CÁNCER DE PRÓSTATA RESISTENTE A LA CASTRACIÓN CON ...HISTORIA NATURAL DEL CÁNCER DE PRÓSTATA...

CÁNCER DE PRÓSTATA RESISTENTE A LA

CASTRACIÓN CON METÁSTASIS ÓSEAS

SINTOMÁTICAS

Joan Carles

Jefe de Sección. Profesor Asociado Oncología UIC

Director del Programa de GU, SNC y Sarcomas

Hospital Universitario Vall d’Hebron

Barcelona

Resistente a la castración Sensible a la castración

HISTORIA NATURAL DEL CÁNCER DE PRÓSTATA

Sintomático ASINTOMÁTICO

No metástasis

Terapia local

Deprivación de andrógenos

Quimioterapia

Postquimioterapia

Death

Desde el punto de vista del tratamiento hormonal existen dos tipos de pacientes: 1. Cáncer de próstata sensible a terapia hormonal 2. Cáncer de próstata resistente a la castración

Metástasis

Tannock et al, NEJM 2004; 351(15): 1502-12 Petrylak et al, NEJM 2004; 351(15): 1513-20

DOCETAXEL IS STANDARD IN FIRST-LINE CPRC

Docetaxel 3 w

Docetaxel

weekly

Intensidad dolor SM (meses) 1-año, % 2-años, % 3-años,%

Mínimo/ninguno PSA-DT > 45 días PSA-DT < 45 días

21.4 32.4 16.5

75 86 72

43 62 33

29 45 25

Leve 15.0 56 20 11

Moderado/ severo 13.1 52 20 4

Oudard S, et al. BJUI 2009

Supervivencia en el CPRC según la intensidad del dolor

90% of patients with mCRPC

have bone metastases

The pelvis, vertebral column,

ribs, and femur are common

sites of bone metastases

Visceral metastases are much

less common and may occur

in the liver, lungs or brain

~70 %

bone

lymph nodes

~20%

bone

visceral

5–10%

lymph node

only

< 5%

visceral only

de Bono et al. Lancet 2010;376:1147. de Bono et al. New Engl J Med 2011;364:1995. Ryan et al. J Clin Oncol 2012;30(suppl.):abstr LBA4518. de Bono et al. J Clin Oncol 2012;30(suppl.):abstr 4519.

Bone is the Most Common Site of Metastases in Prostate Cancer Patients

SREs are defined as:1

Incidence in metastatic prostate cancer:2*

Prior SRE increases the risk of subsequent SREs3

1.www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf

(Accessed 2 March 2011);

2. Saad F et al. J Nat Clin Inst 2002;94:1458–68;

3. Saad F et al. Clin Genitourin Cancer 2007;5:390–6.

Pathological

fracture

Radiation to

bone

Surgery to

bone

Spinal cord

compression

29% 3% 7% 22%

*Proportion of patients with metastatic CRPC (castration-resistant prostate cancer) who experienced SRE(s)

in the placebo arm of a 15-month study

Bone metastases can result in serious and debilitating skeletal-related events (SREs)

GUIAS CLÍNICAS EUA 2014

PREGUNTA 1

Radium-223 Targets Bone Metastases A natural bone-seeker1 because

it is a ‘calcium mimetic’2

Naturally targets new bone growth in and around bone metastases

Half-life: 11.4 days3

Shelf life: 28 days3

No long-lived radioactive waste products after decay2

Radium-223 is excreted by the small intestine

Ca

Sr

Ba

Ra

1. Henriksen et al. Can Res 2002;62:3120. 2. Nilsson et al. Presented at: American Society

for Radiation Oncology annual meeting 2010: Poster 2385, 3,- Xofigo® (radium Ra 223

dichloride) solution for injection Summary of Product Characteristics (SmPC). Berlin,

Germany: Bayer Pharma AG, 4,- . Nilsson S, et al. Int J Radiat Oncol Biol Phys. 2010;

78(3 suppl):S375-S376.

Características Físicas α β

Radionúclidos Radio-223 Estroncio-89, Samario-153

Tamaño

Masa de la partícula 7000 1

Energía inicial(MeV) 5–9 0.05–2.3

Penetración en tejidos (μm) 40–100 50–12,000

LET (KeV/μm) 60–300 0.1–1.0

Carga +2 –1

Pares de iones/μm 2000–7000 5–20

Lesiones en DNA para muerte celular 1–4 > 1000

Semin Nucl Med 2008;38:358

CARACTERISTICAS FISICAS

Cortesía Dra. M.J. Méndez

Beta particle emission

Alpha particle emission

Non-reparable double-strand DNA breaks

Single-strand DNA breaks are

not lethal

Potent Anti-tumour Effects of Radium-223

Radium-223 selectively targets bone, specifically bone metastases

It emits high-energy ionizing alpha particles which cause lethal,

double-strand DNA breaks in adjacent cells

This results in a highly localized anti-tumor effect in bone metastases

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

Short range of alpha emitter

reduces bone marrow exposure

Alpha Emitter Versus Beta Emitters

1

3

Long range of beta emitters

may increase bone marrow exposure

and associated toxicities

Alpha Emitter

(OS benefit + pain palliation)

Beta Emitters

(Pain palliation only)

Marrow

Bone

Radium-223

Marrow

Bone

Strontium-89

and

Samarium-153

1. Henriksen G, et al. Cancer Res. 2002;62:3120-3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

ATI-BC-1 Phase I Study1-3

ALP, alkaline phosphatase 1. Nilsson et al. Clin Cancer Res 2005;11:4451. 2. Nilsson et al. Eur J Nucl Med Mol Imaging 2004;31:Abstract 370.

3. Nilsson et al. Eur J Cancer 2003;1: Abstract 543.

Safety study of single and multiple doses of radium Ra 223 dichloride in patients with bone metastases (n = 31)

• Radium Ra 223 dichloride was well tolerated at therapeutically relevant dosages

• Consistent reduction in total ALP

• Pain relief in more than 50% of patients across all dose levels

• Cleared rapidly from the blood to < 1% initial level at 24 h

KEY

OUTCOMES

BC1-05 Phase I Study1

1. Lewington et al. Presented at ASCO Genitourinary Cancers Symposium 2010: Poster 216.

Study assessing the biodistribution, dosimetry and pharmacokinetics of radium Ra 223 dichloride (2 x 100 kBq/kg) in CRPC and bone metastases (n = 6)

• Rapidly taken up by bone/bone metastases

• Excreted through the GI tract and small intestine

• Spares kidney – radiation dose low

• Radium Ra 223 dichloride was well tolerated and favorable alterations in bone turnover markers

KEY

OUTCOMES

BC1-08 Phase I Study1

1. Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

Dose-finding study assessing safety, biodistribution, dosimetry and pharmacokinetics of radium Ra 223 dichloride in CRPC with bone metastases

(n = 10)

• Total body clearance was largely determined by transit through the gut

• Radium Ra 223 dichloride seen in small intestine within 10 min of dosing, with subsequent fecal transit to colon

• Radium Ra 223 dichloride monotherapy induced PSA declines and favorable alterations in bone turnover markers

• Radium Ra 223 dichloride was well tolerated

KEY

OUTCOMES

BC1-03 Phase II Study: Design

1

7

ALP=alkaline phosphatase; BPI=Brief Pain Inventory; CRPC=castration-resistant prostate cancer; D=day; M=month; W=week.

Nilsson S, et al. Eur J Cancer. 2012;48:678-686. Copyright 2012 Elsevier Ltd. Published by Elsevier Inc. User rights governed by an Open Access license.

• Randomized, double-blind phase II trial

• Aim: To investigate the pain-relieving effect of single doses of radium-223 in patients with CRPC with painful bone metastases

Evaluation Phase

M24 D1

Follow-up Phase

Drug Injection

Patient Visits

W2 W4 W8 W12 W16

Safety/ Survival

Men with CRPC and painful bone

metastases (N=100)

Radium-223 5 kBq/kg (n=26)


R A N D O M I Z E



CRPC with painful bone metastases (n = 100)

Single doses: 5, 25, 50 or 100 kBq/kg

• A significant dose-dependent pain response was observed with Radium Ra 223 dichloride


• Hematologic toxicity was generally mild

BC1-03 Phase II Study1

1. Nilsson et al. Eur J Cancer 2012;48(5):678

KEY

OUTCOMES

BC1-04 Phase II Study: Design

1

9

CRPC=castration-resistant prostate cancer; D=day; M=month; PSA=prostate-specific antigen; W=week.

Parker C, et al. Eur Urol. 2013;63:189-193. Reprinted from European Urology. Copyright 2013, with permission from Elsevier.

• Double-blind, randomized, dose-finding phase II trial

• Aim: To assess the efficacy and safety of repeat doses of radium-223 (25, 50, or 80 kBq/kg) in patients with bone metastases from CRPC

Patients with CRPC (N=122)

Radium-223 25 kBq/kg


R A N D O M I Z E


Treatment

M24 D1

Posttreatment

3 Injections of study drug every 6 weeks

W7 W13 W24 (M6)

PSA Safety

Survival

M12

Bone markers PSA

Safety Survival

CRPC with bone metastases (n = 122)

Multiple doses: 3 × 25, 50 or 80 kBq/kg at 6-week intervals

• Bone-ALP response in > 60% of patients receiving 50 or 80 kBq/kg


• No evidence of a dose-limiting effect

• No grade 3/4 neutropenia was observed

BC1-04 Phase II Study1

KEY

OUTCOMES

ALP, alkaline phosphatase 1. Parker et al. Eur J Can Suppl 2009;7:406:Abstract 7003.

BC1-02 Phase IIb Study1,2:Radium Ra 223

• Compared with placebo, Radium Ra 223 dichloride significantly reduced PSA, ALP, other bone markers

• Well tolerated with little hematologic toxicity • Median survival was 40% longer in the radium Ra 223 dichloride group vs. the

placebo group2

CRPC with bone metastases requiring EBRT (n = 64) Multiple doses: 4 × 50 kBq/kg or placebo at 4-week intervals

Radium Ra 223 dichloride

Placebo

Median OS, months

15.0 (65 weeks)

10.7 (46 weeks)

Hazard ratio 0.48

95% CI 0.581–0.832

P 0.017

1.00

0.75

0.50

0.25

0.00 0 20 40 60 80 100 120

Time (weeks)


Placebo

Pro

po

rtio

n s

urv

ivin

g

ALP, alkaline phosphatase; EBRT, external beam radiation therapy; PSA, prostate-specific antigen

1. Nilsson et al. Lancet Oncol 2007;8:587. 2. Nilsson et al. Eur J Cancer Suppl 2009;7:412 P-7018.

KEY

OUTCOMES

Introduction to ALSYMPCA

Based on the positive results from the randomized Phase II trial, the

decision was taken to proceed with a Phase III trial

ALSYMPCA (ALpharadin* in SYMptomatic Prostate CAncer)

ALSYMPCA was an international multicenter, double-blind,

randomized, placebo-controlled Phase III trial conducted in >

900 patients with symptomatic CRPC and bone metastases

The primary endpoint was overall survival

*Radium Ra 223 dichloride was formerly known as ‘Alpharadin’.

PREGUNTA 2

Phase III ALSYMPCA Trial Design

Primary endpoints: overall survival Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety and HRQoL

*Plus best standard of care.

Parker et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512. Presented at ASCO 2012. www.clinicaltrials.gov. NCT00699751.

R 2:1

Radium Ra 223 Dichloride* 50 kBq/kg

Saline* (placebo)

FOLLOW-UP PHASE TREATMENT PHASE 6 injections at 4-week intervals

M36 M16 M24 M12 M0 M28 M6 M20 M32 M8 M10

Month

Stratification factors •Total ALP < 220 U/L vs. ≥ 220 U/L •Bisphosphonate use (Yes vs. No) •Prior docetaxel (Yes vs. No) Key inclusion criteria •Confirmed symptomatic CRPC •≥ 2 bone metastases •No known visceral metastases •Post-docetaxel or unfit for docetaxel

Assessments

n = 921 Metastatic

CRPC

ALSYMPCA Analyses

Planned interim analysis (IA)

314 events from 809 patients randomized at the time of the IA: cut-off October 2010

3 June 2011: the Independent Data Monitoring Committee (IDMC) recommended stopping the trial early, because of evidence of a significant treatment benefit

Updated analysis

528 events from all 921 patients randomized to the study

Updated analysis conducted prior to placebo patients crossing over to radium Ra 223 dichloride and when all patients had completed study drug treatment: cut-off July 2011.

Data first announced in Feb 2012

Q1

2012

Q4

2011

Q3

2011

Q2

2011

Q1

2011

Q4

2010

Q3

2010

Q2

2010

Q1

2010

Q4

2009

Q3

2009

Q2

2009

Q1

2009

Q4

2008

Q3

2008

Q2

2008

DATA CUTOFF LPFV IDMC FPFV

UPDATED ANALYSI

S

CROSSOV

ER

ALSYMPCA: Patient Demographics and Baseline Characteristics

Parameter Radium Ra 223

dichloride (n = 614) Placebo (n = 307)

Age, years Mean

70.2

70.8

Ethnicity, n (%) Caucasian

575 (94)

290 (95)

Baseline ECOG score, n (%) ≤ 1 2

536 (87) 76 (12)

265 (86) 40 (13)

Extent of disease, n (%) < 6 metastases 6–20 metastases > 20 metastases/superscan

100 (16) 262 (43) 249 (41)

38 (12)

147 (48) 121 (40)

WHO ladder, cancer pain index ≥ 2, n (%)

345 (56)

168 (55)

ITT analysis; n = 921 Parker et al. NEJM 2013;369:213-23

ALSYMPCA: Patient Baseline Characteristics

Parameter Median (min, max)

Radium Ra 223 dichloride (n = 614)

Placebo (n = 307)

Hemoglobin, g/dL 12.2 (8.5–15.7) 12.1 (8.5–16.4)

Albumin, g/L 40 (24–53) 40 (23–50)

Total ALP, µg/L 211 (32–6431) 223 (29–4805)

LDH, U/L 315 (76–2171) 336 (132–3856)

PSA, µg/L 146 (3.8–6026) 173 (1.5–14500)

Current bisphosphonates Yes, n (%)

250 (40.7)

124 (40.4)

Prior docetaxel Yes, n (%)

352 (57.3)

174 (56.7)

ITT analysis; n = 921 Parker et al. NEJM 2013;369:213-23

ALSYMPCA: Radium Ra 223 Dichloride Significantly Improved Overall Survival


Placebo

Median OS (months) 14.9 11.3

Hazard ratio 0.695

95% CI 0.581–0.832

P < 0.0001


Placebo

Month

Ra 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 Parker et al. NEJM 2013;369:213-23

Median OS Δ: 3.6 months

Overall survival: time from date of randomization to the date of death

ALSYMPCA: Survival Benefit Across Patient Subgroups

Parker et al. NEJM 2013;369:213-23

ALSYMPCA: OS by Baseline ALP

Total ALP < 220 U/L Total ALP ≥ 220 U/L

Radium Ra 223 dichloride, n = 348 Median: 17.0 months

Placebo, n = 169 Median: 15.8 months

HR = 0.825 95% CI, 0.635, 1.072 P = 0.14945



HR = 0.619 95% CI, 0.486, 0.788 P = 0.00009

Ra 223 266 238 160 95 51 24 10 3 0 0 0

Placebo 138 114 63 28 15 9 3 2 1 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40

Ra 223 348 325 246 179 107 52 31 9 2 0

Placebo 169 151 115 75 44 20 11 5 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36

% %

Month Month

Current bisphosphonate use NO current bisphosphonate use



HR = 0.699 95% CI, 0.525, 0.931 P = 0.01378



HR = 0.736 95% CI, 0.587, 0.923 P = 0.00775

ALSYMPCA: OS by Bisphosphonate Use

Ra 223 364 331 235 159 97 50 27 6 0 0 0

Placebo 183 155 102 58 33 16 10 6 2 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40

Ra 223 250 232 171 115 61 26 14 6 2 0

Placebo 124 110 76 45 26 13 4 1 0 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36

% %

Month Month

ALSYMPCA: OS by Prior Docetaxel Use

Prior docetaxel use No prior docetaxel use

Ra 223 352 327 238 155 88 45 27 5 1 0 0

Placebo 174 152 104 61 35 15 5 4 1 1 0



HR 0.710 95% CI 0.565–0.891 P = 0.00307



HR 0.745 95% CI 0.562–0.987 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

%

Ra 223 262 236 168 119 70 31 14 7 1 0

Placebo 133 113 74 42 24 14 9 3 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36

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

Ra 223 614 496 342 199 129 63 31 8 8 1 0

Placebo 307 211 117 56 36 20 9 7 4 1 0

ALSYMPCA Pre-crossover Analysis Time To First SRE

0

10

20

30

40

50

60

70

80

90

100

%


Placebo

Median OS (months) 15.6 9.8

Hazard ratio 0.658

95% CI 0.52–0.83

P 0.00037


Placebo


Radium Ra 223 dichloride, n (%)

Placebo n (%)

P

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

Confirmed PSA response** 28 (6) 4 (2) 0.032

*In patients who had elevated total ALP at baseline. **≥ 50% reduction from baseline confirmed by a second value ≥ 4 weeks later, by end of treatment. This was not an endpoint in

ALSYMPCA.

Hazard ratio (95% CI) P

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: Secondary Endpoints: ALP and PSA

Phase III ALSYMPCA: FACT-P QoL Responder Analysis

P = 0.012 P = 0.111 P = 0.538 P = 0.004 P = 0.077

*For each subscale, MID = 3. Assessment at week 16 and/or week 24.

Parker et al. Presented at ESMO 2012 Poster 898PD

ALSYMPCA: Grade 3/4 AEs Were Lower With Radium Ra 223 Dichloride Than Placebo

*Safety population comprised patients who received at least 1 dose; 1

patient in the placebo group received one injection of radium Ra 223

dichloride (Week 0) and is included in the radium Ra 223 dichloride safety

analysis.

Parker et al. J Clin Oncol 30, 2012 (suppl; abstr

LBA4512). Data on file, Bayer HealthCare

Pharmaceuticals

ALSYMPCA: Adverse Events

Patients with adverse events (AEs), n (%)

Parker et al. NEJM 2013;369:213-23 .

Conclusions from ALSYMPCA

In CRPC patients with bone metastases

Radium Ra 223 dichloride significantly prolonged overall survival

14.9 months vs. 11.3 months placebo

(P = 0.00007; HR 0.695, 95% CI 0.581–0.832)

Radium Ra 223 dichloride significantly prolonged time to first SRE

12.2 months vs. 6.7 months placebo

(P < 0.0001; HR = 0.64 [95% CI: 0.52–0.78])

Radium Ra 223 dichloride was very well tolerated

Radium Ra 223 dichloride may provide a new standard

of care for the treatment of CRPC patients with bone

metastases

PREGUNTA 3

936P | Safety of Cytotoxic Chemotherapy Following Radium-223

Key Results:

• The proportion of patients treated with CT after completing study drug was 15% in the

radium-223 group and 18% in the placebo group

• In patients receiving CT after study drug, death and its causality were similar between the

treatment groups

Table 6: Number of Deaths and Causality [from Poster]

Parameter Radium-223 (n=93) Placebo (n=54)

During Chemotherapy Administration

Deaths on chemotherapy, % 14 15

Causality: PC and skeletal mets (± other mets) PC with other mets (or mets not specified) Cerebral hemorrhage due to trauma Cardiopulmonary failure

10 3 1 0

13 0 0 2

30 Days After Chemotherapy Administration

Deaths within 30 days after chemotherapy, n % 6 4

Causality: PC and skeletal mets (± other mets) Bronchopneumonia Respiratory failure + pulmonary edema

4 1 0

4 1 0

Mets, metastases; PC, prostate cancer.

Sartor O, et al. Presented at: ESMO, Sept. 28–Oct 2, 2012, Vienna, Austria; Poster 936P.

[TITLE]

Presented By Sten Nilsson, MD, PhD at 2014 Genitourinary Cancers Symposium

[TITLE]


Estudios Actualmente en Marcha

16506: A re-treatment safety study of Ra 223 in subjects with CRPC with bone metastases who received an initial course of six doses of Ra 223 50 kBq/kg every four weeks

Completion of 6 cycles of treatment with radium 223

No related SAE or GR ¾ AE

Radiological progression or (Clinical progression following initial treatment)

> 30 days between initial course and retreatment

N=40

Ra-223 50 kBq/kg

Q4wks x 6 cycles

Primary endpoint: Safety

Exploratory endpoints:

time to radiological bone progression, ALP response rate, Time to total ALP

progression, % change from total ALP, PSA response rate, Time to PSA

progression,

Overall survival , Pain response rate, Time to pain progression, Time to first skeletal related event (SRE), SRE-free

survival

Follow up 2 years active and 7 years LTFU

Milestone Plan Actual

FPFV Sept 2013

22 Dec 2013

FPFT Oct 2013 19 Jan 2014

LPFT Jan 2015

19 Dec 2014

LPLT May 2015

Principal Investigator: Oliver Sartor, MD and Karim Fizazi MD

FDA PMR study


Primary completion

End Jun

2015

Primary completion DB lock

End Jun

2015

Stats report complete (full set of tables)

End Sep

2015

LPLV (end of study)

Jul 2017 on final pt transfer to 16996

Up to date as of 19 Mar

2015

TOTAL USA

# Countries 9 -

# Countries Open 8 Y

# Sites selected 18/27 10

# Sites opened 21 3

# Screened Patients 59 27

# Patients in Screening 0 0

# Patients Randomised 44 21

# Patients Discontinued 36 17

16507: A three arm randomized open-label Phase II study of Ra 223 50 kBq/kg vs 80 kBq/kg, and vs 50kBq/kg in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to

the bone

ALSYMPCA population

N=360

Ran

do

miz

ed, 1

:1:1

Radium 223 50 KBq/Kg

q4wks X 6 inj


q4wks X 6 inj

Primary endpoint: SRE FS

Secondary endpoints:

Safety,

OS,

pain response,

time to pain progressions

Time to first SRE

rPFS

Follow up 2 years active and 7 years LTFU


q4wks X 12 inj

Mile-stone

Plan Actual

FPFV Mar 14 10 Mar 14

FPFT Apr 14 10 Apr 14

LPFT Sep 15

LPLT Sep 16

Principal Investigator: M. Hussain, MD and C. Sternberg, MD

FDA PMC study


Primary completion

Jul 2017


Aug 2017


Oct 2017

LPLV (end of study)

Feb 2018 (when last pt transfers to 16996 study

Up to date as of 19 Mar

2015

TOTAL USA

# Countries 17 -

# Countries Open 13 Y

# Sites selected 95 13

# Sites opened 55 13




# Patients Discontinued 70 4

16544: A randomized phase IIa study of quantified bone scan response following treatment with Ra 223 alone or in combination with abiraterone acetate or enzalutamide in subjects with CRPC who have bone

metastases

ALSYMPCA population

N=66

Ran

do

miz

ed, 1

:1:1

Ra-223 50 kBq/kgQ4wks x 6 cycles

Ra-223 50 kBq/kgQ4wks x 6 cycles plus abiraterone

1’endpoint

BSLA response Week 24

2’endpoints

Safety of each combination, describe rPFS, SSE-FS, OS

Follow up - 2 years active and 7 years LTFU

Ra-223 50 kBq/kgQ4wks x 6 cycles plus enzalutamide


FPFV 17-Mar-14 7-Mar-14

FPFT 21-Mar-14 28-Mar-14

LPFT 12-Dec-15

LPLV 25-Jun-18

Principal Investigator: D. Petrylak, MD


Primary completion 20-Jul -16


8-Sep-16


29-Oct-16

LPLV (end of study) 25-Jun-18

Up to date as of 20 Mar 15 TOTAL

# Countries 1

# Countries Open 1

# Sites selected 22 of 22

# Sites opened 13

# Patients Screened 33

# Patients in Screening 2

# Patients Randomised 19 (17

treated)

# Patients Discontinued 9

15396: Phase III study in combination with abiraterone in asymptomatic/mildly symptomatic CRPC

Chemo –naïve metastatic CRPC patients; Progressive disease after previous anti-

androgen therapy and withdrawal ; No known brain

metastasis or visceral metastasis; Asymptomatic or

mildly symptomatic

N=800

Ran

do

miz

ed, 1

:1

Radium 223 dichloride

50 KBq/Kg/4wks X 6 IV

+ Abiraterone + Prednisone/Prednisolone

Matching Placebo

+ Abiraterone + Prednisone/Prednisolone


Primary completion

July 2017


Aug 2017


Sep 2017

LPLV (end of study)

Jul 2020 or when last pt transferred to LTFUP study

1’ endpoint: SSE-FS

2’ endpoints:

OS

Time to opiate use

Time to pain

Time to chemotherapy

rPFS

Follow up – 7 years LTFU

Principal Investigator: Dr Celestia Higano & Dr Matthew Smith


FPFV Mar-14 30-Mar -14

FPFT Apr-14 24-Apr-14

LPFT Dec-15

LPLT Jun-16

Up to date as of 23 Mar 15 TOTAL USA

# Countries 19 -

# Countries Open 15 -


# Sites opened 101 19




# Treated patients 85 11

16298: Phase II of Ra 223 dichloride vs placebo in metastatic HER2 negative hormone receptor positive metastatic breast cancer patients with bone metastases treated with hormonal

treatment

Patient population

N=227

Ran

do

miz

ed, 1

:1

BAY 88-8223 50 KBq/Kg/4wks X 6 IV

+ HT (except exemestane), BP/denosumab

Matching Placebo

+ HT (except exemestane), BP/denosumab

Primary endpoint:

SSE-FS

Secondary endpoint:

Safety, rPFS, OS, bone markers endpoints,

bone pain

Follow up

TBD

Principal Investigator: Robert Coleman, MD

Up to date as of 20 Mar 15 Total USA

# Countries 23 (EU & AP) 1

# Countries Open 1 1


# Sites opened 3 5

# Sites CMC ready 63 12



FPFV 28FEB2015 17FEB2015

FPFT 20MAR2015

LPFT 30JUN16

LPLT 29NOV16


Primary completion

17MAY17


17MAY17


05SEP17

LPLV (end of study)

17MAY17

17096: Phase II trial of Ra 223 vs placebo in metastatic HER2 negative hormone receptor positive breast cancer with bone metastases treated with exemestane and everolimus

Patient population

N=310

Ran

do

miz

ed, 1

:1

BAY 88-8223 50 KBq/Kg/4wks X 6 IV

+ Exemestane + everolimus, BP/denosumab

Matching Placebo

+ Exemestane + everolimus, BP/denosumab

Primary endpoint:

SSE-FS

Secondary endpoint:

Safety, rPFS, OS, bone markers endpoints,

bone pain

Follow up

TBD

Principal Investigator: Hope Rugo, MD

Up to date as of 20 Mar 2015 TOTAL USA

# Countries 2 -

# Countries Open 1 -


# Sites opened 3 5

# Sites CMC ready 63 12


Mile-stone

Plan Actual

FPFV May 2015

FPFT June 2015

LPFT Jan 2017

LPLT June 2017


Primary completion


Sep 2017


Nov 2017

LPLV (end of study)

Jul 2017

Sites are open for 17096 but must wait for

Amendment 1 approval prior to enrolment

CONCLUSIONES

Se trata de un fármaco con actividad antitumoral

que es capaz de incrementar la supervivencia

global en enfermos afectados de un CPRC

Debido a su actividad y escaso perfil de toxicidad es

un fármaco a tener en cuenta tanto en pre como

en post-docetaxel.

Fármaco seguro con datos de seguimiento a largo

plazo.

CÁNCER DE PRÓSTATA RESISTENTE A LA CASTRACIÓN CON ...HISTORIA NATURAL DEL CÁNCER DE PRÓSTATA...

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