What is the optimal sequence for

your patient with CRPC?

SAMO Interdisciplinary Workshop on Urogenital Tumors

17th and 18th April 2015Aurelius Omlin

What is the optimal sequence for yourpatient with CRPC?

• Overview treatment options for CRPC

• First-line treatments

• Second-line and third-line treatments

• Outlook

• St.Gallen approach to CRPC management

CRPC

Docetaxel + P* vsMitoxantrone + P

NEJM 200419.2 vs 16.3m

**Zoledronat vs Placebo JNCI 2004; 16 vs 10.5m

* Prednisone** Time to first skelettal related event

Treatment landscape for CRPC until 2010

CRPC

Docetaxel + P*NEJM 2004

**19.2 vs 16.3m

Cabazitaxel + P*LANCET 2010**15.1 vs 12.7

Sipuleucel-TNEJM 2010

**25.8 vs 21.7

Abiraterone + P*NEJM 2011

**15.8 vs 11.2 EnzalutamidNEJM 2012

**18.4 vs 13.6Radium-223NEJM 2013

**14.9 vs 11.3

Abiraterone + P*NEJM 2013

**34.7 vs 30.3EnzalutamidNEJM 2014

**32.4 vs 30.2

***Zoledronat JNCI 2004; 16 vs 10.5m

***Denosumab LANCET 2011; 20.7 vs 17.1m

* Prednisone** median OS***median time to first SRESlide: adapted from S. Gillessen

Treatment landscape for CRPC 2015

Mechanism of Action

Docetaxel

Cabazitaxel

Weaver Cancer Cell 2005

Enzalutamide

Abiraterone

Radium-223Sipuleucel-T

Taxan Behandlung

Conceptual Framework: Advanced ProstateCancer

M0 M0

Castration-Naive Castrations-Resistant

M1M1

first-lineM1

second-lineM1

third-line

PSA: elevatedTestosteron: normal

PSA: FluctuatingTestosteron: suppressed

ADT

ADT

SituationM0

SituationM1

ADT: Androgen deprivation therapyM0: No evidence of metastases on imagingM1: Imaging proven metastatic disease

What is the optimal sequence for yourpatient with CRPC?

• Overview treatment options for CRPC

• First-line treatments

• Second-line and third-line treatments

• Outlook

• St.Gallen approach to CRPC management

CRPC first-line

76 y old patient

Rising PSA on ADT

Testosteron: <0.35 nmol/l

Bone scintigraphy: multiple bone metastases

Choice of first-line therapy?

- Clinic?

- Past medical history? Duration of response to ADT?

- CT scan for evaluation of soft-tissue metastases?

15 2241

85

01

.01

.20

…

01

.02

.20

…

01

.03

.20

…

01

.04

.20

…

01

.05

.20

…

01

.06

.20

…

01

.07

.20

…

PSA

Fit for chemo

Visceral Disease

Docetaxel Symptomatic

Radium-223?

Response to ADT<12m

Yes

Yes No

YesNo

YesNo

Possible Algorithm first-line CRPC

★ CH: not approved before chemotherapy★★ CH: not approved in the presence of visceral disease before chemotherapy

Docetaxel

Abiraterone? ★★

Enzalutamide★

AbirateroneEnzalutamide★

AbirateroneEnzalutamide★

Docetaxel

Visceral Disease

Radium-223

BSC? Steroid?AR Antagonist?Enzalutamide★Abiraterone★★

No

Yes No

Symptomatic

Yes No

AbirateroneEnzalutamide ★

BSC? Steroid?AR Antagonist?

What is the optimal sequence for yourpatient with CRPC?

• Overview treatment options for CRPC

• First-line treatments

• Second-line and third-line treatments

• Outlook

• St.Gallen approach to CRPC management

Abiraterone + Prednison (COU-301)

• Abiraterone + Prednison (mOS 15.8 vs 11.2; HR 0.74)

Enzalutamid (AFFIRM)

• Enzalutamide (mOS 18.4 vs 13.6; HR 0.63)

Cabazitaxel + Prednison (TROPIC)

• Cabazitaxel plus Prednison (mOS 15.1 vs 12.7; HR 0.7)

Radium-223 (subgroup, ALSYMPCA)

• Radium-223 (mOS 14.4 vs 11.3; HR 0.71, subgroup 57% pts)

Docetaxel

Second-line: Prospective Phase III Trial Data

Hormones (Abiraterone or Enzalutamid) first-line

→ Radium-223 (only bone disease, symptomatic, not fit for chemo)

→ Docetaxel (rapid progression, visceral metastases)

Second-line possible selection criteria

Chemotherapy (Docetaxel) first-line

→ Abiraterone (Cave: cardiac function, EF <50%, diabetes, interactions)

→ Enzalutamid (Cave: Seizures or risk factors, QTc prolongation, interactions)

→ Cabazitaxel (Docetaxel refractory? Rapid PD after docetaxel)

→ Radium-223 (symptomatic, no visceral disease)

Radium-223 first-line

→ Reason for radium-223 first-line?

→ Abiraterone/Enzalutamide

CRPC third-line: NO prospective Phase IIITrial Data

Enzalutamide after Abiraterone and Docetaxel

N mOS PFS ≥50% PSA decline

First-line (PREVAIL) 1717 32.4 NR 78%

Second-line (AFFIRM) 1199 18.4 8.3 54%

Third-line (10 pooled case series) 536 8.3 3.1 22.9%

Cabazitaxel after Docetaxel and Abiraterone or Enzalutamide

N mOS PFS ≥50% PSA decline

Second-line (TROPIC) 755 15.1 2.8 39.2%

Third-line case series1

case series2

5979

15.810.9

4.64.4

39%35%

PSA Waterfall Plot

Scher et al NEJM 2012Beer et al NEJM 2014Petrelli Clin Gen Cancer 2014De Bono Lancet 2010Pezaro Eur Urol 2014Al Nakouzi Eur Urol 2014

What is the optimal sequence for yourpatient with CRPC?

• Overview treatment options for CRPC

• First-line treatments

• Second-line and third-line treatments

• Outlook

• St.Gallen approach to CRPC management

Harris Nature Reviews Urology 2009Guo Int J Biol Sci 2011

Androgen Receptor – Splice Variants

*

Antonarakis NEJM 2014 and ESMO 2014, Madrid

Enzalutamide Abiraterone

AR-V7 and Response to Abiraterone orEnzalutamide

* *

Antonarakis ASCO GU 2015

AR-V7 and Response to Docetaxel

PSA response to therapy : 41% in AR-V7+ vs 65% in AR-V7- (p=0.19)Median PFS was similar in both groups, 5.1 vs 6.9 months (p=0.11)

AR-V7+ patients retain sensitivity to taxanes

What’s maybe next?

Expected Phase III Trial Results 2015/2016:

Castrations-Naive• ADT + Docetaxel vs ADT (STAMPEDE)

CRPC first-line• Ipilimumab vs Placebo (pre-Docetaxel)• PROSTVAC vs Placebo (pre-Docetaxel)• Tasquinimod vs Placebo (pre-Docetaxel)• Docetaxel vs Cabazitaxel (first-line, FIRSTANA)

CRPC second-line Chemotherapie• Cabazitaxel 25mg/m2 vs 20mg/m2 (PROSELICA)• Cabazitaxel plus Custirsen vs Cabazitaxel

What is the optimal sequence for yourpatient with CRPC?

• Overview treatment options for CRPC

• First-line treatments

• Second-line and third-line treatments

• Outlook

• St.Gallen approach to CRPC management

Summary of Treatment Options CRPC 2015

Metastatic CRPC First-line

Metastatic CRPC Second-Line Metastatic CRPC Third-LineAsymptomatic or

minimally symptomatic

Symptomatic

Prospective phase IIItrial data• Docetaxel• Abiraterone***

Enzalutamide• Sipuleucel-T**

Prospective phase III trialdata• Docetaxel• Radium-223*

Prospective phase III trial data (post-

docetaxel) 2nd line:

• Cabazitaxel

• Abiraterone

• Enzalutamide

• Radium-223*

No prospective phase III trial data for

2nd line post: abiraterone,

enzalutamide, radium-223 or

sipuleucel-T

Options for patients in good PS:

• Docetaxel

• Cabazitaxel

• Abiraterone

• Enzalutamide

• Radium-223

No prospective phase III

trial data

Options for patients in

good PS:

• Cabazitaxel

• Abiraterone

• Enzalutamide

• Radium-223

• Docetaxel re-challenge

Consider clinical trial participation

*Bone metastases and symptomatic, no visceral or bulky lymph node metastases, not fit, unwilling to have no access to chemotherapy or post-chemotherapy** Good performance status, low tumour volume, no visceral metastases*** no visceral metastases

Challenges 2015

Treatment selection

Treatment monitoring

Rapidly changing treatment landscape

Significant costs of all the new treatments

How to make best use of the available treatmentoptions?

Collaboration: Discuss patients at interdisciplinarytumour boards!

Save the dateAdvanced Prostate Cancer ConsensusConference APCCC 9-11 March 2017

www.prostatecancerconsensus.org

prostatecancerconsensus@kssg.ch

Akaza Hideyuki, JapanAttard Gerhardt, UKBeer Tomasz, USBeltran Himisha, USChinnaiyan Arul M., USDaugaard Gedske, DenmarkDavis Ian, AustraliaDe Bono Johann, UKDe Santis Maria, AustriaDrake Charles G., USEeles Rosalind A., UKEfstathiou Eleni, Greece/USFanti Stefano, ItalyFizazi Karim, FranceGillessen Silke, SwitzerlandGleave Martin E., Canada

Halabi Susan, USHeidenreich Axel, GermanyHussain Maha H.A., USJames Nicholas D., UKLecouvet Frédéric, BelgiumLogothetis Christopher J., USNelson Peter, USNilsson Sten, SwedenOh William K., USOlmos David, SpainOmlin Aurelius, Switzerland(Scientific Comittee)Padhani Anwar, UKParker Chris, UKRubin Mark A., USRyan Charles J., US

Sartor Oliver A., USSchalken Jack A., HollandScher Howard I., USSella Avishay, IsraelShore Neal, USSmall Eric, USSmith Matthew R., USSoule Howard R., US(Scientific Comittee)Sternberg Cora N., ItalySuzuki Hiroyoshi, JapanSweeney Christopher, USTannock Ian, CanadaTombal Bertrand, Belgium

Consensus Expert Panel Members 2015

Thank you for your attention!

Third-line: Prospective Phase III Trial (CARD)

Update Phase III from 2014

Proven OS benefit

Update COU-302 Abiraterone before Chemotherapie (Ryan ESMO 2014)• mOS 34.7 vs 30.3m, HR 0.81

Lack of OS benefit

2x Phase III Orteronel (TAK-700)• pre-Docetaxel (de Wit ASCO 2014)• Post-Docetaxel (JCO 2015)

Phase III Ipilimumab post-Docetaxel (Kwon Lancet Onc 2014)• Subgroup with favourable prognostic markers (ALP <1.5ULN, Hb ≥11, no

visceral disease) with OS benefit

2x Phase III Cabozantinib (Press release 09/2014)• COMET-1 (ASCO GU 2015)• COMET-2

Phase III Docetaxel plus Custirsen vs Docetaxel (Chi ESMO 2014)

CRPC first-line: Prospective Phase III Trial Data

Asymptomatic/minimally symptomatic, no visceral disease

• COU-302: Abiraterone + Prednisone (mOS 34.7 vs 30.3, HR 0.81)

• IMPACT: Sipuleucel-T (mOS 25.8 vs 21.7, HR 0.78)

Asymptomatic/minimally symptomatic

• PREVAIL: Enzalutamide (mOS 32.4 vs 30.2, HR 0.71)

Symptomatic or asymptomatic

• TAX327: Docetaxel plus Prednisone (mOS 19.2 vs 16.3; HR 0.76)

Symptomatic, not fit for chemo or declines chemotherapy

• ALSYMPCA: Radium-223 (mOS 16.1 vs 11.5; HR 0.74 subgroup 43%,

chemo-naive)