Treatment for Metastatic

Treatment for Metastatic

Castration-Resistant Prostate Cancer

Tony Wu.

Kaohsiung Veterans General Hospital

1

2014.7.25

Definition of mCRPC

• Patients with ongoing androgen deprivation therapy had serum testosterone level < 50 ng/dl (1.7 nmol/L)

• Patients have three consecutive rises of PSA levels, at least one week apart, resulting in two 50% increases over the nadir and absolute PSA level > 2.0 ng/ml.

• Antiandrogen withdrawal for at least 4 weeks for flutamide and for at least 6 weeks for bicalutamide

• Progression or appearance of two or more osseous lesions on

bone scan or soft tissue lesions using Response Evaluation

Criteria in Solid Tumors and with nodes >2 cm in diameter.

Goals of Treatment for mCRPC

• Overall survival

• Delay symptoms

• Maintain quality of life

Zoledronic acid

Docetaxel

Sipuleucel-T Abiraterone Cabazitaxel

Enzalutamide

Alpharadin Denosumab

2002 2004 2010 2011 2012 2013

Reimbursement of docetaxel (2006) Status in Taiwan

Approval of cabazitaxel (2012)

Approval of

abiraterone (2013)

Reimbursement of

Docetaxel

TAX-307

• 1006 men with mCRPC and good performance status

• docetaxel 75mg/M2 every three weeks

• docetaxel 30mg/M2 weekly

• mitoxantrone 12mg/M2 weekly

5

Median OS HR P value

Docetaxel q3w 18.9 months 0.76 0.009

Docetaxel q1w 17.4 months 0.91 0.36

Mitoxantrone 16.5 months 1

Tannock N Eng J Med 2004,351:1502

Modified Regimen in KSVGH

• Docetaxel 75 mg/M2  130 mg

• Titrated from 80 mg  100 mg  120 mg (maximal)

• Every 3 wks  every 4 wks

• Maximal: 10 cycles

• LHRH-A: 3-month regimen

Sipuleucel-T

Antigen presenting cells

PA2024

IV q2w x 3

Sipuleucel-T

IMPACT trial

• 512 men with asymptomatic or minimally-symptomatic mCRPC and good functional status

• sipuleucel-T vs. placebo on a 2:1 ratio

• Median survival : 25.8 months vs. 21.7 months

• 22% reduction in risk of death (HR=0.78, p=0.03)

• <10% of treatment arm exhibit PSA decline or reduction of radiographic tumor volume

9

mCRPC Patients failed after

docetaxel treatment

FIRSTANA ( NCT01308567)

Objectives

Primary Endpoint: Superiority of cabazitaxel in OS

Secondary Endpoint:

• Safety

• Progression Free Survival (PFS)

• Tumor response in patients with measurable disease

Study population

● mCRPC patients >18 yo

● Progressive disease while receiving hormonal therapy or after surgical castration

Study design

Phase III, multi-center,

randomized, open-label study in patients with mCRPC

N=1170

RANDOMIZE

Cabazitaxel 25 mg/m² 21-day cycle

Docetaxel 75 mg/m² 21-day cycle

Cabazitaxel 20 mg/m²

21-day cycle

Androgens Are Synthesized by Endocrine and Intracrine Sources: Measurable in Serum

• Androgens are

produced at 3 sites:

–Testes

–Adrenal glands –Prostate tumor

cells

Ryan et al. AACR Conference 2012; Abstract LB-434 (Oral presentation)

Abiraterone

CYP17 Inhibition With Abiraterone:

Durable Androgen Suppression

10.5 12.5 1

0 2.5 5.0 7.5

Start of

treatment 28 56 At

progression 0

2.5 7.5 12.5 10.5

Testosterone

DHEA

28 56

Androstenedione

Estradiol

5.0

nmol/L

0 20 40 60

pmol/L

50 30

10

Days Post Treatment Days

20 60 At

progression 0

3 6 5

ng/dL

2

10 70

Start of treatment

4

Lower limit of sensitivity

Start of

treatment 28 56 At

progression 2

1

nmol/L

Days 0.07

Days

CYP17, cytochrome P450 c17

Attard et al. J Clin Oncol 2008 ;26: 4563-4571

Ryan et al. AACR Conference 2012; Abstract LB-434 (Oral presentation)

投影片 21

A2 Permission required.

作者, 2011/1/31

COU-AA-301

Abiraterone for chemo-refractory mCRPC

Abiraterone acetate 1000 mg daily

Placebo daily

Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)

Prednisone 5mg twice daily Prednisone 5mg twice daily

Baseline, Cycle 1 (Day 15), subsequent treatment cycles (Day 1) Brief Pain Inventory (BPI) questionnaire

Primary end point:

• OS

Secondary end points:

• PSA response

• rPFS

Additional end points:

• Pain

• SREs

Efficacy end points

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

1195 mCRPC Failed one or two chemotherapy containing docetaxel

Randomized 2:1

Overall Survival – Interim Analysis

AA 797 736 657 520 282 68 2 0

Placebo 398 355 306 210 105 30 3 0

21 Hazard ratio = 0.65 (0.54-0.77) P < 0.001

Placebo + Prednisone:

10.9 months (95% CI, 10.2-12.0)

Abiraterone + Prednisone:

14.8 months (95% CI, 14.1-15.4) 100

80 60 40 20

Survival (%)

0 0 3 6 9 12 15 18

Placebo AA

Time to Death (Months)

Planned Interim Analysis

• August 20, 2010 – independent data monitoring committee (IDMC) recommended unblinding study

–552 events at time of interim analysis

–Improvement in overall survival crossed predetermined boundary for stopping

–IDMC recommended placebo arm patients be offered treatment with abiraterone acetate

de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )

All Secondary End Points Achieved Statistical Significance

Abiraterone + Prednisone

(n = 797)

Placebo + Prednisone

(n = 398)

HR 95% 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

Summary of AEs

Abiraterone + Prednisone (n = 791)

Placebo + Prednisone (n = 394)

All Grades Grades 3/4 All Grades Grades 3/4

All treatment-emergent AEs 98.9% 54.5% 99.0% 58.4%

Serious AEs 37.5% 32.1% 41.4% 35.3%

AEs leading to discontinuation 18.7% 10.5% 22.8% 13.5%

AEs leading to death 11.6% 14.7%

Deaths within 30 days of last dose 10.5% 13.2%

Underlying disease ^{7.5% 9.9%}

Other specified cause ^{2.9% 3.3%}

de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

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

Conclusions

• Abiraterone + prednisone

– 35.4% risk reduction of death (HR = 0.65)

– Median OS improved (14.8 vs. 10.9 months, p<0.001)

– Median time to PSA progression and median time to rPFS significantly improved

– AEs: Fluid retention, Hypokalaemia, LFT abnormalities, Hypertension

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

Updated Analysis (775 Events): OS Benefit of AA Increased from 3.9 to 4.6 Months

HR (95% CI): 0.74 (0.64-0.86) p < 0.0001

Abiraterone + prednisone:

15.8 months (14.8-17.0)

Placebo + prednisone:

11.2 months (10.4-13.1)

100

80

60

40

20

0 0

Survival (% )

6 12 18 24

797 398

657 306

473 183

273 100

15 6 Time to Death (Months)

30

0 0 AA

Placebo

AA

Placebo

Abiraterone for chemo-refractory mCRPC

• With longer follow-up, the magnitude of the treatment effect of

abiraterone + prednisone on OS increased in patients with mCRPC who had progressed post-docetaxel

– Median OS increased from 3.9 to 4.6 months – 26% risk reduction of death (HR = 0.74)

• Significantly improved pain palliation and reduced time to pain palliation

• Delayed pain progression

• Delayed time to SREs

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

Experience of AA in Taiwan

• Patient enrolled: 30

• Age: median:69 year, (55~84)

• Gleason score: G8~10:21, G7:6, G6:1, unknown:2

• Extent of disease: bone:30 (100%), LN:17(26.7%), lung:6 (20%), liver:4 (13.3%)

• All have at least one cycle of docetaxel treatment:

– Median cycles :8 (1~33)

– Median accumulated dose: 800 mg (58~2550)

• Five with 2nd line C/T:

– cabazitaxel:3, estramustine:2

• PSA at C1D1: median:328.5 ng/ml (8.1~3051.3)

Results

• FPFT: 2011/8/30, LPFT: 2012/7/2

• Enrolled: 30 subjects

• 2 subjects did not complete cycle 1 treatment, due to – dis. prog.  died 0.5 month after C1D1

– poor compliance  died 1.9 mo after C1D1

• 28 subjects can be evaluated

• Last followup: 2014/5/6 – ongoing treatment: 4

– survival followup only: 7

Cycles of AA Treatment

• 9 subjects completed planned 15 cycles treatment

• Median cycles completed: median: 8 (0.5~28.0)

• Reasons of end of treatment:

– Disease progression : 17 – Poor compliance: 1

– AE: 2 (bone pain, LV dysfunction, both after cycle 7)

– SAE: 1 (lung meta.  obs. pneumonia  death)

PSA Change , n=28

• Start to decline at C2D1:23(82.1%), C3D1: 1(3.6%) C4D1: 1(3.6%), never:3 (10.7%), (2 excluded)

• Decrease from C1D1:

>50%:15 (53.6%) , [PCR 2007: 43%]

>75%:12 (42.9%), >90%: 7(25%)

• Nadir: C2D1:9(32.1%), C3D1:4(14.3%),

C4D1:2(7.1%), C5D1:3(10.7%), C6D1:1(3.6%),

C7D1:1(3.6%), C8D1:3(10.7%),C11D1:1(3.6%),

C17D1:1(3.6%)

PSA Change

-100.0%

-50.0%

0.0%

50.0%

100.0%

150.0%

-100.0%

-50.0%

0.0%

50.0%

100.0%

150.0%

-100.0%

-50.0%

0.0%

50.0%

100.0%

150.0%

C2D1 C3D1 C4D1

Decrease: 22/27 Median: - 35.1%

Decrease: 16/25 Median: - 56.6%

Decrease: 20/26

Median: - 41.6%

PSA Change

-100.0%

-50.0%

0.0%

50.0%

100.0%

150.0%

C2 C3 C4

Survival, n=30

• Median overall survival: 19.2 months

• Mortality: 19 (63.3%)

– 18 subjects died on CaP

– 1 died on sepsis (12 days after EOT due to D.P)

– Median survival : 9.4 mos (0.5~22.9), mean:10 mos

• Alive: 11 (36.7%)

– 4 ongoing treatment, 7 survival FU

– Survival: mean: 24.7 mos (22.8~27.6)

0 . 0 5 . 0 1 0 . 0 1 5 . 0 2 0 . 0 2 5 . 0 3 0 . 0 m o n t h s

0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0

Proabability of survive %

Survival

p=0.0095

PSA responders

PSA nonresponders mean: 21.8 mos

mean: 12.2 mos

Treatment Emergent AEs Reported in ≥ 20% Patients

Taiwan

(n=30) Korea

(n=52) Combined

(n=82) Abiraterone

(n=791) Placebo (n=394) Total no of patients

with TEAEs 93% 94% 94%

Bone Pain 6 (20%) 10 (19%) 20% 194 (25%)

Hypokalemia 7 (23%) 6 (12%) 16% 143 (18%) 36 (9%)

Cardiac disorders 8 (27%) 3 (6%) 13% 126 (16%) 46 (12%)

Hypertension 7 (23%) 3 (6%) 12% 88 (11%) 32 (8%)

Alk-P increased 8 (27%) 0 10%

Abnormal LFT 6 (20%) 1 (2%) 9% 89 (11%) 35 (9%)

Insomnia 6 (20%) 1 (2%) 9%

COU-AA-301

Gr. 3 / 4 Liver Function Impaired

• #88600105: had liver meta. at entry, Gr.3 AST, ALT, Bil. increase, Gr.4 Alk-P increase never recovered

• #88600205: Gr.3 AST increase, persisted to death due to sepsis

• #88600508: Gr.3 AST,ALT increase, recovered

• #8200315: Gr.3 ALT increase, recovered

PCR 2007, 2013/1

Common AEs

• Most AEs were mineralocorticoid excess related

– Hypokalemia  G1~2: potassium supplement, G3~4: hold – Hypertension  Adjust dose of antihypertensive drugs

– No investigation into which patients actually need steroids and at what dosage to prevent ME

• Adrenal insufficiency: 0.5% in AA, 0.2% in placebo

Management of abnormal liver function tests

• Gr. 1, 2: closely monitor LFT (every week)

• Gr. 3 (AST/ALT increase > 5~20x UNL, T.Bil.> 3~10x UNL) – Hold abiraterone, till returned to baseline or Gr.1

– Resume with 750 mg

• Gr.4 (AST/ALT increase > 20x UNL, T.Bil.> 10x UNL)

– Discontinue AA immediately and no rechallenge allowed

Conclusions

Abiraterone acetate plus prednisolone effectively achieved PSA response rate in 53.6% of Taiwanese patients with chemo-

refractory mCRPC

43% of Taiwanese & Korean (PCR 2007, 2013/1) 38% Co-AA-301

82.1% of patients had PSA declined on C2D1, 46.4% reached PSA nadir on C3D1

Median overall survival=19.2 months

COU-AA-301: 15.8 months

PSA responders have much better survival (21.8 vs. 12.2 mo)

All AEs are manageable

Enzalutamide

Second-generation antiandrogen

Bind and inhibit AR, with no reported agonistic effects

Overall Survival AFFIRM Trial

Saad, Ther Adv Urol 2013,5:201

AFFIRM, TTPP, rPFS

AFFIRM Secondary Endpoints

48 Saad, Ther Adv Urol 2013,5:201

All Grades Grade ≥3 events MDV3100

(n=800)

Placebo (n=399)

MDV3100 (n=800)

Placebo (n=399)

Fatigue ^{33.6% 29.1% 6.3% 7.3%}

Diarrhea ^{21% 9%}

Hot flash ^{20% 0}

Headache ^{12% <1%}

Muscular pain ^{14% 1%}

Cardiac disorders

•Myocardial infarction

6.1%

0.3%

7.5%

0.5%

0.9%

0.3%

2.0%

0.5%

LFT abnormalities ^{1.0% 1.5% 0.4% 0.8%}

Seizure ^{0.6% 0.0% 0.6% 0.0%}

Enzalutamide - AFFIRM: Adverse Events

Possible Side Effects Associated with Enzalutamide: Seizures

CASE 1 2 3 4 5

Time on

study 2 months 10 months 2 months 5 months 10 months

On study

drug? Yes Yes Yes Off trial drug

for 26 days Yes Seizure type Focal onset Generalized Complex

partial status Focal onset Unknown, fall not witnessed

Recurrence No No No No No

Potential confounding factors

Large 5 x 4-cm temporal lobe

brain metastases

IV lidocaine inadvertently administered just before

seizure

Atrophy and leukoaraiosis on brain MRI;

Multiple CNS metastases:

Eye, meninges, cerebellar

Alcohol excess;

started on haloperidol 7

days prior

De Bono JS et al. Proc ASCO 2012;Abstract 4519.

Scher HI. N Engl J Med 2012;367(13):1187-97.

Practical Management - enzalutamide

• Dose:

– 160 mg qd (4 x 40 mg

capsules swallowed whole) – With or without food at same

time each day

– Maintain GnRH analog if already taking

 Dose modifications:

– Grade ≥3 toxicity or intolerable SE, withhold dosing for

1 week or until symptoms improve to Grade ≤2

• Caution in following populations:

– History of seizures

– End- stage renal disease – Severe hepatic impairment – Avoid engaging in activities

where loss of consciousness may cause serious harm

• Monitoring:

– INR monitoring for patients

also receiving warfarin

Treatment for chemo-naïve

mCRPC patients

COU-AA-302

Abiraterone for Chemo-naïve mCRPC

Abiraterone 1000 mg daily +

Prednisone 5 mg BID (actual n = 546)

Co-primary end points:

• rPFS (central review)

• OS

Placebo daily +

Prednisone 5 mg BID (actual n = 542) Progressive mCRPC

without prior chemotherapy;

Asymptomatic or mildly symptomatic

Patient Population

BID, twice daily; rPFS, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG

a

Stratification by ECOG PS 0 vs 1.

R A N D M O Z I E D 1:1

Secondary end points:

• Time to opiate use

• Time to initiation of chemotherapy

• Time to ECOG PS deterioration

• Time to PSA progression

Exploratory end points:

• HR-QoL

Abiraterone Doubled Time to rPFS

IA3 data. rPFS assessed by investigator review at prespecified IA.

100

80

60

40

20

0 0 Subjects Without Progression or Death (%)

6 12 18 24 30 36

546 542

389 244

240 133

157 78

20 7

0 0 Abiraterone

Prednisone

117 45 Months From Randomization Abiraterone

Prednisone

Abiraterone (median): 16.5 months Prednisone (median): 8.2 months

HR (95% CI): 0.52 (0.45-0.61) p Value: < 0.0001

15 9

3 21 27 33

485 406

311 176

195 99

131 62

66 20

4 0

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

COU-AA-302 Overall Survival

100

80

60

40

20

0 0

Subjects Without Death (%)

6 12 18 24 30 36

546 542

524 508

482 465

421 400

68 67

0 0 Abiraterone

Prednisone

333 283 Months From Randomization Abiraterone

Prednisone

Abiraterone (median): 35.3 months Prednisone (median): 30.1 months

HR (95% CI): 0.79 (0.66-0.95) p Value

: 0.0151

15 9

3 21 27 33

538 534

503 492

452 437

393 361

175 153

15

9

Subsequent therapy was common

a

First patient crossover after unblinding on 7 May 2012. IA3 data clinical cut-of f date on 22 May 2012.

b

Prior to unblinding (eg. not per protocol). IA3 data.

Abiraterone (n = 419)

n (%)

Prednisone (n = 482)

n (%) No. with selected subsequent

therapy for mCRPC

274 (65) 347 (72)

Docetaxel 239 (57) 304 (63)

Cabazitaxel 60 (14) 70 (15)

Ketoconazole 39 (9) 63 (13)

Abiraterone

38 (9) 78 (16)

Sipuleucel-T 33 (8) 28 (6)

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

Improvement in All Clinical End Points

Abiraterone Prednisone Median

(months) Median

(months) HR (95% CI) p Value Secondary end points

Time to opiate use (cancer-

related pain) NR 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 Exploratory end points

Time to BPI-SF pain

interference progression 10.3 7.4 0.80 (0.68-0.93) 0.0049

Time to degradation in

FACT-P (total score) 12.7 8.3 0.79 (0.67-0.93) 0.0046

Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone

• 29% of patients in the prednisone control arm had a decline in PSA of ≥ 50%

• 69% of patients in the abiraterone arm had a decline in PSA of ≥ 50%

-25

Maximal Decline From Baseline (%)

-50 -75 -100 0 25 50 75 100

Prednisone

IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.

Abiraterone

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

Safety Profile Remains Favorable

Abiraterone (n = 542)

%

Prednisone (n = 540)

%

Adverse event All grades Grades 3/4 All grades Grades 3/4

Fatigue 40 2 35 2

Fluid retention 29 1 24 2

Hypokalemia 17 3 13 2

Hypertension 22 4 14 3

Hyperglycemia 9 3 8 2

Weight gain 5 0 7 0

Cardiac disorders 21 7 18 4

ALT increased 12 6 5 1

AST increased 11 3 5 1

Abiraterone for chemo-naïve mCRPC

• Reduces risk of disease progression by 48%

• Decreases risk of death by 21%

• Delays time to opiate use and chemotherapy

• rPFS, OS, and TTPP were positively associated with the magnitude of PSA decline and inversely associated with baseline PSA in a step-wise fashion

• Improves quality of life measures (BPI-SF, FACT-P)

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

PREVAIL Study

Chemo-naïve mCRPC, viscera involvement allowed

ECOG PS 0/1, asymptomatic or minimally symptomatic Enzalutamide 160 mg/day vs. placebo

Coprimary endpoints: rPFS, OS

Secondary endpoints: time to C/T, time to SRE, time to PSA progression, best overall soft tissue response, a decline in the PSA level of 50% or more

1717 patients enrolled, enzalutamide:872, placebo:845 Stopped after planned interim analysis because of

significant benefit in treatment group ₆₂

Radiographic Progression Free Survival

enzalutamide placebo

Radiographic progress or death 118/832(14%) 321/801(40%)

Overall Survival

64

enzalutamide placebo

Death 241/872(28%) 299/845(35%)

Median overall survival 32.4 months 30.2 months Beer et al. NEJM 2014

Time to Initiation of Chemotherapy

66

enzalutamide placebo Median time to C/T 28 months 10.8 months

Beer et al. NEJM 2014

Time to PSA Progression

68

Radium-223 Targets Bone Metastases

• Alpha-particles induce ds DNA breaks in adjacent tumour cells ¹

• Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue

Range of alpha-particle

Radium-223

Bone surface

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care R

A N D M O I S E D

2:

1

N = 921 PATIENTS

• Confirmed symptomat ic CRPC

• ≥ 2 bone metastases

• No known visceral metastases

• Post-

docetaxel or unfit for docetaxel

Planned follow-up is 3 years

• Total ALP:

< 220 U/L vs

≥ 220 U/L

• Bisphosphonate use:

Yes vs No

• Prior docetaxel:

Yes vs No

STRATIFICATION

Clinicaltrials.gov identifier: NCT00699751

ALSYMPCA Study Endpoints

• Primary Endpoint

– Overall survival (OS)

• Secondary Endpoints

– Time to first SRE

– Time to total ALP progression – Total ALP response

– Total ALP normalization – Time to PSA progression – Safety

– Quality of life

ALSYMPCA Updated Analysis Overall Survival

Radium-223, n = 614 Median OS: 14.9 months Placebo, n = 307

Median OS: 11.3 months

HR = 0.695

95% CI, 0.581, 0.832 P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

0 10 20 30 40 50 60 70 80 90 100

%

Prior docetaxel use No prior docetaxel use

ALSYMPCA Updated Analysis OS by Stratification Variables: Prior Docetaxel Use

Radium-223, n = 352 Median: 14.4 months

Placebo, n = 174 Median: 11.3 months

HR = 0.710 P = 0.00307

Radium-223, n = 262 Median: 16.1 months

Placebo, n = 133 Median: 11.5 months

HR = 0.745 P = 0.03932

100 90 80 70 60 50 40 30 20 10 0

0 4 8 12 16 20 24 28 32 36 40 Month

%

100 90 80 70 60 50 40 30 20 10 0

0 4 8 12 16 20 24 28 32 36

%

Month

ALSYMPCA Updated Analysis:

Radium-223 Improved OS Across All Patient Subgroups

SUBGROUP

PATIENTS (n) MEDIAN OS (months)

HR 95% CI RADIUM-

223 PLACEBO RADIUM-

223 PLACEBO

All patients 614 307 14.9 11.3 0.70 0.58-0.83

Total ALP

<220 U/L 348 169 17.0 15.8 0.82 0.64-1.07

≥220 U/L 266 138 11.4 8.1 0.62 0.49-0.79

Current use of bisphosphonates

Yes 250 124 15.3 11.5 0.70 0.52-0.93

No 364 183 14.5 11.0 0.74 0.59-0.92

Prior use of docetaxel

Yes 352 174 14.4 11.3 0.71 0.56-0.89

No 262 133 16.1 11.5 0.74 0.56-0.99

Baseline ECOG PS

0 or 1 536 265 15.4 11.9 0.68 0.56-0.82

≥2 77 41 10.0 8.4 0.82 0.50-1.35

Extent of disease

<6 Metastases 100 38 27.0 NE 0.95 0.46-1.95

6-20 Metastases 262 147 13.7 11.6 0.71 0.54-0.92

>20 Metastases 195 91 12.5 9.1 0.64 0.47-0.88

Superscan 54 30 11.3 7.1 0.71 0.40-1.27

Opioid use

Yes^a 345 168 13.9 10.4 0.68 0.54-0.86

No^b 269 139 16.4 12.8 0.70 0.52-0.93

Favors

Radium‐223 Favors Placebo

ALP, alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.

a. Includes patients with a score of 2 or 3 on the World Health Organization (WHO) ladder for cancer pain. 

b.Includes patients without pain or opioid use at baseline and patients with a score of 1 on the WHO ladder for cancer pain.

SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213‐23.

0.5 1.0 2.0

74

Month 0 3 6 9 12 15 18 21 24 27 30

Radium- 614 487 332 193 125 62 31 8 8 1 0

ALSYMPCA Updated Analysis

Time To First Symptomatic Skeletal Event

HR = 0.64 P < 0.0001

Radium-223, n = 614 Median: 12.2 months

Placebo, n = 307 Median: 6.7 months

0 10 20 30 40 50 60 70 80 90 100

%

76

SSE (ALSYMPCA) SRE

Symptomatic Skeletal Event Skeletal Related Event

Definition Spinal cord compression Spinal cord compression

Tumor-related orthopedic Surgical intervention

Surgery to bone

New symptomatic pathological fractures

Pathological fractures

Use of EBRT to relieve skeletal symptoms

Radiation therapy to bone

Hypercalcemia of malignancy

Characteristics No regular radiologic image and

more clinical relevant

ALSYMPCA Updated Analysis

Secondary Endpoints: ALP and PSA

Radium-223 n (%)

Placebo n (%)

P value Total ALP response

30% reduction 50% reduction

233 (47) 135 (27)

7 (3) 2 (<1)

<0.001

<0.001 Total ALP

normalization* 109 (34) 2 (1) < 0.001

Hazard ratio

95% CI P value

Time to Total ALP progression

0.167

( 0.129, 0.217) <0.00001 Time to PSA progression 0.643

( 0.539, 0.768) <0.00001

ALSYMPCA Updated Analysis AEs of Interest

All Grades Grades 3 or 4

Patients with AEs n, (%)

Radium-223 n = 600

Placebo n = 301

Radium-223 n = 600

Placebo n= 301 Hematologic

Anemia 187 (31) 92 (31) 77 (13) 39 (13)

Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)

Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2)

Non-Hematologic

Bone pain 300 (50) 187 (62) 125 (21) 77 (26)

Diarrhea 151 (25) 45 (15) 9 (2) 5 (2)

Nausea 213 (36) 104 (35) 10 (2) 5 (2)

Vomiting 111 (19) 41 (14) 10 (2) 7 (2)

Constipation 108 (18) 64 (21) 6 (1) 4 (1)

ALSYMPCA: <br />Grade 3/4 Hematologic AEs by Prior Docetaxel Use

Safety of Cytotoxic Chemotherapy Following Radium-223 Dichloride (Rd-223) Therapy

•Number of deaths and causality

during 30 days post Chemo and limited available hematologic data were similar in both groups

2012 ESMO

1.5-Year Posttreatment Follow-up <br />of Radium-223 Dichloride (Radium-223) <br />in Patients With Castration-Resistant Prostate Cancer (CRPC) and <br />Bone Metastases From the <br />Phase 3 ALSYMPCA Study

ALSYMPCA Long-term Follow-Up

Presented By Sten Nilsson at 2014 Genitourinary Cancers Symposium

Conclusions

Optimizing Ra-223

Ongoing clinical trial

• 80 kBq/kg x 6 doses

• 50 kBq/kg x 12 doses

• 50 kBq/kg x 6 doses

84

Ketoconazole

• A weak inhibitor of CYP11A and CYP17A that suppresses synthesis of adrenal and tumor tissue androgens

• Must be given with replacement steroids

• AE: Nausea, hepatotoxicity

• Numerous single-arm studies show PSA response rates (>50% decline in PSA) of 30-60%

• Ketoconazole has not shown significant OS

improvements in patients with symptomatic,

chemotherapy-naive mCPRC

Drug Failed

• Orteronel (TAK-700) + prednisolone

– similar to abiraterone, inhibits 17, 20 lyase activity of CYP17A but does not inhibit 17-hydroxylase to the same extent

– for chemo-naïve mCRPC (C21004)

• rPFS: 11.0 vs. 8.3 months (HR=0.7, p<0.001)

• OS: 31.4 vs 29.5 months (HR=0.9, p=0.314) – For chemo-refractory mCRPC (C21005)

• rPFS: HR:0.755, p=0.00029

• OS: HR:0.894, p=0.226

Drugs Under RCT

• Tasqinimode:

– a dual angiogenesis inhibitor and immune modulatory agent

• ARN-509:

– a novel small molecule AR antagonist

• Lipilimumab:

– human monoclonal antibody blocking immune

checkpoint cytotoxic T lymphocyte antigen (CTLA)- 4 receptors enhancing or prolonging T-cell

activation

Prostate Cancer Disease Stages<br />

Optimal Sequences of Therapies ???

• mCRPC  docetaxel (prior abiraterone era)

• mCRPC  abiraterone/enzalutamide  taxane – Current trend of shifting

– Good for Gle.<8, durable response to initial ADT

• mCRPC  docetaxel  AA/enzalutamide  cabazitaxel – For Gle.8~10, poor or short response to initial ADT

• Ra-223: symptom relief and survival benefit

• Combination therapy ?

Recommendation from PCWG-2?

To edit footers: "insert tab>header and footer" and apply to all 03.19.2012 90

Minimum exposure of 12 weeks; PSA values within first 3

months should not be used for clinical

decision making

Continue treatment, when there is no clear evidence of progression or

safety not compromised

Key safety issues with novel agents

• Safety is even more important then efficacy

• Caucasian data might not be explored to Asian patients

• Long term safety data

– Understand any treatment emergent AEs going to encounter – Identify patients at risk to develop AEs

• Management of AEs

– Understand how to avoid / prevent / manage AEs

– Dose modifications: when and how?

Management of Bone Health

Recommended: Calcium and vitamin D supplement

• Published data on the use of supplemental calcium and

vitamin D to minimize bone mineral density loss in patients receiving ADT are confusing, and the discussion contentious

Optional: denosumab or zoledronic acid

• Delay time to first SRE

• Decrease incidence of SRE

92

• ASCO recommends eliminating treatment that is unlikely to be effective in patients who meet all of the following criteria:

– Patients with low performance status (3 or 4)

– Who have not benefited from prior standard therapy

– Who have no further standard treatment options for their disease

– Who are not eligible for a clinical trial

• When treatment is no longer likely to work, our chief

responsibility as physicians is to help our patients live in comfort and dignity

• Handle the bone pain, voiding problem, lymphedema, anemia,

spinal cord compression

Thanks for Your Attention

Chemo-naïve mCRPC

PSA decline

>50%

PSA decline

>90% rPFS

months

Time To C/T (mos)

OS mos

Abiraterone 70% 36% 16.5 26.5 35.3

Prednisolone 30% 9% 8.3 16.8 30.1

HR 0.52 0.61 0.79

Enzalutamide 78% 47% NR 28 32.4

Placebo 3% 1% 3.9 10.8 30.2

HR 0.19 0.35 0.19

docetaxel 45% 18.9

Chemo-refractory mCRPC

PSA decline

>50% TTPP

(mos)

Objctive response

rPFS (mos)

OS (mos)

Abiraterone 29.1% 10.2 14% 5.6 15.8

Prednisolone 10.1% 6.6 3.6 11.2

HR 0.58 0.67 0.74

Enzalutamide 54% 8.3 29% 8.3 18.4

Placebo 2% 3.0 2.9 13.6

HR 0.25 0.4 0.63

CBZ 39.2% 6.4 6.4 15.1

Ra223 (-24%) 3.6 14.9

Placebo (+45%) 3.4 11.3

HR 0.643 0.695