Emerging Role of Chemotherapy and Hormonal Therapy in Advanced Prostate Cancer Treat CRPCgpgu.org › wp-content › uploads › 2016 › 10 › 14-EMERGING-ROLE... · 2019-11-05 ·

Emerging Role of

Chemotherapy and Hormonal

Therapy in Advanced

Prostate Cancer to Treat CRPC

Daniel P. Petrylak , MD

Professor of Medicine and UrologyDirector, Genitourinary DART

Co-Director, Signal Transduction ProgramSmilow Cancer Center

Yale University School of medicine

Sequencing CRPC therapy – 2010

Zoledronic acid with CRPC (metastatic disease)

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel

chemotherapy

Secondary

hormonal RxDocetaxel

MitoxantroneBest supportive care

not known 3 months not knownSurvival

benefit

Sequencing CRPC therapy – 2017

Abiraterone or Cabazitaxelacetate

Metastatic,

minimally

symptomatic

CRPC

Symptomatic

or poor-

prognosis

CRPC

Progression after

docetaxel

chemotherapy

Secondary

hormonal RxDocetaxel

not known 3 months not known

Sipuleucel-T Docetaxel

4 months 3 months 4 months 2.5 months

Denosumab or Zoledronic acid with CRPC (metastatic disease)

Survival

benefit

Survival

benefit

Mitoxantrone

Best supportive care 2010

2014

MDV3100 – 4.8 months

Rad 223 – 3.1 monthsMDV3100 – 2.2 months

Abiraterone – 5.2 months

Rad223 – 4.6 months

Classes of Agents

• Immunotherapeutic

– Sipuleucel T

• Hormonal

– MDV3100, Abiraterone , ?Docetaxel

• Cytotoxic

– Docetaxel, Cabazitaxel

• DNA Damage

– Rad 223

How do we sequence these

agents?

• Clinical Characteristics

– Symptomatic vs Asymptomatic

– Visceral vs Non Visceral

– Pre vs Post Docetaxel

• Biological Markers

– Androgen Receptor

– TRPMSS2-ERG

Development of Castrate Resistant Prostate Cancer

ALTERN.

SPLICING

ABERRANT

MODIFICATION

•GF, cytokines

•Src

Sumo

AC

P

COFACTOR

PERTURBATION

•CoAct gain

•CoR loss/dismissal

CoACT

INTRACRINE

ANDROGEN

SYNTHESIS

T

MUTATION•gain of function

AR

selective

pressure

Hormone Therapy

adaptation

CRPC

RESTORED AR ACTIVITY

(rising PSA)

RECURRENT TUMOR DEVELOPMENT

>30% CRPC

AR

DEREGULATION

•amplification

•overexpression

Penning and Knudsen. Trends Endocrinol Metab. 2010;21(5):315-24.

Abiraterone Acetate:Androgen Biosynthesis Inhibitor

Pregnenolone

DHEA Androstenedione Testosterone DHT

17OH-Pregnenolone

Cortisol

Aldosterone

Androgens

Cholesterol

Abiraterone

Abiraterone

COU 301: Overall Survival

2 prior chemo OS: 14.0 months abiraterone acetate vs 10.3 months placebo1

1 prior chemo OS: 15.4 months abiraterone acetate vs 11.5 months placebo1

Updated results: 4.6-month difference in median survival with abiraterone acetate2

PlaceboAbiraterone

AcetateMedian OS (months) 10.9 14.8 Hazard Ratio 0.6595% CI 0.54-0.77P value <0.001

Placebo

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Ove

rall

Surv

ival

(%

)

Days from Randomization

Abiraterone Acetate

Median OS Δ: 3.9 months35.4% reduction in risk of death

1. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 2. Fizazi K, et al. European Multidisciplinary Cancer Congress; 2011. Abstract 7000.

COU 302: Abiraterone AcetatePhase III Trial in Chemonaïve mCRPC

• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada

• Stratification by ECOG performance status 0 vs 1

1:1

N = 1088• Progressive

chemonaïve mCRPC patients

• Asymptomatic or mildly symptomatic

Abiraterone Acetate 1000 mg dailyPrednisone 5 mg bid

n = 546

Placebo dailyPrednisone 5 mg bid

n = 542

Primary Endpoints:• Radiographic progression-free

survival (rPFS) by central review• OS

Secondary:• Time to opiate use

(cancer-related pain)• Time to initiation of

chemotherapy• Time to ECOG PS deterioration• Time to PSA progression

Saad F, et al. AUA 2013. Abstract 713

Statistically Significant Improvement Over Placebo in rPFS and all Secondary Endpoints

Patient reported outcomes favored AA + prednisone vs placebo + prednisone Full data to be reported

*Pre-specified alpha level 0.0035 Note: All secondary end points remain significant after adjusting for multiplicity testing

Outcome AA + PrednisoneMedian (months)

Placebo + PrednisoneMedian (months) HR (95% CI) P Value

rPFS 16.5 8.3 0.53 (0.45, 0.62) < 0.0001

OS 35.3 30.1 0.79 (0.66, 0.96) 0.0151 *

Time to opiate use

(cancer related pain)Not reached 23.7 0.71 (0.59, 0.85) 0.0002

Time to chemotherapy initiation

26.5 16.8 0.61 (0.51, 0.72) < 0.0001

Time to ECOG PS deterioration

12.3 10.9 0.83 (0.72, 0.94) 0.0052

Time to PSA progression 11.1 5.6 0.50 (0.43, 0.58) < 0.0001

Saad F, et al. AUA 2013. Abstract 713

Ryan et al. Final Overall Survival Analysis of COU-AA-302,a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic

Castration-Resistant Prostate Cancer Patients Without Prior Chemotherapy

• Median follow-up of 49.2 mos

• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)

100

80

60

40

20

0

0

Ove

rall

Surv

ival

(%

)

9 21 30 48 6039

546542

525509

422401

296261

5942

00

AbirateronePrednisone

202148

Time to Death (Months)24123 36 45 54

538534

453438

359322

189132

1510

HR (95% CI): 0.81 (0.70-0.93)

p Value: 0.0033

Prednisone, 30.3 mos

Abiraterone, 34.7 mos

6 15 18 27 33 42 51 57

01

11884

218176

504493

483466

394363

330292

273227

235201

Enzalutamide• Oral drug rationally

designed to target AR signaling, impacting multiple steps in AR signaling pathway

• No demonstrated agonist effects in pre-clinical models

Tran C et al. Science 2009;324:787-790.

T

T

AR

Nucleus

EnzalutamideInhibits Binding of Androgens to AR

Inhibits Nuclear Translocation of AR

Inhibits AssociationOf AR with DNA

Tumor Death

AR

Cytoplasm

X

X

X

Enzalutamide Prolonged Survival, Reducing Risk of Death

Scher HI, et al. N Engl J Med. 2013; 367:1187-1197

Median OS Δ: 4.8 months37% reduction in risk of death

Enzalutamide Placebo

MedianOverall Survival (months)

18.4 13.6

Hazard ratio 0.63 95% CI 0.53, 0.75P value < 0.001

1°end point: OS and PFS

Enzalutamide 160mg QD

Placebo QD

PREVAIL Phase III Trial of Enzalutamide in Asymptomatic or Mildly Symptomatic

mCRPC Pre Chemotherapy

RANDOMIZE

1:1

mCRPCasymptomatic or

mildly symptomatic patients < 4 BPI

(n=1,680)Fully Accrued

A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer (PREVAIL)(NCT01212991). Available at www.clinicaltrials.gov. Accessed August 21, 2013.

PREVAIL Phase III Trial of Enzalutamide in Asymptomatic or Mildly Symptomatic mCRPC

Pre Chemotherapy Prelimianry Results

• Overall Survival 30% reduction in the risk of death

(Hazard Ratio=0.70; 95% confidence interval,0.59-0.83)

• Progression Free Survival: 81% reduction in risk of

radiographic progression or death compared with

placebo (Hazard Ratio=0.19; 95% confidence interval,

0.15-0.23).

PREVAIL: Overall Survival

Beer T, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA 1.

Median OS: Enzalutamide, 32.4 Months; Placebo, 30.2 months

Enzalutamide

Placebo

100

90

80

70

60

50

40

30

20

10

0

Hazard Ratio: 0.706

(95% CI: 0.60, 0.84)

P < 0.0001

Duration of Overall Survival (Months)

Surv

ival (%

)

211815129630 3633302724

Patients still alive at data cut off

Enzalutamide: 72%; Placebo: 63%

Antonarakis, et al AR-V7 and Resistance to

Enzalutamide and Abiraterone in Prostate

Cancer

Outcome AR-V7[–] → AR-V7[–]

(n=36)

AR-V7[–] → AR-V7[+]

(n=6)

AR-V7[+] → AR-V7[+]

(n=16)

PSA Response68%

(95%CI, 52 – 81%)

17%

(95%CI, 4 – 58%)

0%

(95%CI, 0 – 19%)

PSA Progression-Free Survival6.1 months

(95%CI, 5.9 mo – NR)

3.0 months

(95%CI, 2.3 mo – NR)

1.4 months

(95%CI, 0.9 – 2.6 mo)

Progression-Free Survival6.5 months

(95%CI, 6.1 mo – NR)

3.2 months

(95%CI, 3.1 mo – NR)

2.1 months

(95%CI, 1.9 – 3.1 mo)

AR-V7, the most important AR

transcriptional variant, is expressed at

detectable levels in CTCs in a significant

proportion of CRPC patients

Does the Earlier Use of

Chemotherapy or Next Generation

AR Targeting Agents Improve

Survival?

Chemohormonal therapy for CSPC

• CHAARTED Study

– High volume disease: ≥4 bony metastases, at least one outside of axial skeleton and/or visceral metastases

– 17 mo overall survival benefit only in high volume disease(pre-specified analysis)

– No overall survival benefit in low volume disease

• STAMPEDE Study

– Did not stratify by low vs high volume disease

• Conclusions

– Standard of care for high volume disease: ADT + docetaxel

– Standard of care for low volume disease:

ADT alone (CHAARTED) or

ADT + docetaxel (STAMPEDE)

Slide 31

Presented By Charles Ryan at 2017 ASCO Annual Meeting

Setting and hypothesis


Outcome measures


Abiraterone comparison: patients


Patient characteristics


Slide 36


Slide 37


Slide 38


Slide 39


Slide 40


Slide 41


Overall study design of LATITUDE

Presented By Karim Fizazi at 2017 ASCO Annual Meeting

Treatment arms were well balanced


Statistically significant 38% risk reduction of death


Comparing Overall Survival Across Studies

Presented By Eric Small at 2017 ASCO Annual Meeting

Docetaxel vs. Abiraterone

Slide 20

Presented By Eric Small at 2017 ASCO Annual Meeting

Docetaxel vs. Abiraterone

Selection of Treatment

● Based on side effects

– Preexisting neuropathy

– CHF

– Liver function abnormalities

– Health care costs

Waterfall plot showing maximum PSA falls after docetaxel administration in patients previously treated with abiraterone acetate.

Mezynski J et al. Ann Oncol 2012;annonc.mds119

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Kaplan–Meier plot showing overall survival (A) and time to PSA progression (B).

Mezynski J et al. Ann Oncol 2012;annonc.mds119

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

4

0

TROPIC: Phase III Registration Study

146 Sites in 26 Countries

Primary endpoint: OS

Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety

Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

cabazitaxel 25 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=378)

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=377)

*Oral prednisone/prednisolone: 10 mg daily.

Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease

mCRPC patients who progressed during and after treatment with a docetaxel-based regimen

(N=755)

4

1

Primary Endpoint: Overall Survival (ITT

Analysis)

MP 377 300 188 67 11 1

CBZP 378 321 231 90 28 4Number

at risk

Proportionof OS (%)

80

60

40

20

0

100

0 months 6 months 12 months 18 months 24 months 30 months

15.112.7Median OS (months)

0.59–0.8395% CI

<.0001P-value

0.70Hazard Ratio

CBZPMP

FIRSTANA: Study Design

159 centers worldwide

• CBZ 20 + PRED• Cabazitaxel 20 mg/m² Q3W

• + prednisone 10 mg/d n = 389

mCRPC and no prior chemotherapy

N = 1,168 pts

R

A

N

D

O

M

I

Z

E

• CBZ 25 + PRED• Cabazitaxel 25 mg/m² Q3W


• DOC + PRED• Docetaxel 75 mg/m² Q3W


FIRSTANA: Overall Survival

Median OS, months (95% CI)

DOC + PRED

CBZ 20 + PRED

CBZ 25 + PRED

24.3 (22.18–27.60)

24.5 (21.75–27.20)

25.2 (22.90–26.97)

CBZ 20 vs DOC

HR 1.009 (0.85–1.197)

P = 0.9967

CBZ 25 vs DOC

HR 0.97 (0.819–1.16)

P = 0.7574

0 3 6 9 12

366 336 307

356 319 296

345 325 296

15 18 21 24 27 30 33 36

Time (months)39 42 45 48 51 54

Number at risk

DOC + PRED

3

91 CBZ 20 + PRED

389

CBZ 25 + PRED 388

243

234

239

192

192

197

133

133

138

57

49

70

18

19

28

3

3

5

0

0

0

Pro

ba

bil

ity

of

overa

lls

urv

ival(%

)

0

10

20

30

40

50

60

70

80

90

100

DOC + PRED

CBZ 20 + PRED

CBZ 25 + PRED

Genomic aberrations of mCRPC

>90% of mCRPCs harbor actionable

mutations

Robinson D. Cell 2015

AR

TP53

PTEN

ETS fusion

~23% harbor mutations in DNA repair

pathway, including bi-allelic loss of

BRCA2, ATM, BRCA1, FANCA, RAD51B,

RAD51C and CDK12

50 mCRPCs 11 HG Un-tx PC

Approximately 50% (24 cases of mCRPC) with

aberration in DNA repair genes

Grosso 2012. Nature

PARP (Poly-(ADP-ribose) Polymerase)

PARP

Chromatic

modification

Cell DeathDNA repair

Transcriptiona

l regulation

DSB SSB/BER Apoptosis Necrosis

Olaparib in Prostate Cancer

• TOPARP study: n=49 patients with mCRPC, who are docetaxel-pre-treated. (Mateo et al. 2015)

– 32.7 % (16/49) response rate in “unselected” mCRPC patients.

– A post-hoc analysis of their prospectively obtained tumor tissue:

• 16 (33%) had mutations in DNA repair pathway (ATM, BRCA2 and others) (biomarker positive)

–14 of these patient responded

• 33 (67%) had no such mutations (biomarker negative)

–2 of these patients responded.

Conclusions

• The optimal sequence of agents is yet to be

determined

• Docetaxel chemotherapy for hormone

sensitive patients should be offered to high

disease volume patients

• The effect of lyase inhibitors on

chemotherapy is unknown.

Conclusions

• ArV7 is promising biomarker for sensitivity to

enzalutamide and abiraterone

• PARP inhibition is a promising therapeutic

target in patients with BRCA mutations

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