contra-indications: patients who had a seizure,

with predisposing factors for seizure, or using concomitant

medications that may lower the seizure threshold. Avoid

CYP3A4, CYP2C9 and CYP2C19 substrates with a

narrow therapeutic index. Xtandi® Summary of Product Characteristics (SmP) accessed on Nov 1, 2017 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/002639/WC500144996.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002639/WC500144996.pdf

Urologie

Gillessen S et al. Eur Urol. 2017 Jun 24. pii: S0302-2838(17)30497-9

What is your preferred choice between Abiraterone and Enzalutamide at any time

in the treatment sequence in men with mCRPC if all options are available in case

of the following medical situations?

Enzalutamide Abiraterone Either

Stable brain metastases 6% 73% 10%

History of falls 2% 94% 4%

Baseline significant fatigue 6% 88% 6%

Baseline significant

neurocognitive impairment4% 84% 10%

Long QTc-syndrome or men

on not replaceable drugs with

potential QT prolongation

27% 31% 24%

Diabetes mellitus requiring

prescription drug therapy84% 6% 10%

Cardiac ejection fraction

below 45-50%63% 6% 27%

Active liver dysfunction 68% 8% 14%

Urologie

CRPC prostate cancer is an

heterogonous disease

Early enzalutamide or abiraterone is

the new reference treatment of early

asymptomatic mCRPC

There is no valid reason to delay

treatment

Optimal sequencing is based on the

administration of a maximum of agents

taking in consideration the very high

rate of cross-resistance between

agents.

Conclusion

Documents

Management of mCRPC: Hormonal therapy and treatment ...gpgu.org/wp-content/uploads/2018/03/27-Bertrand-Tombal.pdf · Urologie Management of mCRPC: Hormonal therapy and treatment sequence