The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa,...

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The art of the start The Pope of the stop! Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

Transcript of The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa,...

Page 1: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

The art of the start The Pope of the stop!

Karim Fizazi, MD, PhD

Institut Gustave Roussy

Villejuif, France

Page 2: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

Disclosure

Participation to advisory boards/honorarium for:

Amgen, Astellas, Astrazeneca, Bayer, Clovis,

Essa, Genentech, Janssen, Orion, Sanofi

Page 3: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

Questions

• When to start?

– AR axis targeting agents

– Taxanes

– Radium-223

– Bone targeted agents

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APCCC 2015

(In men with CRPC), the optimal time point to initiate treatment remains uncertain.

For practice

Gillessen S, Ann Oncol 2015; 26: 1589-604

Page 5: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

APCCC 2015

In mCRPC with PSA progression, no radiographic PD, no symptoms, no imminent complications:

Survival-prolonging agents should be initiated within 4-8 weeks: YES: 63% NO: 38%

(treatment can be postponed with adequate monitoring)

Gillessen S, Ann Oncol 2015; 26: 1589-604

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100

90

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

Progression-Free Survival in TERRAIN P

atie

nts

wit

ho

ut

PFS

eve

nt

(%)

184

191

159

133

131

85

107

61

86

44

71

30

52

13

33

7

21

4

13

2

8

2

5

1

ENZA BIC

Time (months) ENZA Patients at risk BIC Patients at risk

Enzalutamide Median (95% CI):

15.7 months (11.5, 19.4)

Bicalutamide Median (95% CI):

5.8 months (4.8, 8.1)

Hazard ratio (95% CI): 0.44 (0.34, 0.57); P <0.0001

Shore N, Lancet Oncol 2016; 17: 153-163

Page 7: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

STRIVE trial: PFS (M0 and M1 CRPC)

Penson D, et al. AUA, May 15-19, 2015. Oral Presentation. LBA-10.

PFS included PSA progression, radiographic progression, and death events

Page 8: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

Abiraterone/Enzalutamide start: My interpretation of Terrain/Strive

• Indicates superiority vs bicalutamide: OK

• Does not really demonstrate that earlier is better in CRPC !!!

• Two possible practical interpretations:

– Stop using bicalutamide, go straight to enza/abi

– Give a try to bicalutamide, see your (asymptomatic) patient again after 1-2 months, then decide whether to continue or to switch

Page 9: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

What about docetaxel? Never too late, really?

Page 10: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

… Well, I already saw patients with CRPC when it was too late for

docetaxel

So, make sure your patient has the opportunity to receive taxanes before it is too late: - In « early » CRPC if short response to ADT? - Right after abi/enza failure?

Page 11: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

When to start/Stop denosumab/ZA?

No

Yes

Probably Yes

Personal answer: - Try your best to identify patients at risk of SSE - Try to avoid monthly injections for > 2-3 years

Page 12: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

The risk of ONJ increases with time: Probably wise to stop before its onset

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1

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Zoledronic Acid

Denosumab

Perc

enta

ge o

f S

ubje

cts

Month 0 - 12 Month 12 - 24 Month 24 - 36

0

5

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15

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1 2 3Years

M1 CRPC (103 trial) M0 CRPC (147 trial)

1%

2%

3%

Saad F, Ann Oncol 2012; 23: 1341-7. Smith M, Lancet 2012; 379: 39-46 Gartrell BA, Eur Urol 2014; 65: 278-86

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When to start Radium-223? When Alkaline Phosphatase is rising?

Variable Subgrou

p N Hazard Ratio HR 95% CI

Overall Survival 921 0.695 0.581-0.832

Total ALP # < 220 U/L

≥ 220 U/L 517

404

0.825

0.619

0.635-1.072

0.486-0.788

Current Use of

Bisphophonates #

Yes

No 374

547

0.699

0.736

0.525-0.931

0.587-0.923

Prior Use of Docetaxel

#

Yes

No 526

395

0.710

0.745

0.565-0.891

0.562-0.987

Baseline ECOG Status 0 or 1

≥ 2 801

118

0.675

0.820

0.555-0.821

0.498-1.351

Favors

Placebo

Favors

Radium-223

Makes sense from mechanism.

But:

- Subgroup analysis

- Interaction test negative

- Trend if normal Alk Phos

Parker C, N Engl J Med 2013; 369: 213-23

Page 14: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

Questions

• When to start? – AR axis targeting agents

– Taxanes

– Radium-223

– Bone targeted agents (Dmab, ZA)

• When to stop? – AR axis targeting agents

– Taxanes

– Radium-223

– Bone targeted agents (Dmab, ZA)

Page 15: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

APCCC 2015 Treatments with a proven survival benefit should in general not be stopped for PSA progression alone (in the absence of radiographic or clinical progression).

Consensus (82% of the panel) that ≥2 criteria (PSA, radiographic PD, and clinical deterioration), should be fulfilled to stop treatment.

Gillessen S, Ann Oncol 2015; 26: 1589-604 Fuerea A, Eur J Cancer 2016; 61:44-51

True for routine?

Probably true for AR drugs if PSA decline followed by a rise I disagree if immediate PSA rise at 2-3 months: I do stop.

For practice

Page 16: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

APCCC 2015

In case of significant clinical progression that is very likely related to disease without a rise in PSA or radiographic progression, treatment should be changed.

Gillessen S, Ann Oncol 2015; 26: 1589-604

I can’t agree more

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European Consensus 2014

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European consensus panel 2014

• 81% of panelists agreed that it was inappropriate to switch therapy based solely on confirmed PSA progression.

• No sufficient data to support continuing AR pathway-targeted therapy beyond progression at this time (ongoing trials).

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Trials testing treatments beyond progression on Enzalutamide

PLATO: mCRPC PD on Enza n=509

Abiraterone + Enzalutamide

Abiraterone + Placebo

R

NCT01995513

PFS

NCT02288247 NCT02685267

PRESIDE PCCT Consortium mCRPC PD on Enza n=650 (Preside) n=100

R

Docetaxel + Enzalutamide

Docetaxel + Placebo

PFS

Page 20: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

For research

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« No longer clinically benefiting » concept in PCWG3

Page 22: The art of the start The Pope of the stop! · Amgen, Astellas, Astrazeneca, Bayer, Clovis, Essa, Genentech, Janssen, Orion, Sanofi . Questions • When to start? –AR axis targeting

Post-chemotherapy PSA flare

Definition: Early increase in PSA on chemotherapy, followed by a subsequent decrease. Incidence: 20% of patients on docetaxel!

Disease free survival p = 0.001

112833

148

111

0,0

0,2

0,4

0,6

0,8

1,0

0 6 12 18 24 30

M onths

No surge (n=33 pts)

Surge (n=8 pts)

Progression (n=11 pts)

At risk

Thuret R, Ann Oncol 2008; 19: 1308-11 0

50

100

150

200

250

Practical message: Don’t stop chemotherapy

within 2-3 months if PSA is rising (except if clinical deterioration)

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Mr Mar in 2009 before abiraterone

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Mr Mar.: progression after 2 years on abiraterone

Dec 09 May 11 Aug 11 Oct 11 Jan 12 Mar 12

PSA

Abiraterone

rPFS event

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Mr Mar (on abiraterone since 2009)

12/2014 03/2015

Abi Abi

11/2016 Enza Doce Cabazi

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Conclusion: When to Start/Stop

• No level I evidence, clinical judgment still key

• “Indolent” CRPC: starting/ switching early not always needed (monitoring)

• Be more cautious with bad cancers:

– Do your best to make the right decision at first

– Monitor rapidly the patient to check the decision was right indeed

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Thanks again John