The art of the start The Pope of the stop!

Karim Fizazi, MD, PhD

Institut Gustave Roussy

Villejuif, France

Disclosure

Participation to advisory boards/honorarium for:

Amgen, Astellas, Astrazeneca, Bayer, Clovis,

Essa, Genentech, Janssen, Orion, Sanofi

Questions

• When to start?

– AR axis targeting agents

– Taxanes

– Radium-223

– Bone targeted agents

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

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

100

90

80

70

60

50

40

30

20

10

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

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

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

What about docetaxel? Never too late, really?

… 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?

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

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

0

1

2

3

4

5

Zoledronic Acid

Denosumab

Perc

enta

ge o

f S

ubje

cts

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

0

5

10

15

20

25

30

35

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

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

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)

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

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

European Consensus 2014

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).

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

For research

« No longer clinically benefiting » concept in PCWG3

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)

Mr Mar in 2009 before abiraterone

Mr Mar.: progression after 2 years on abiraterone

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

PSA

Abiraterone

rPFS event

Mr Mar (on abiraterone since 2009)

12/2014 03/2015

Abi Abi

11/2016 Enza Doce Cabazi

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

Thanks again John