mKDPK’de Sonunda Gerçek İlerleme!

Kanıt: Klinik çalışmalarda ZYTIGA

Dr. Sevil Bavbek

5. Türk Tıbbi Onkoloji Kongresi

Mart 2014, Antalya

Endocrine therapies

Testosterone

DNA

Cell division

Testis Adrenals

Autocrine

secretion

Castration

(aLHRH or Surg.) Abiraterone

Orteronel

Abiraterone

Orteronel

Androgen Receptor inhibitors:

-Bicalutamide

-MDV 3100

-ODM-201

-ARN 509

Abiraterone:

CYP17 blockade inhibits androgen synthesis b

COU-AA-301: Abiraterone acetate

Phase III post-chemotherapy

Abiraterone 1000mg daily

Prednisone 5mg BID

n=797

Primary end point:

• OS (25% improvement;

HR 0.8)

Secondary end points:

• TTPP

• rPFS

• PSA response

Efficacy end points (ITT)

Placebo daily

Prednisone 5mg BID

n=398

R A N D O M I Z E D

2:1

• 1195 patients with

progressive mCRPC

• Failed 1 or 2

chemotherapy

regimens, 1 of which

contained docetaxel

BPI, Brief Pain Inventory; HR, hazard ratio; ITT, intent to treat;

TTPP, time to PSA progression;

rPFS, radiographic progression-free survival;

PSA, prostate-specific antigen

Fizazi et al. Lancet Oncology 2012 3(10):983-92

Harland et al. Eur J Cancer 2013 Aug 22. pii: S0959-8049(13)00720-X. doi:

10.1016/j.ejca.2013.07.144. [Epub ahead of print]

Prospective data collection: Day 1 of Cycles 1, 4, 7, 10, and every

6 cycles thereafter until the end of study treatment

FACT-P questionnaire

ECOG performance status 0-1 vs 2

Worst pain over previous 24 hours BPI short form; 0-3 (absent) vs 4-10 (present)

Prior chemotherapy 1 vs 2

Type of progression PSA only vs radiographic with or without PSA

Stratification by:

COU-AA-301 Baseline Demographics

Abiraterone(n=797)

Placebo (n=398)

Total (n=1195)

Median age, years (range)

69.0 (42-95)

69.0 (39-90)

69.0(39-95)

Race, %

White 93.3 92.7 93.1

Black 3.5 3.8 3.6

Asian 1.4 2.3 1.7

ECOG PS 2, % 10.7 11.1 10.8

Significant pain present, % 44.3 44.0 44.2

2 Prior chemotherapies, % 28.2 28.4 28.3

Baseline Disease Characteristics

Abiraterone + Prednisone(n = 797)

Placebo +Prednisone(n = 398)

Extent of disease

Bone 89% 90%

Node 45% 41%

Liver 11% 8%

Lung 13% 11%

Other Visceral 6% 5%

Prostate mass 8% 6%

Other tissue 5% 5%

Viscera, NOS 0.1% 0

PSA (median, ng/mL) 128.8 (0.4-9253) 137.7 (0.6-10114)

Hemoglobin (median, g/dL) 11.8 11.8

LDH (median, IU/L) 223.0 237.5

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005 (Supplementary Data)

Baseline Disease Characteristics

Abiraterone + Prednisone

(n = 797)

Placebo + Prednisone

(n = 398)

Gleason score at initial

diagnosis

≤7 48.9% 46.0%

≥8 51.1% 54.0%

PSA at initial diagnosis (ng/mL)

Median (range) 27 (0.1-16065.9) 35.5 (1.1-7378.0)

Previous cancer therapy

Surgery 54% 49%

Radiotherapy 72% 72%

Hormonal 100% 100%

Other* 100% 100%

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005 (Supplementary Data)

* Includes chemotherapy

Survival Benefit Observed With AA Is Consistent For Majority of Subgroups

Fizazi et al, abstr #7000, ECCO 2011

Survival by Baseline ECOG Status

Favors AA for ECOG 0-1, but not for ECOG 2;

May be Attributed by the Small Sample Size

Median OS – Abiraterone + prednisone vs. Placebo + prednisoneECOG 0-1: 17 vs. 12.3 months (HR=0.74; 95% CI: 0.63-0.87; p=0.0002)

ECOG 2: 7.3 vs. 7 months (HR=0.77; 95% CI: 0.50-1.17; p=0.2166)

ECOG 0-1

20

0

0 6 12 18 24

715353

608281

452174

26397

146

Time to Death (Months)

Surv

ival

(%

)

30

00

ECOG 2 (10% of patients)

100

80

60

40

20

0

0 6 12 18 24

8245

4925

219

103

10

Time to Death (Months)

Surv

ival

(%

)30

00

100

80

60

40

Abiraterone + prednisone:

7.3 months

Abiraterone + prednisone:

17 months

Placebo +

prednisone:

7 months

Placebo + Prednisone:

12.3 months

Fizazi et al. Lancet Oncol 2012; 13(10): 983-992 (Supplementary Appendix)

Survival Benefit Observed

With AA Across All Age Groups

Median OS – Abiraterone + prednisone vs. Placebo + prednisone: < 65 years: 15.0 vs. 11.2 months (HR=0.69; 95% CI: 0.53-0.91)≥ 65 years: 16.2 vs. 11.1 months (HR=0.76; 95% CI: 0.63-0.90)≥ 75 years: 15.6 vs. 9.3 months (HR=0.64; 95% CI: 0.48-0.85)

Placebo +

prednisone :

11.2 months

Placebo +

prednisone :

11.1 months

Placebo +

prednisone :

9.3 months

< 65 Years ≥ 65 Years ≥ 75 Years

0

232119

18388

13755

7522

20

Time to Death (Months)

Surv

ival

(%

)

0

6 12 18 24 30

00

20

40

60

80

100

0

565278

474218

336128

19878

136

Time to Death (Months)

Surv

ival

(%

)

0

6 12 18 24 30

00

20

40

60

80

100

0

220111

18082

13144

7627

64

Time to Death (Months)

0

6 12 18 24 30

00

20

40

60

80

100

Surv

ival

(%

)

Abiraterone +

prednisone :

15.0 months

Abiraterone +

prednisone :

16.2 months

Abiraterone +

prednisone :

15.6 months

Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

Survival Benefit Observed With AA

for Subgroups With and Without Visceral Disease at Study Entry

Median OS – Abiraterone + prednisone vs. Placebo + prednisone: Without visceral disease: 17.1 vs. 12.3 months (HR = 0.69; 95% CI: 0.58-0.82)

With visceral disease: 12.9 vs. 8.3 months (HR = 0.79; 95% CI: 0.59-1.05)

Placebo +

prednisone :

8.3 months

With Visceral Disease

100

80

60

40

20

0

0 6 12 18 24

544299

466242

345146

20278

155

Time to Death (Months)

Surv

ival

(%

)

30

00

100

80

60

40

20

0

0 6 12 18 24

25399

19164

12837

7122

01

Time to Death (Months)

Surv

ival

(%

)

30

00

Without Visceral Disease

Abiraterone + prednisone :

17.1 months

Placebo +

prednisone :

12.3 months

Abiraterone + prednisone :

12.9 months

Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

All Secondary End Points Achieved

Statistical Significance

Abiraterone + Prednisone

(n = 797)

Placebo + Prednisone

(n = 398)

HR95% CI

P Value

TTPP (months) 10.2 6.6 0.58(0.46, 0.73)

< 0.001

rPFS (months) 5.6 3.6 0.67(0.58, 0.78)

< 0.001

PSA response rate

Total 38.0% 10.1% - < 0.001

Confirmed 29.1% 5.5% - < 0.001

Objective response

(RECIST)14.0% 2.8% - < 0.001

de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Total and Confirmed PSA Response

Rates Were Significantly Higher With AA

0

5

10

15

20

25

30

35

40

45

Abiraterone + prednisone Placebo + prednisone

Total

Confirmed38.5

29.5

10.1

5.5

p < 0.0001

p < 0.0001

PS

A R

esp

on

se R

ate

(%

)

Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

Fizazi et al. Lancet Oncol 2012; 13(10): 983-992

AE, adverse event.

COU-AA-301: Similar AE incidence rates were

observed in both groups*

Abiraterone +

Prednisone

(n=791)

Placebo + Prednisone

(n=394)

All

Grades

Grades

3/4

All

Grades

Grades

3/4

All AEs 99% 60% 99% 61%

Serious AEs 42% 36% 44% 38%

AEs leading to

discontinuation 21% 11% 24% 14%

AEs leading to death 13% – 16% –

Fizazi et al. Lancet Oncology 2012 3(10):983-92

de Bono et al. New Eng J Med 2011; 364: 1995-2005

*Grade 1 or 2 urinary tract infections were higher with abiraterone compared with

placebo: 12% vs 7%, p=0.02

COU-AA-301: AEs of special interest

Abiraterone + Prednisone

(n=791)

Placebo + Prednisone

(n=394)

All

Grades Grade 3 Grade 4

All

Grades Grade 3 Grade 4

Fluid retention

and edema 31% 2% <1% 22% 1% 0

Hypokalemia 17% 3% <1% 8% 1% 0

Cardiac disorders 13% 3% 1% 11% 2% <1%

LFT abnormalities 10% 3% <1% 8% 3% <1%

Hypertension 10% 1% 0 8% <1% 0

Fizazi et al. Lancet Oncology 2012 3(10):983-92

de Bono et al. New Eng J Med 2011; 364: 1995-2005

Abiraterone ile klinikyararlanım Gleason skorundan bağımsız

Gleason skoruprediktif değil

Pain IntensityAbiraterone + Prednisone

(n=797)

Placebo +Prednisone

(n=398)

P

Value

HR

(95% CI)

Palliation rate45%

(157/349)

28.8%

(47/163)0.0005 -

Time to palliation

(median)5.6 months 13.7 months 0.0018 1.675

(1.119–2.341)

Time to progression

(25th percentile)7.4 months 4.7 months 0.0088 0.717

(0.557-0.922)

Duration of palliation

(median)4.2 months 2.1 months 0.0056 -

Logothetis et al. Lancet Oncol 2012: 2012; 13: 1210–17

Symptomatic Improvement –Pain Interference

AA

(n = 797)

Placebo

(n = 398)

P Value

Palliation, n (%) 132/223 (59.2) 38/100 (38.0) 0.0004

Time to palliation (months)

Median (95% CI)1.02 (0.92-1.91) 3.71 (2.69-4.44) 0.0009

Time to progression (months)

25th percentile (95% CI)9.27 (7.39-12.88) 4.57 (2.79-6.47) 0.0019

Outcomes

AA

(n = 797)

Placebo

(n = 398)

P Value

Overall survival

Median, months 14.8 10.9 < 0.0001

PSA response rate

Total 38.0% 10.1% < 0.0001

Confirmed 29.1% 5.5% < 0.0001

Radiographic PFS

Median, months 5.6 3.6 < 0.0001

Time to first SRE (pathologic fracture/spinal cord compression/

palliative radiation/bone surgery)

25th percentile, days 301.0 150.0 < 0.0001

Logothetis et al Lancet Oncol 2011

AA Was Associated With

Higher FACT-P ResponsesPlacebo + prednisone (n = 398)Abiraterone + prednisone (n = 797)

* **

*p = 0.284 †

† *

70

40

30

10

0

Pat

ien

ts W

ith

Imp

rove

me

nt

(%)

20

60

50

* p < 0.001† p < 0.05

48 32 46 28 54 48 54 39 41 28 58 40 46 2544 33

Harland et al. ECCO 2011: Abstract 7001 (oral presentation)

AA Delayed Time to Deterioration of QoL

* p<0.001450

250

200

100

0

Me

dia

n t

ime

to

de

cli

ne

(d

ays

)

150

300

400

350

50

*

P=0.325

*

* *

*

*

Placebo + prednisone (n=398)Abiraterone + prednisone (n=797)

363 253 339 240 168 89 424 226 424 274 262 142337 169 253395

*

Harland et al. ECCO 2011: Abstract 7001 (oral presentation)

COU-AA-301 Conclusions

Median OS improvement of approximately 5 months

– 36% improvement in median survival

– 35% risk reduction of death (HR = 0.65)

Improved TTPP, PFS, and PSA response rate

– 38% of patients had a >50% reduction in PSA

Clinical benefit for treatment of bone metastases:

–Improved pain palliation

–Delayed pain progression and time to SRE

–Effect sustained over treatment cycles

Favorable Safety Profile

Abiraterone acetate prolonged OS in patients with mCRPCwho have progressed after docetaxel-based chemotherapy

Prostate cancer drug development

Chemotherapy

Tum

or

volu

me

& a

ctiv

ity

NOTE: This diagram represents typical disease progression. Some patients are metastatic at diagnosis and are thus still castrate sensitive. Abiraterone

AcetateSipeuleucel-T

Castration

Docetaxel AbirateroneAcetateCabazitaxelAlpharadinEnzalutamide