CHEMOTHERAPY

A/Prof. Arun Azad MBBS PhD FRACP

Medical Oncologist – Monash Health, Melbourne, Australia

Translational Researcher - Monash University, Melbourne, Australia

Chair - Translational Research Committee, ANZUP Clinical Trials

Group

2

Disclosures

Research Support/P.I. Astellas

Employee N/A

Consultant Astellas, Janssen, Novartis

Major Stockholder N/A

Speakers Bureau Astellas, Janssen, Novartis, Amgen

Honoraria Astellas, Janssen, Novartis, Tolmar, Amgen, Pfizer

Scientific Advisory Board Astellas, Novartis, Sanofi, Astra-Zeneca, Tolmar, Pfizer

3

Shifting Treatment Landscape for CRPC: Positive Phase 3 Trials

Mitoxantrone

Zoledronic Acid

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Docetaxel

Enzalutamide

Abiraterone acetate

Cabazitaxel

Denosumab

Radium-223

Sipuleucel-T

Symptom benefit

Skeletal Related Event (SRE) benefit

Overall survival benefit ± symptom/SRE benefit

4

Phase III CRPC Trials Showing OS Benefit

Drug Prior Therapy

Symptom

Improvement/D

elay

Control

OS

Median Δ (Months) HR

Docetaxel Chemo-naïve + MTX 2.4 0.76

Sipuleucel-T +/- chemo - Placebo 4.1 0.78

Cabazitaxel Post-docetaxel +/- MTX 2.4 0.70

Abiraterone Post-docetaxel + Prednisone 4.6 0.74

Enzalutamide Post-docetaxel + Placebo 4.8 0.63

Radium-223 +/- chemo + Placebo 3.6 0.70

Abiraterone Chemo-naïve + Prednisone 4.4 0.81

Enzalutamide Chemo-naïve + Placebo 2 0.70

Chemotherapy in mCRPC: Current

Landscape

6

Chemotherapy in mCRPC: Current Landscape

▪ Mitoxantrone

▪ Docetaxel

▪ Cabazitaxel

▪ Other cytotoxics

Mitoxantrone: The First “Proven” Therapy

Mitox +

Prednisone

(N = 80)

Prednisone

(N = 81)

Pain

responsea 23 (29%) 10 (12%)

Analgesic

responseb 7 (9%) 7 (9%)

Total

palliative

response

30 (38%) 17 (21%)

• Palliative responses without survival benefit• Set the stage to treat only symptomatic patients

Tannock IF et al. J Clin Oncol. 1996;14:1756-1764.

a ≥2-point decrease on 6-point pain scale.b ≥50% decrease in analgesic use.

8

Chemotherapy in mCRPC: Current Landscape

▪ Mitoxantrone

▪ Docetaxel

▪ Cabazitaxel

▪ Other cytotoxics

Docetaxel: First to Improve Overall Survival

Median OS: 18.9 vs 16.5 months

HR: 0.76 (CI 0.62-0.94); P = .009

Tannock IF et al. N Engl J Med. 2004;351:1502-1512.

TAX 327

DOC q3w DOC q1w MITOX

Pain

Response

35%

P = .01

31%

P = .0722%

PSA

Response

45%

P = .005

48%

P < .00132%

QOL

Response

(FACT-P)

22%

P = .009

23%

P = .00513%

Objective

Response12% 8% 7%

Docetaxel: First to Improve Overall Survival

Median OS: 17.5 vs 15.6 months

HR: 0.80 (CI 0.67-0.97); P = .02

Petrylak DP et al. N Engl J Med 2004. 351(15):1513-20

SWOG9916Docetaxel +

Estramustine

Mitoxantrone +

Prednisolone

Pain

Response

NR

P = NSNR

PSA

Response

50%

P < 0.00127%

Progression-

free survival

(median)

6.3 months

P < 0.0013.2 months

Objective

Response

17%

P = 0.3011%

11

Docetaxel: Does treatment schedule matter?

Kellokumpi-Lehtinen PL et al. Lancet Oncol 2013. 14(2):117-124

12

Docetaxel: Does prior abiraterone or enzalutamide matter?

de Bono JS et al. Eur Urol 2017. 71(4):656-664

13

Chemotherapy in mCRPC: Current Landscape

▪ Mitoxantrone

▪ Docetaxel

▪ Cabazitaxel

▪ Other cytotoxics

Cabazitaxel: Improved OS Post-DocetaxelOverall Survival

Median OS: 15.1 vs. 12.7 months

HR 0.70 (CI 0.59-0.83); P < .0001

de Bono JS et al. Lancet. 2010;376:1147-1154.

Secondary Endpoints

MP CBZP HR

(95% CI)P Value

Tumor assessment

Response rate

(%)

4.4 14.4 — .0005

Median TTP

(mo)

5.4 8.8 0.61

(0.49-0.76)

.0001

PSA assessment

Response rate

(%)

17.8 39.2 — .0002

Median TTP

(mo)

3.1 6.4 0.75

(0.63-0.90)

.0001

Pain assessment

Response

rate (%)

7.7 9.2 — .63

Median TTP

(mo)

NR 11.1 0.91

(0.69-1.19)

.52

Cabazitaxel instead of Docetaxel? FIRSTANA trial

Median OS: 24.5 vs. 25.2 vs. 24.3 months

HR: 1.01 (CI 0.85-1.20); P = .997

Oudard S et al. J Clin Oncol 2017. 35(28); 3189-3197

CABAZI 20 CABAZI 25 DTX

Pain PFS

(median)

8.2 months

P = NS

9.2 months

P = .NS8.3 months

PSA

Response

61%

P = .052

69%

P = NS68%

Objective

Response

32%

P = .NS

42%

P = .0431%

16

Cabazitaxel: Does dose matter? PROSELICA trial

Eisenberger M et al. J Clin Oncol 2017. 35(28):3198-3206

17

Chemotherapy in mCRPC: Current Landscape

▪ Mitoxantrone

▪ Docetaxel

▪ Cabazitaxel

▪ Other cytotoxics

18

Other cytotoxics

Sternberg CN et al. J Clin Oncol 2009.

27(32):5431-8

19

Other cytotoxics

▪ Re-challenge with docetaxel

– Retrospective studies suggest approx. 30%-40% PSA RR in patients who previously responded to docetaxel

▪ Single agent carboplatin

– 9-17% objective RR

▪ Carboplatin + Etoposide

– 9% objective RR in Ph II study (n = 60) mCRPC with neuroendocrine differentiation or visceral mets (Flechon A et al, Ann Oncol 2011)

▪ Cyclophosphamide (oral, metronomic)

– Retrospective single centre studies suggest PSA RR as high as 30%

20

Summary: Chemotherapy in mCRPC - Current Landscape

▪ Docetaxel 75 mg/m2 q3w remains front line for mCRPC

– Docetaxel 50mg/m2 q2w is an acceptable alternative

▪ Has not become SOC, at least in Australia

▪ Cabazitaxel remains an option only post-docetaxel

– 20mg/m2 is now SOC based on PROSELICA

– Has become 1st line for mCRPC in some men treated with upfront docetaxel

(CHAARTED, STAMPEDE)

▪ Prior use of abiraterone or enzalutamide does appear to be

associated with lower efficacy

Chemotherapy in mCRPC: Improving

outcomes

22

Chemotherapy in mCRPC: Improving outcomes

▪ Treating more patients with chemo

▪ Combinations

▪ Biomarkers & patient selection

Improved Survival After Introduction of Docetaxel as Standard Therapy

Survival after Palliative XRT to Bone

R. Zielinski et al, Can Urol Assoc J, 8(7-8):E520-3, 2014

Pre-docetaxel era (1998-2001, N=919): Median 7.5 m

Post-docetaxel era (2006-2009, N=957): Median 10.3 m

HR: 0.79 (95% CI 0.70-0.89)

Only 37% got chemotherapy!

Docetaxel: Population Based Outcomes

24

Chemotherapy in mCRPC: Improving outcomes

▪ Treating more patients with chemo

▪ Combinations

▪ Biomarkers & patient selection

Target Agent N1o End

PointResult

VEGFDocetaxel ± bevacizumab

(NCT00110214) 1,050 OS

OS not improved HR, 0.91; 95% CI, 0.78 to 1.05

VEGFDocetaxel ± aflibercept

(NCT00519285) 1,224 OS

OS not improvedHR, 0.94; 95% CI, 0.82 to 1.08

Endothelin Receptor ADocetaxel ± atrasentan

(NCT00134056) 991

OS and

PFSOS not improved

HR, 1.01; 95% CI, 0.87 to 1.18

Endothelin Receptor ADocetaxel ± zibotentan

(NCT00617669) 1,052 OS

OS not improvedHR, 1.00; 95% CI, 0.84 to 1.18

Src KinaseDocetaxel ± dasatinib

(NCT00744497) 1,380 OS

OS not improvedHR, 0.99; 95% CI, 0.87 to 1.13

ImmuneDocetaxel ± GVAX

(NCT00133224) 408 OS

OS inferior HR, 1.70; 95% CI, 1.15 to 2.53

ImmuneDocetaxel ± lenalidomide

(NCT00988208) 1,059 OS

OS inferiorHR, 1.53; 95% CI, 1.17 to 2.00

Vitamin D Docetaxel ± calcitriol

(NCT00273338) 953 OS

OS inferior HR, 1.42; 95% CI, 1.13 to 1.86

ClusterinDocetaxel ± custirsen

(NCT01188187) 1000 OS

OS not improved*

HR, 0.93; P = 0.207

Docetaxel combination studies: A Graveyard

*Chi, ESMO, 2014

26

Cabazitaxel + OGX-011: AFFINITY trial

Beer TM et al. Lancet Oncol 2017

27

Cabazitaxel combination studies ongoing

▪ Cabazitaxel +/- Carboplatin

– PSA RR 44% vs. 60% (Gettys Corn et al, ASCO ASM 2015)

▪ Cabazitaxel + Abiraterone

▪ Cabazitaxel + Enzalutamide

▪ Cabazitaxel + Clarithromycin (CYP3A4 inhibitor)

– CYP enzymes potentiate resistance to taxanes

28

Chemotherapy in mCRPC: Improving outcomes

▪ Treating more patients with chemo

▪ Combinations

▪ Biomarkers & patient selection

29

CTC AR-V7 and Outcomes with Docetaxel

ARV7 -: PSA RR 65%

ARV7 + : PSA RR 41%

ES Antonarakis et al, JAMA Oncol. 2015;1(5):582-591

30

ERG and taxane resistance

▪ ERG binds to microtubules, thereby potentially mediating resistance

to taxanes

▪ Increasing evidence that ERG expression or TMPRSS2:ERG

rearrangement is linked to worse outcomes on docetaxel

– PSA RR 15% vs. 62% in ERG+ and ERG- patients by IHC (p = 0.004)

– TMPRSS2:ERG rearrangement in PBMCs correlated with lower PSA RR (13%

vs. 68%, p = 0.005)

– PSA RR for TMPRSS2:ERG+ in tissue 45% vs. TMPRSS2:ERG- 79%, p =

0.056

Reig O et al. Eur Urol 2016. 70(5):709-713

Song W et al. Oncotarget 2016. 7(50):83735-83743

Galletti G et al. Nat Commun 2014. 5:5548

31

Homologous recombination deficiency (HRD)

ALL PATIENTS HAD

BRCA2 INACTIVATION

OR LOSS

Cheng HH et al. Eur Urol 2016; 69(6):992-5

Cabazitaxel vs. Abiraterone or Enzalutamide in

Poor-Prognosis mCRPC

CBZP: cabazitaxel; ENZA: enzalutamide

ClinicalTrials.gov: NCT02254785

OZM-054: A phase 2, randomized, multicenter study

R

A

N

D

O

M

I

Z

E

CBZP

AA or ENZA

P

R

O

G

R

E

S

S

I

O

N

n = 50

n = 50

ARM A

ARM B

CROSSOVER

TO AA or ENZA

CROSSOVER

TO CBZP

ARM B

ARM A

1ST LINE THERAPY 2ND LINE THERAPY

P

R

O

G

R

E

S

S

I

O

N

mCRPC

• Liver metastases

• CRPC <12 mo from

initial ADT

• Poor prognosis by

index

Whole Blood:

cfDNA Collection

RNA Collection

Whole Blood:

cfDNA Collection

RNA Collection

Whole Blood:

cfDNA Collection

RNA Collection

33

Chemotherapy in mCRPC: Conclusion

▪ Docetaxel remains the 1st line choice for mCRPC

– Unless if given upfront with ADT, in which case cabazitaxel would be typically

given

▪ Cabazitaxel 2nd line choice for mCRPC

▪ Interesting and emerging role for platinum combination therapy

especially if HRD

▪ ERG also looks promising as a negative predictive biomarker

34

THANK YOU