esmo.org

MCRPC;

Choosing and sequencing drugs

in Practise

Ronald de Wit

ErasmusMC Cancer Institute, Rotterdam NL

r.dewit@erasmusmc.nl

DISCLOSURE SLIDE

- Consultancy,

Sanofi, Merck, Lilly, Bayer, Janssen, Roche, Clovis

- Speaker fees

- Sanofi, Merck

-

- Institutional financial interests,

- Sanofi,Bayer

2004: TAX 327 Survival benefit despite confounding effects on OS

Improved median survival by 2.9 months: • as compared with alternativeeffective treatment (mitoxantrone)• despite 30% crossover• despite imperfect design

(first PSA evaluation at 6 weeks)

Tannock et al, N Engl J Med 2004; 1502-1512Berthold et al , J Clin Oncol 2008; 242-245

Docetaxel exposure and OS in mCRPCPhase II study in Asiatic patients ( n:229)

Docetaxel (75 )/ pred vs Mitoxantrone/ pred (as TAX327).

gr ≥3 neutropenia almost twice as TAX327 (57.7% versus 32%)

OS benefit was 8 months (21.9 versus 13.7 months, HR 0.63)

Ti Zou et al, Plos one 2015

Phase III clinical trials in mCRPC

Optimal choice and sequence of current agents undefined

• Most trials conducted in parallel

• Optimal sequence undefined

• OS benefit likely smaller in subsequent lines of treatment;

is there any benefit to be expected in 3rd or even 4th line?

Limited efficacy of crossing over between AR targeted agents

Enza: enzalutamide; ABI: abiraterone acetate; DOC: docetaxel

Author Yearpublished

N pts MedianABI duration

� PSA≥50%

Median PFS

No prior ENZA

De Bono et al.1

(COU-AA-302) 2011 797 8 mo 29% 5.6 mo

ENZA �ABI

Loriot et al.2 2013 38 3 mo 8% 2.7 mo

Noonan et al.3 2013 30 3 mo 3% 3.6 mo

1. De Bono et al. NEJM 2011;364:1995-2005; 2. Loriot Y et al. Ann Oncol 2013;24:1807-12; 3. Noonan KL et al. Ann Oncol 2013;24:1802-7

Poor response to ABI in patients progressing on ENZ A

Author Yearpublished

N pts MedianENZ duration

� PSA≥50%

Median PFS

No prior ABI

Scher et al.1 2012 800 8.3 mo 54% 8.3 mo

ABI � ENZ

Schrader et al.2 2013 35 4.9 mo 29% -

Thomsen et al.3 2014 24 4.0 mo 17% 2.8 mo

Badrising et al.4 2014 61 3.0 mo 21% 2.8 mo

Bianchini et al.5 2014 39 2.9 mo 23% 2.8 mo

Schmid et al.6 2014 35 2.8 mo 10% 3.1 mo

Azad et al.7 2015 68 4.1 mo 22% 4.6 mo

Brasso et al.8 2014 137 3.2 mo 18% -

Joshua et al.9 2015 507 2.6 mo - -1. Scher HI. NEJM 2012; 2. Schrader AJ. Eur Urol 2014; 3. Thomsen F. Scand J Urol 2014;. Badrising S. Cancer 2014; 5. Bianchini D. Eur J Cancer 2014; 6. Schmid SC. Adv Ther 2014; 7. Azad AA. Eur Urol 2015; 8. Brasso K. Eur Urol 2014 9. Joshua A. Prostate 2015

Poor response to ENZA in patients progressing on AB I

Cross-resistance between ART

� PLATO - Prospective, phase IV, double-blind, Pbo-controlled trial in 251 chemo-naïve mCRPCwith PSA response to ENZA >3 months

� Randomized at PSA progression to ENZA+ABI/P vs Pbo+ABI/P

� PFS* (primary endpoint): 5.7 vs 5.6 months, P=0.22

Attard G et al. J Clin Oncol 2018 ; 36: 2639-46

Best PSA response

*PFS: progression free survival (radiological progression or unequivocal clinical progression)

100

75

50

25

0

PS

A C

ha

ng

e F

rom

Ba

seli

ne

, %

-25

-50

-75

-100

ENZA+ABI/P

� PSA ≥50% = 0.8%

Pbo+ABI/P

�PSA ≥50% = 2.5%

Is a taxane in between the cross-over reversing cross-resistance to ART?

Miyake H et al. Clin. GU Cancer 2016; 15: e217-22016

ART (ABI or ENZA)

in first-line

ART � DOC � ART

(response with 2nd ART)

63.6% 29.6%20.6%

ART � ART

(response with 2nd ART)

Best PSA response

302 patients with chemonaive mCRPC treated with new AR-targeted agents (ART) , ABI or ENZA

Optimal choice and sequence of current agents undefined

• Most trials conducted in parallel

• Optimal sequence undefined

• OS benefit likely smaller in subsequent lines of treatment;

is there any benefit to be expected in 3rd or even 4th line?

Limited efficacy of crossing over between AR targeted agents

• Need for biomarkers for response on taxanes and AR targeted agents

Primary resistance to AR-targeted agents

1. De Bono et al. N Engl J Med 2011; 364: 1995–2005; 2. Scher H et al. N Engl J Med 2012; ;367:1187-97 PFS: progression-free survival

Potential but not yet validated biomarkersof resistance to ART

Antonarakis ES et al. NEJM 2014;371:1028-38; Antonarakis ES et al. JAMA Oncol 2015;1:582-91 CTC: circulating tumor cell

PSA response rate:

AR-V7 positive: 0% (95% CI: 0-26%)

AR-V7 negative: 52.6% (95%CI: 29-76%)

P=0.004

PSA response rate:

AR-V7 positive: 0% (95% CI: 0-46%)

AR-V7 negative: 68.0% (95% CI: 46-85%)

P=0.004

PSA response rate:

AR-V7 positive: 41% (95% CI: 18-67%)

AR-V7 negative: 65% (95%CI: 41-85%)

P=0.19

AR-V7 positive AR-V7 negative

Abiraterone Enzalutamide Taxane*

PS

A c

ha

ng

e,

%

100

50

–50

–

100

100

5

0

0

–50

–100

100

5

0

0

–50

–100

*Docetaxel, N=30

Cabazitaxel, N=7

Initial Gleason score may guide treatment choice in chemo-naive mCRPC patients

1. van Soest R et al Eur Urol 2013 (epub ahead of print); 2. Fizazi K, J Clin Oncol 2014; 32 (suppl 4): abstract 20; Mo: months; P: prednisone

Short response to first ADT may predict poor response to Enzalutamide

( Oudard, discussant ESMO 2017)

Retrospective cohort of 173 patients, including 57 treated with enzalutamide in AFFIRM trial

TTCRPC: time to castration resistance; PFS: progression-free survival

Loriot Y et al. Eur J Cancer 2015 sept ; 51(14): 1946-52

Sequence of progression events

� Clinical Sequence of events is known in men treated with ART

� Influence of type of progression on overall survival in men treated with first-line chemotherapy; not documented

Ryan C, Smith M, de Bono J et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N EnglJ Med. 2013;368(2):138–48. Beer T, Armstrong A, Rathkopf D et al. Enzalutamide in metastatic prostate cancer before chemotherapy. Med, N Engl J. 2014;371(5):424–33.

Primary resistance – How to identify?

� PSA is a pharmacodynamic measureof AR signaling1 � PSA falls when AR signalling is blocked

1. Rescigno P et al, Eur Urol. 2016: 724-731; 2. Fuerea A et al, Eur J Cancer 2016; 61: 44-51

• No PSA decline ≥ 30% at 1 month with ART associated with poor OS 1-2

� Imaging

� Bryce AH et al, Prostate Cancer Prostatic Dis 2017; 20: 221-227

Of 265 chemonaive mCRPC patients with radiological

progression and evaluable PSA levels on enzalutamide,

65 (24.4%) had a non rising PSA

Regular imaging is needed +++

Bryce AH et al, Prostate Cancer Prostatic Dis 2017; 20: 221-227

Post-hoc analysis of VENICE and TAX327

To explore the prognostic impact of type of progres sion at initiation of first-line chemotherapy on overall survival

� VENICE - training dataset

n = 1224

1st line DOC + aflibercept or placebo

� TAX-327 - validation dataset

n = 1006

1st line 3w DOC vs 1w DOC vs mitoxantrone

Robbrecht et al , ESMO 2018 poster

Post-hoc analysis of VENICE and TAX327

Type of progression at baseline:

Group 1 PSA progression only

Group 2 - Radiological progression (+/- PSA progression)

Group 3 - Clinical progression based on pain

(+/- PSA progression, +/- radiological progression)

• Radiological or clinical progression defined by PCWG2 criteria

• Pain recorded by using the Present Pain Intensity scale + analgesic score

• Clinical progression = main PPI of ≥ 2 and/or mean AS of ≥ 10

Results

Median OS in 3w DOC arm: 29.4, 24.4 and 15.5 months in G1, G2 and G3 resp. (p <0.001)

(p < 0.001)

(p < 0.001)

Median OS in 3w DOC arm:Not reached, 21.8 and 15.5 months in G1, G2 and G3, resp. (p<0.001)

Sequence of progression events duringdocetaxel treatment

PSA progression first event in 45-57%

* irrespective of type of progression at baseline

~50% clinical ór radiological progression first event during treatment, irrespective of baseline type of progression

~ 30% clinical progression preceding radiological progression

No association between type of progression at baseline and a specific sequenceof progression events during treatment

DO NOT RELY ON PSA ALONE

Optimal choice and sequence of current agents undefined

• Most trials conducted in parallel

• Optimal sequence undefined

• OS benefit likely smaller in subsequent lines of treatment;

is there any benefit to be expected in 3rd or even 4th line?

Limited efficacy of crossing over between AR targeted agents

• Need for biomarkers for response on taxanes and AR targeted agents

• Cross resistance between ART and taxanes

Cross resistance between taxanesand AR targeted agents

in vivo model of CRPC with acquired resistance to e nzalutamide

Van Soest, de Wit et al. Eur Urol 2014

Impaired Efficacy of Docetaxel Post-Abiraterone

1. Tannock et al. Lancet Oncol 2013; 14:760-8; 2. Mezynski & De Bono Annal Oncol 2012. 23: 2943–2947; 3. Schweizer MT et al. Eur Urol 2014; 66:646-52; 4. Azad et al. The Prostate 2014; 74:1544-1550; 5. De Bono et al. Eur Urol 2017

Cabazitaxel remains active in patients progressing with an AR -targeted agent

Progression-free survival Overall survival

Prospective, randomized phase 2 study of cabazitaxel± budesonide

Van Soest et al. Eur Urol 2016

1st line taxane phase III study ; FIRSTANA (ASCO 2016)

FIRSTANA: Overall Survival

FIRSTANA: Prior Treatment

1st line taxane in mCRPC

� Cabazitaxel 20mg and 25mg show a similar OS benefit as

Docetaxel in a non resistant population

( only 2% of patients treated with prior ABI or ENZA)

� 1 st line efficacy of Cabazitaxel as compared to Docetaxel in patients

progressing after ABI or ENZA is not known

If there is no benefit after 3 cycles of docetaxel in a post-abi/enza setting

consider to switch to cabazitaxel ( 20mg /m2)

ALSYMPCA Phase III Study Design

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer)Phase 3, multinational, multicenter, randomized, do uble-blind, placebo-controlled study

(149 sites ; USA, Europe, Australia, Latin America, Canada & Asia)

900 patients with HRPC & skeletal metastases (≥ 2

hot spots)

No intention to use cytotoxic

chemotherapy within the next 6

months

Regular analgesia for cancer related

bone pain or treatment with EBRT for bone

pain

Randomised 2:1

Alpharadin 50 kBq/kg bw6 IV doses

Placebo 6 IV doses

Best supportive care

Best supportive care

Primary end point:

• OS

Secondary end points:• TTPP

• TTP in total-ALP• Safety• HRQoL

www.clinicaltrials.gov identifier: NCTNCT00699751Targeted Therapy, 28 maart 2013

ALSYMPCA: Survival benefit across patient subgroups

Targeted Therapy, 28 maart 2013

Variable Subgroup N Hazard ratio HR 95% CIAll patients 809 0.695 0.552-0.875

Total ALP <220 U/L 452 0.691 0.497-0.962≥220 U/L 357 0.689 0.504-0.941

Current use of bisphosphonates Yes 331 0.582 0.397-0.85 4

No 478 0.752 0.567-0.999

Prior use of docetaxel Yes 470 0.755 0.565-1.009No 339 0.611 0.423-0.883

Baseline ECOG status 0 or 1 696 0.691 0.535-0.8922 or higher 110 0.731 0.398-1.343

0 0.5 1 1.5 2Favours

Radium-223Favours placebo

14 years of progress in theManagement of Prostate Cancer

� mCRPC; 2011 paradigm shift

Novel AR targeted agents

pre-chemotherapy

� mHSPC; 2014 paradigm shift

Docetaxel in addition to ADT

in men presenting with M1 disease

� mHSPC; 2017 shift addition of abiraterone to ADT

Combination of ADT and docetaxel

CHAARTED (M1) STAMPEDE (M0/M1)

Phase III randomized trial in 790 men with metastastic hormone-naïve PCa

Phase III randomized trial in M0/M1 patientswith hormone-naïve PCa

DOC: Docetaxel

1Sweeney C et al. N Engl J Med. 2015;373:737-46; 2James N et al. Lancet. 2015, December

ADT +/- abiraterone(AA)+P in mHSPC ; LATITUDE

mCRPC post CHAARTED/ LATITUDE 2018 treatment options

In many cases, treatment sequence in metastatic PCa likely to be as follows:

Need to define what is the optimal sequence(AR-targeted agent or CABA in 3rd line)

OR

1t line 2nd line 3rd line

GETUG 15 in metastatic HS PCaActivity of subsequent therapies

Lavaud P et al. J Clin Oncol 2016; 34 (suppl); abstract 5080

Modest PSA response and PFS in patients initially treated with ADT+DOC and rechallenged with DOC at disease progression

> Do NOT rechallenge

Short response to first ADT may predict poor response to Enzalutamide

( Oudard, discussant ESMO 2017)

Retrospective cohort of 173 patients, including 57 treated with enzalutamide in AFFIRM trial

TTCRPC: time to castration resistance; PFS: progression-free survival

Loriot Y et al. Eur J Cancer 2015 sept ; 51(14): 1946-52

CABA is effective in patients progressingduring or rapidly after last DOC cycle

CABA also acts in cases of primary resistance to DO C3

Subgroup analysis of the TROPIC (Overall survival) N HR (95% CI)

Progression during treatment with DOC 219 0.71 (0.53-0.96)

Progression <3 months after the last DOC cycle 339 0.70 (0.56-0.89)

In favour of CABA In favour of mito

0.25 0.5 1.00 2.00

TROPIC trial 1-2

1. De Bono J et al. Lancet 2010;376:1147-54 2. Oudard S et al. Future Oncol 2011;7:497-506

3. Di Lorenzo G et al. Eur Urol 2014;65:502-7

post CHAARTED/ STAMPEDE(doce) 2018 treatment

� For pts > 12 months response duration on ADT

reasonable option AR-targeted therapy

(subsequent line would be cabazitaxel)

� For pts< 12 months response duration on ADT choice would

appear cabazitaxel

ADT +/- abiraterone(AA)+P in mHSPC ; LATITUDE

LATITUDE subsequent life-prolonging therapy

Concern with design:double-blind

study !! (abi vs no abi)

>

*Patients who discontinued treatment and were eligible for subsequent therapy.

In 2018 Multiple Choices and Sequences

• mHSPC early taxane /late taxane /early abi/late abi

• mCRPC abi/enza (ART) predoce/ postdoce/pre/postcaba

• mCRPC Radium 223 post ART pre/ post taxane

• >Even after 4 lines many mCRPC patients opt to receive systemic therapies

• >New avenues: PSMA guided therapy

Molecular targeted therapies

Immunotherapy

Genomic data on prostate cancer

Cell, Volume 161, Issue 5, 21 May 2015, Pages 1215–1228

CPCT: Dutch Collab. study WGS 197pts

Future studies and hopefully treatment will be increasingly biology directed!

Remainder at this time : ART and taxanes

Rationale combining taxaneswith ART? ; yes

� Ongoing phase Ib- III clinical studies

Tagawa et al, Eur Urol 2016 ; Abiraterone + Docetaxel, ph 1b PSA RR: 85%

Massard et al. Ann Onco 2017; Abiraterone + Cabazitaxel PSA RR: 46%

ABIDO trial, Spain; Abiraterone + Docetaxel ongoing

CABA ENZA trial, UK; phase I/II trial,

Doce + Enza , as well as Caba + enza randomized phase II ongoing

Several more

NEED TO AWAIT PHASE 3 RESULTS

Influence of Enzalutamide on CabazitaxelPharmacokinetics

a Drug–Drug Interaction Study in mCRPC Patients

Belderbos , de Wit et al , Clin Cancer Res 2017; 24(3); 541–6

Combination Taxane with ART

� NO standard

� ONLY in context clinical trials

� That need to be well designed , incorporating drug-drug interaction data

� Cabazitaxel 20 mg/m2 is not inferior to 25 mg/m2 for OS * � however if 20 is used with enza this results in sub-

therapeutical levels of cabazitaxel

* PROSELICA De Bono et al. JCO 2016

Management of mCRPC

� 14 years of progress

� Many new agents, some remaining questions about sequence

� New avenues that need to be tested in well designed Phase III trials

� Future studies will be increasingly biology directed

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ACKNOWLEDGEMENTS