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This program has been accredited by the CUA as a Group Learning Activity (Section 1) as defined by the

Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Completion of this program enables participants to

claim a maximum of two (2) Section 1 credits

Managing Bone Metastases in CRPC: From Bone-targeted Therapies to Radiopharmaceuticals: Update 2016

The scientific content of this

program was developed by the

Canadian Urological Association

Disclosure of Commercial Support

• This program has received financial support from Bayer Inc. and Amgen Inc. in the form of an educational grant.

• This program has received in-kind support from Bayer Inc. and Amgen Inc. in the form of logistical support.

Editorial Committee

• Fred Saad, MD, FRCSC (Program Lead) Professor and Chief, Urology Director of G-U Oncology Centre Hospitalier l’Université de Montréal Université de Montréal Endowed Chair in Prostate Cancer Research Montreal Cancer Institute Montreal, Quebec

• Robert J. Hamilton, MD, MPH, FRCSC

Urologist Division of Urology University Health Network – Princess Margaret Hospital Toronto, Ontario

• Alan So, MD, FRCSC Associate Professor Department of Urologic Sciences University of British Columbia Research Scientist Prostate Centre Vancouver General Hospital Vancouver, British Columbia

• Shawn Malone, MD, FRCSC Associate Professor University of Ottawa Radiation Oncologist The Ottawa Hospital Ottawa, Ontario

All Faculty have adhered to the:

• CMA Code of Ethics (Update 2004)

• CMA Guidelines for Physician Interactions with Industry (2007)

• Innovative Medicines Canada Code of Ethical Practices (2016)

Disclosure of Commercial Support

• Potential for conflict(s) of interest:

• Insert speakers name has received funding from Bayer.

• Insert speakers name has received funding from Amgen.

• Bayer benefits from the sale of a product that will be discussed in this program: Radium-223 (Xofigo)

• Amgen benefits from the sale of a product that will be discussed in this program: denosumab (Xgeva)

Faculty/Presenter Disclosures Company/ Organization

Details

I am a member of an Advisory Board or equivalent with a commercial organization.

I am a member of a Speakers bureau.

I have received payment from a commercial organization (including gifts or other consideration or ‘in kind’ compensation).

Faculty/Presenter Disclosures Company/ Organization

Details

I have received a grant(s) or an honorarium from a commercial organization.

I hold a patent for a product referred to in the CME/CPD program or that is marketed by a commercial organization.

I hold investments in a pharmaceutical organization, medical devices company or communications firm.

I am currently participating in or have participated in a clinical trial within the past two years.

The CUA is committed to providing high-quality CPD programs that are fair and balanced. If you have perceived any bias in this presentation or

have any feedback, please contact:

Tal Erdman Coordinator, CPD Programs and Accreditation,

Office of Education 185 Dorval, #401, Dorval, QC - H9S 5J9

T: (514) 395-0376 ext. 43 - F: (514) 395-1664 [email protected]

mailto:[email protected]

Learning Objectives

By participating in this educational session, health care providers can expect to:

• Discuss the rationale for the use of radiopharmaceuticals in the management of castrate-resistant prostate cancer (CRPC)

• Review the evidence for the use of radium-223 as monotherapy and in combination for the treatment of men with metastatic CRPC (mCRPC)

• Discuss practical considerations for the use of radium-223 in clinical practice

Rationale for the Use of Bone-targeted Therapy/Radiopharmaceuticals

• > 90% of patients with advanced prostate cancer have bone metastases1

– Negative impact on survival2-4

– Associated with bone pain and the need for opioids5,6

• Bone metastases can lead to a variety of SREs: Fracture, radiation to bone, spinal cord compression, surgery to bone

– Associated with significant morbidity and lower QOL7

1. Tannock IF, et al. N Engl J Med 2004;351:1502-12; 2. DePuy et al. Support Care Cancer 2007;15:869-76;

3. Norgaard et al. J Urol 2010;184:162-7; 4. Oefelein MG, et al. J Urol 2002;168:1005-7;

5. Goh P, et al. Curr Onc 2007;14:9-12; 6. Inoue T, et al. Urology 73:1104–9, 2009; 7. Weinfurt KP, et al. Ann Onc 2005;16:579-84

QOL = Quality of life

SRE = Skeletal-related event

Bone Metastases Associated with SREs in CRPC*†

Saad F, et al. J Natl Cancer Inst 2002;94:1458-68

Saad F, et al. J Natl Cancer Inst 2004;96:879-82

Saad F. Personal communication. 2008

*Placebo patients from the pivotal zoledronic acid trial. Patients may have

experienced more than one SRE. †Note for each group a number of patients who

had SREs were asymptomatic

33%

26%

8%

4%

0

10

20

30

40

50

Radiation to

bone

Pathologic

fracture

Spinal cord

compression

Surgery

to bone

Pa

tie

nts

(%

)

24 Months

SREs Associated with Decreased Survival

• Among patients with ≥ 1 SRE, survival at 360 days was worse in those with multiple SREs (22.4%) vs. those with 1 SRE (29.8%) (p < 0.01)

De Puy V, et al. Support Care Cancer 2007;15:869-76

0

1

Pro

bab

ility

Survival (days)

No SREs ≥ 1 SREs 0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

90 180 270 360

Survival at 360 days

P HR

Patients with no SREs 49.7% 0.02 1.30

Patients with ≥ 1 SRE 28.2%

Burden of Metastatic Bone Disease: Retrospective Cohort Study (Quebec)

• Cohort study of RAMQ database: Men with PCa diagnosis and ≥ 1 health care claim

• 626 MBD patients and 1,671 controls (no MBD)

• Adjusted mean all-cause healthcare costs were $11,820 higher in MBD patients vs. controls

• MBD-related costs were $3,091 higher in MBD patients vs. controls

– Most common SRE = radiotherapy (received by 85% of MBD patients)

Perrault L, et al. Can Urol Assoc J 2015;9:307-14

MBD = Metastatic bone disease

RAMQ = Régie de l’Assurance Maladie du Québec

SSEs vs. SREs

Symptomatic skeletal events (SSEs)

Skeletal-related events (SREs)

Radiation to bone Radiation to bone

Symptomatic pathologic fracture Pathologic fracture

Surgery to bone Surgery to bone

Symptomatic spinal cord compression

Spinal cord compression

Burden of SSEs in CRPC with Bone Metastases: Real-World Canadian Data

• Retrospective chart review of 393 patients at CHUM, PMCC, VGH

• Median survival from onset of MBD = 23.9 months

• 833 SSEs in 275 patients

• Mean of 2.12 SSEs per patient

• 70% of MBD patients had ≥ 1 documented SSE

• Mean MBD-related HRU costs:

– ≥ 1 SSE: $22,191 (observed) to $34,670 (adjusted)

– 0 SSEs: $9,550

Saad F, et al. AUA 2016 (Abstr 16-2136)

CHUM = Centre Hospitalier de l'Université de Montréal;

HRU = Health care resource use; PMCC = Princess Margaret Cancer Centre;

VGH = Vancouver General Hospital

BTT Use Varies Among Canadian Centres

• Centre Hospitalier de l'Université de Montréal (CHUM) had fewer SSEs, longer median time to first SSE and smaller proportion of patients received palliative radiation vs. Princess Margaret Cancer Centre (PMCC) or Vancouver General Hospital (VGH)

• Similar proportions of patients at CHUM (64%) and PMCC (60%) received BTTs: – ZA given predominantly on monthly schedule at CHUM (77%) and

every 3 mos at PMCC (70%)

• Few patients received a BTT at VGH (24%)

• Standardization of BTT practices needed

Saad F, et al. AUA 2016 (Abstr MP50-17) BTT = Bone-targeted therapy

Time to SSE in Three Canadian Sites

Saad F, et al. AUA 2016 (Abstr MP50-17)

1.0

0.8

0.6

0.4

0.2

0.0 0 50 100

Time to SSE (months)

Even

t P

rob

abili

ty

150 200

Median time to SSE, months (95% CI)

25.0 (18.5, 32.6) 14.6 (9.7, 16.8) 17.3 (14.8, 24.0)

CHUM (n = 130 PMCC (n = 154) VGH ( n = 109)

Multiple SSEs in Three Canadian Sites

Saad F, et al. AUA 2016 (Abstr MP50-17)

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Nu

mb

er

of

Pati

ents

Number of SSEs

CHUM (n = 130) PMCC (n = 154) VGH (n = 109)

Bone-targeted Agents

• Inhibit the activity of osteoclasts involved in osteolysis and bone resorption at bone metastatic sites:

– Bisphosphonates (ie, zoledronic acid)1

– RANKL inhibitors (eg, denosumab)

• Monoclonal antibody that binds to and inhibits the activity of RANKL2

1. Saad F, et al. J Natl Cancer Inst 2004;96:879-82

2. Fizazi K, et al. Lancet 2011;377:813-22 RANKL = Receptor activator of nuclear factor-kappa B ligand

Mode of Action of Denosumab and Bisphosphonates

Adapted from Fornier MN. J Clin Oncol 2010;28:5127-31

BMP = Bone morphogenetic proteins; FGFs = Fibroblast growth factors; IGFs = Insulin-like growth factors;

IL = Interleukin; PDGF = Platelet-derived growth factor; PGE2 = Prostaglandin E2; PTHrP = Parathyroid hormone-related

protein; TGF-b = Transforming growth factor-beta; TNF = Tumour necrosis factor;

M-CSF = Macrophage colony-stimulating factor; RANK = Receptor activator of Nuclear Factor κ B;

RANKL = RANK ligand

Tumour cell Tumour cell

Tumour cell

PTHrP IL-1,6,8 PGE2

TNF M-CSF

Proteoclast

RANK

Denosumab

RANKL

Osteoclast RANK

Osteoclast in apoptosis

BMP PDGF FGFs IGFs TGF-b

Denosumab 1. Binds to RANKL and neutralizes its

activity 2. Reduces osteoclast activity and bone

resorption

Bisphosphonates 1. Inhibit tumour cell adhesion

to bone 2. Inhibit osteoclast activity 3. Induce osteoclast apoptosis

Differentiation

PTHrP

Bone-targeted Agents Reduce Complications but Have No Proven Survival Benefit

1. Saad F, et al. J Natl Cancer Inst 2002;94:1458-68

2. Fizazi K, et al. Lancet 2011;377:813-22

Therapeutic Primary end point

Primary end point efficacy

Zoledronic acid vs placebo

Reduced SREs p = 0.0211

Denosumab vs zoledronic acid

Prevention of SREs

p = 0.0082

RADIOPHARMACEUTICALS

Alpha- vs. Beta-emitting Particles Alpha-emitters Beta-emitters

High-LET a-particles produce double-strand DNA breaks1,2

• Difficult to repair1,2 • Repair failure leads to apoptosis

(programmed cell death)1

• Misrepairs create chromosomal aberrations that result in mitotic cell death1

Low-LET b-radiation produces single-strand DNA breaks1

• Easily repaired using the opposite strand as a template1

• Less likely to induce cell death1

Examples: • Strontium-89 • Samarium-153:

Rhenium-186:

1. Hall E, Giaccia A. Radiobiology for the Radiologist. 6th Ed.

Philadelphia: Lippincott William & Wilkins; 2006

2. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s. LET = Linear energy transfer.

Beta-emitting Radioisotopes Impact Pain but Have No Proven Survival Benefit

1. Porter AT, et al. Int J Radiat Oncol Biol Phys 1993;25:805-13;

2. Oosterhof GO, et al. Eur Urol 2003;44:519-26; 3. Sartor O, et al. Urology 2004;63:940-5;

4. Han SH, et al. J Nucl Med 2002;43:1150-6

Therapeutic Primary end point

Primary end point efficacy

Overall survival efficacy

Strontium-89 Bone pain p < 0.0021 Favoured palliative radiotherapy2

Samarium-153 Bone pain p < 0.0083 N/A3

Rhenium-186 Bone pain p = 0.054 NS4

• β-emitting radioisotopes have been shown in phase 3 trials to

impact pain but not survival

Radium-223 Dichloride (223 RaCl2)

• Calcium mimetic

• Targets new bone growth in and around metastases

20

Ca 38

Sr 56

Ba 88

Ra

Properties of Radium-223

• Ra-223 dichloride

• t ½ - 11.43 days

• 4 α particles

– ~28 MeV, ~ 95%

• 2 β particles

• Multiple X/γ emissions allow imaging

Sartor O, et al. J Nucl Med Radiat Ther 2012;3:1-8

CLINICAL EFFICACY OF RADIUM-223

A Phase 3 Trial of Radium-223 vs. Placebo in mCRPC (ALSYMPCA)

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

ALSYMPCA = Alpharadin in Symptomatic Prostate Cancer Patients

ALP = Alkaline phosphatase

PSA = Prostate-specific antigen

R A N D O M I Z E D

2:1

Radium-223 +

Best supportive care n = 614

Placebo +

Best supportive care n = 307

Patient population:

921 patients with confirmed symptomatic CRPC

≥ 2 bone metastases

No visceral metastases

Post-docetaxel/unfit for docetaxel

Primary end point: Overall survival

Secondary end points:

Time to first symptomatic skeletal event

Time to increase in total ALP

Total ALP response

ALP normalization

Time to increase in PSA

6 injections at 4-week intervals

Statistical assumption: 90% power; HR = 0.76; 0.05 two-sided alpha

ALSYMPCA: Patient Demographics Parameter Radium-223

(n = 614) Placebo (n = 307)

Age, median (range) 71 (49-90) 71 (44-94)

Total alkaline phosphatase < 220 U/L, n (%) 348 (57) 169 (55)

Current use of bisphosphonates, n (%) 250 (41) 124 (40)

Any prior use of docetaxel, n (%) 352 (57%) 174 (57%)

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

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

Lactate dehydrogenase, U/L 315 (76–2171) 336 (132–3856)

ECOG performance-status score, n (%) 0 1 ≥ 2

165 (27) 371 (60) 77 (13)

78 (25)

187 (61) 41 (13)

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

100 (16) 262 (43) 195 (32)

38 (12)

147 (48) 91 (30)

Parker C, et al. N Engl J Med 2013;369:213-23 ECOG PS = Eastern Cooperative Oncology Group performance status

ALSYMPCA Trial: Primary End Point – OS


100

80

90

70

60

40

30

10

50

20

0 0 3 6 9 12 15 39

Months since randomization

HR 0.70 (95% CI 0.58-0.83) p < 0.001

No. at risk

Radium-223 Placebo

614 307

578 288

504 228

369 157

274 103

178 67

18 21 24 27 30

105 39

60 24

41 14

18 7

7 4

33

1 2

36

0 1

0 0

Radium-223 (median OS 14.9 mos)

Placebo (median OS 11.3 mos)

OS

(%

)

ALSYMPCA: Previous Docetaxel Use and Survival

Previous docetaxel use No previous docetaxel use

Hoskin P, et al. Lancet Oncol 2014;15:1397-406

Radium-223, n = 352 Median: 14.4 months (95% CI 12.5–15.5)

Placebo, n = 174 Median: 11.3 months (95% CI 10.0-12.9)

HR 0.70 (95% CI 0.56–0.88; p = 0.002) 100

80

60

40

20

0 0 4 8 40

Treatment period

0 4 8 36 32

Treatment

period

Radium-223, n = 262 Median: 16.1 months (95% CI 13.9–17.8)

Placebo, n =1 33 Median: 11.5 months (95% CI 9.5–14.1)

HR 0.69 (95% CI, 0.52–0.92; p = 0.01)

36 32 28 24 20 16 12 28 24 20 16 12

352

174

327

152

238

104

0

0

262

133

236

113

168

74

0

0

1

1

0

1

1

1

5

4

27

5

45

15

88

35

157

61

7

3

14

9

31

14

70

24

120

42

Radium-223

Placebo

Number

at risk

Sur

viva

l (%

)

Months Months

ALSYMPCA Trial: Secondary End Point – Time to First Symptomatic Skeletal Event


100

80

90

70

60

40

30

10

50

20

0 0 3 6 9 12 15 30

Months since randomization

HR 0.66 (95% CI 0.52-0.83) p < 0.001

No. at Risk

Radium-223 Placebo

614 307

496 211

342 117

199 56

129 36

63 20

18 21 24 27

31 9

8 7

8 4

1 1

0 0

Radium-223 (median time to first symptomatic

skeletal event, 15.6 mos)

Placebo (median time to first symptomatic

skeletal event, 9.8 mos)

Pat

ient

s w

ithou

t sym

ptom

atic

skel

etal

eve

nt(%

)

ALSYMPCA: Current Bisphosphonate Use and Symptomatic Skeletal Events

Current bisphosphonate use No current bisphosphonate use

Sartor O, et al. Lancet Oncol 2014;15:738-46

Number at risk

Radium-223

Placebo

0 4 8 12 16 20 24 28 32

250

124

193

71

115

29

61

17

25

10

8

3

3

3

1

1

0

0

Time (months)

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32

364

183

247

103

120

41

68

19

30

9

12

4

5

1

0

0

0

0

Time (months)

Placebo, n = 183

Median: 8.4 months

(95% CI 6.4–19.5)

HR = 0.77 (0.58–1.02)

p = 0.07

Treatment period

Pat

ient

s w

ithou

t

sym

ptom

atic

ske

leta

l eve

nts

(%)

Radium-223, n = 364

Median: 11.8 months (95% CI 9.3–13.6)

Treatment period

Placebo, n = 124

Median: 10.2 months

(95% CI 7.8–29.0)

HR = 0.49 (0.33–0.74)

p = 0.00048 Radium-223, n = 250

Median: 19.6 months

(95% CI 16.5 – not estimable)

0

20

40

60

80

100

Pat

ient

s w

ithou

t

sym

ptom

atic

ske

leta

l eve

nts

(%)

ALSYMPCA: Quality of Life

Nilsson S, et al. Ann Oncol 2016;27:868-74

*Response = Increase in score of ≥3 points from baseline at week 16 and/or week 24 for all

scales except pain, and an increase in score of ≥2 from baseline for the pain scale

34.9

24.5 24.7 26.5

22.5 24.7

17.9

21.9

16.5 14.9

0

5

10

15

20

25

30

35

40

45

Prostate Cancer

Subscale

Physical Well-Being Subscale

Social/Family Well-Being Subscale

Emotional Well-Being

Subscale

Functional Well-Being Subscale

Radium-223 (n = 434) Placebo (n = 191)

% R

esp

on

der

s* 30.2

20.1

Pain-Related Subscale

p = 0.012

p = 0.063 p = 0.446 p = 0.006

p = 0.029

p = 0.010

ALSYMPCA: Adverse Events


All grades Grades 3 or 4

Adverse event 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) 7 (2)

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

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

ALSYMPCA: Improvements in Secondary End Points


ITT, Intention-to-treat population

*In patients who had elevated total ALP at baseline

SSE = Symptomatic skeletal event

Radium-223 (n=614)

Placebo (n=307)

Hazard ratio (95% CI)

p

Median time to first SSE, months 15.6 9.8 0.66 (0.52–0.83)

< 0.001

Median time to total ALP progression, months

7.4 3.8 0.17 (0.13–0.22)

< 0.001

Median time to PSA progression, months

3.6 3.4 0.64 (0.54–0.77)

< 0.001

Total ALP response (≥ 30% reduction), n/total n (%)*

233/497 (47) 7/211 (3) — < 0.001

Total ALP normalization, n/total n (%)*

109/321 (34) 2/140 (1) — < 0.001

ALSYMPCA: OS in Patients With and Without ALP Declines

Heinrich D, et al. EAU 2014

0

0

Ra-223 patients

without confirmed

tALP decline

n = 97

Median: 10.4 months

Ra-223 patients

with confirmed

tALP decline

n = 400

Median: 17.8 months

HR = 0.45

95% CI 0.34-61

p < 0.001

Months

Per

cent

age

of P

atie

nts

100

90

80

70

60

50

40

30

20

10

40 30 20 10

ALSYMPCA: Hematological Values in Patients Receiving Chemotherapy After Radium-223

Sartor O et al. Ann Oncol 2012;23(suppl. 9). Abstr 936P Post-hoc analysis

Placebo

Radium-223 Month 0 on the X axis =

the start of chemotherapy

Impact of Radium-223 on New Hormonal Therapies

• Favourable safety profile of radium-223 supports combination with other agents for additional beneficial effect1

• Hormonal agents abiraterone acetate and enzalutamide improved overall survival in CRPC patients with bone metastases2,3

– Safety profiles suggest nonoverlapping toxicity with rRadium-223

• Ongoing trials are studying the impact of radium-223 on new hormonal therapies1

1. Petrylak DP, et al. J Clin Oncol 2014;32(suppl):5S. Abstr TPS5103

2. De Bono JS, et al. N Engl J Med 2011;364:1995-2005

3. Scher HI, et al. N Engl J Med 2012;367:1187-97

Radium-223 Early Access Program: Study Design

Saad F, et al. Lancet Oncol 2016. [Epub ahead of print]

BPI-SF = Brief Pain Inventory-Short Form; HRPC = Hormone-refractory

prostate cancer; OS = Overall survival; SAE = Serious adverse events;

TEAE = Treatment-emergent adverse events

CRPC/HRPC patients with: • Bone

metastasis • ≥ 2 skeletal

metastases on imaging

• No lung/liver/ brain metastases

Radium-223 50 KBq/kg q4w x 6 injections Best standard of care (BSoC)

Treatment assessments each cycle Variables: Safety (SRE, TEAE, SAE, ECOG PS, Lab tests, QOL (BPI-SF) and OS Exploratory variables: SRE, ALP and PSA (changes in levels and time-to-event data)

Follow-up for safety data SRE, TEAE, SAE and secondary malignancies

Radium-223 Early Access Program: OS by Baseline Concomitant Use of Novel Endocrine Agents

NA = Not achieved

NE = Not estimated

OS = Overall survival

Concomitant use of abiraterone or enzalutamide

Yes No

Patients, n 189 507

Events, n (%) 42 (22%) 164 (32%)

Median OS, months (95% CI) NA (16–NE) 13 (12–16)


0

0

4

3

48

75

142

296

Concomitant use of abi or enza

No concomitant use of abi or enza

Patients at risk

Concomitant use of abiraterone or enzalutamide

No concomitant use of abiraterone or enzalutamide

Time from start of treatment (months)

0 6 12 18 24 0

10

20

30

40

50

60

70

80

90

100

Ove

rall

surv

ival

(%

)

189

507

Radium-223 Early Access Program: OS by Baseline Concomitant Denosumab Use

NA = Not achieved

NE = Not estimated


Concomitant use of denosumab

Yes No

Patients, n 136 560

Events, n (%) 34 (25%) 172 (31%)

Median OS, months (95% CI) NA (15–NE) 13 (12–NE)


0

0

3

4

39

84

102

336

138

560


No concomitant use of denosumab

Patients at risk


No concomitant use of denosumab

0 6 12 18 24 0

10 20 30 40 50 60 70 80 90

100


Ove

rall

surv

ival

(%

)

Radium-223 Early Access Program: OS by Baseline Pain

*Measured by the Brief Pain Inventory Short Form (BPI-SF) questions 3 “Worst pain”,

4 “least pain”, 5 “average pain”, 6 “pain right now”

NA = Not achieved; NE = Not estimated; OS = Overall survival

Baseline pain* (n = 669)

No pain Mild Moderate-severe

Patients, n 139 370 158

Events, n (%) 23 (17%) 110 (30%) 64 (41%)

Median OS, months (95% CI) NA (16–NE) 14 (13–NE) 11 (9–13)


0

0 0

2

4 1

32

66 20

94

238 88

139

370 158

No pain

Mild pain Moderate-severe pan

Patients at risk

No pain

Mild pain

Moderate-severe pain

0 6 12 18 24 0

10

20

30

40

50

60

70

80

90

100


Ove

rall

surv

ival

(%

)

Radium-223 Early Access Program: OS by Baseline ECOG PS

NE = Not applicable


ECOG PS

0 1 ≥ 2

Patients, n 261 348 87

Events, n (%) 42 (16%) 117 (34%) 47 (54%)

Median OS, months (95% CI) NA (17–NA) 13 (11-NA) 7 (5-11)

0 0

4 3

62 55

183 226

261 348

ECOG 0 ECOG 1

Patients at risk

ECOG PS 0

ECOG PS ≥ 2


0 0 6 29 87 ECOG ≥ 2

ECOG PS 1

0 6 12 18 24 0

10

20

30

40

50

60

70

80

90

100


Ove

rall

surv

ival

(%

)

PRACTICAL CONSIDERATIONS FOR THE USE OF RADIUM-223

Strategies to Minimize Hematological Effects of Radium-223

• Evaluate at baseline and prior to each injection:

• Discontinue treatment if counts do not recover to above values within 6-8 weeks despite supportive care (transfusions and growth factors)

Xofigo PM. March 2015

*Note: Patients may be accepted into clinical trials with hemoglobin

levels < 100 g/L

Before 1st administration

Before subsequent administrations

Absolute neutrophil count

≥ 1.5 x 109/L 1.0 x 109/L

Platelet count ≥ 100 x 109/L ≥ 50 x 109/L

Hemoglobin ≥ 100 g/L* ≥ 10 g/dL*

Radium-223: Instructions for Patients

• Remain well hydrated and monitor oral intake

• Report signs of bleeding or infection

• Report signs of dehydration, hypovolemia, urinary retention or renal failure/insufficiency

• For a least 1 week post-injection:

– Flush toilet several times after use

– Promptly wash soiled clothing separately

Xofigo PM. December 2013

CLINICAL VIGNETTES

PATIENT WHO HAS UNDERGONE CHEMOTHERAPY WITH DOCETAXEL

Clinical Vignette #1


• 67 yo male, diagnosed with PCa in June 2008

– PSA 11 ng/mL, cT2a, GS 4+4 = 8 in 4/10 cores

– CT and bone scan –ve for metastases

• Sept 2008: Treated with radical prostatectomy

– pT3a, GS 4+4 = 8, N1 (lymph nodes in 2 regional LN)

– No adjuvant treatments initiated, ADT discussed

ADT = Androgen-deprivation therapy; CT = Computed tomography

GS = Gleason score; LN = Lymph node;


Clinical Vignette #1 (cont’d)

• PSA rose quickly after surgery

• June 2009: Intermittent androgen blockade started

• Jan 2012: CRPC developed; PSA 22 ng/mL; bone scan showed metastases

0.4

3.2

5.5

0

2

4

6

Jan 2009 March 2009 May 2009

PSA

ng/

mL


• March 2012: Started on abiraterone acetate + prednisone and denosumab 120 mg q 4 weeks

– PSA continued to rise

• How would you have intervened over these 7 months?

• Bone scan showed worsening bony mets (spine, femur) (right and left), and multiple ribs; CT showed no visceral disease

24

33

45

0

10

20

30

40

50

July 2012 Oct 2012 Jan 2013

PSA

ng/

mL


• Sept 2014: Finished 10 cycles of docetaxel and prednisone

– PSA 23 ng/mL

– No change in bone scan

– CT scan shows no visceral disease

– Worsening bony pain, especially in spine

Discussion Questions

• Would you refer for consideration of a radiopharmaceutical for this patient?

• Why/why not?

• What other agent would you initiate at this time, if any? Why/why not?

PATIENT WHO HAS PROGRESSED ON DOCETAXEL AND IS ENROLLED IN A CLINICAL TRIAL



• July 2002: 65 yo male with high-risk prostate cancer

– cT2B, Gleason 8, PSA 38 ng/mL

– Staging –ve

– Radical external radiation therapy

– 3 years adjuvant LHRH

• Jan 2007: PSA relapse, staging –ve

• ADT initiated

ADT = Androgen-deprivation therapy


LHRH = Luteinizing hormone-releasing hormone

September 2009

• Disease progression

– Bone pain

– Progression on bone scan

– Rising PSA

• What would you do next?

November 2009

• Receives docetaxel

• Zoledronic acid started

• Docetaxel discontinued due to severe mucositis and bone marrow toxicity (2 cycles)

Discussion Question

What is your next step?

• Androgen receptor axis-targeted therapy?

• Initiate denosumab?

• Refer for chemotherapy (cabazitaxel)?

• Refer for radium-223?


• Nov 2009: Patient referred for radium-223

• At initiation:

– Diffuse bone pain/anorexia/fatigue

– PSA 785 ng/mL, ALP 448 U/L, hemoglobin 96 g/L

– PSADT 4 months

– Diffuse bone metastases

– Morphine sulfate (timed-release) 15 mg bid + breakthrough morphine

PSADT = PSA doubling time


• 6 cycles of radium-223 (50 kBq/kg IV Q4 weekly)

• Subjective clinical benefit (discontinued narcotics within 6 weeks)

• Complete pain relief last 4 months

• PSA stabilized/ALP normalized (101 U/L)

• Single palliative external-beam radiation to humerus for pain

• Toxicity: – No gastrointestinal adverse effects

– No systemic reactions

Bone Scan Response to Radium-223

May 2010 Jan 2011


• May 2010: Patient progresses – bones/nodes

• No response to abiraterone acetate + prednisone and discharged to palliative care hospital for supportive care

• What benefits could have been actualized if the patient had received a bone-targeted therapy?

• How else might you have sequenced therapy for this patient?

PATIENT WHO PROGRESSES ON ABIRATERONE ACETATE + PREDNISONE



• Aug 2011: 74-year-old man with PCa

– PSA: 420 ng/mL

– Biopsy: Gleason 8

• Multiple BM on bone scan, no visceral metastases in abdominal CT, clear chest X-ray

• Initial treatment: ADT = leuprolide and bicalutamide from time of diagnosis

• Question: This was 2011. What would you have done with this patient today?

PSA Rising: Indication for New Treatment

• May 12, 2013

– PSA 12 ng/mL, testosterone 0.6 nmol/L, ALP 95 IU/L, Hb 12.1 g/dL

– Multiple BM on bone scan, no visceral metastases in abdominal CT and chest X-Ray

• June 14, 2013

– PSA 25 ng/mL

• June 21, 2013

– Abiraterone acetate + prednisone initiated

PSA Rising: Indication for New Treatment (cont’d)

• March 2014 – Patient became symptomatic of progressive BM

needing NSAID and occasional codeine for pain relief

1.5

8 11

25

05

1015202530

Sept2013

Jan2014

Feb2014

March2014

PSA

ng/

mL

Symptoms

• Pain: variable intensity, regular NSAID with occasional codeine 30 mg on average 1-2/day when active

• Patient reduced activities but was able to continue regular walks with spouse with the use of codeine

• Sleep occasionally disturbed due to pain

• Bothered by constipation due to analgesic use


• April 2014: PSA: 52 ng/mL, testosterone 0.6 nmol/L, ALP 312 IU/L

– Imaging:

• Bone metastases: multiple metastases (approximately 10-12) mainly in spine, sacrum and right hip - No evidence of visceral metastatic disease

Discussion Questions

• What are the options for this patient who has had symptomatic progression on abiraterone acetate + prednisone?

• What is your therapeutic sequence/clinical maneuver with this man?

• What are the characteristics of the right patient for:

– Radium-223?

– Chemotherapy?

– Bone-targeted therapy?

What We Did

• The patient was offered docetaxel or radium-223 given progression on abiraterone acetate + prednisone and the appearance of symptoms

• The patient selected radium-223 after discussing the advantages and disadvantages of each

• Patient made aware that chemotherapy could still be an option after radium-223 and vice versa

• April 2011: Radium-223 initiated (6 cycles)

Radium-223 Treatment

• Radium-223 was administered with no dose interruptions

• Concomitant treatment for PCa: leuprolide

• Comorbidities: well-controlled hypertension

Other Key Measures

Hb

g/L

WBC

x109/L

Platelets

/µL

ALP

U/L

PSA

ng/mL

After 1 cycle of

Radium-223

119 5.8 265,000 261 61

After 2 cycles of

Radium-223

117 5.6 241,000 243 75

After 3 cycles of

Radium-223

118 6.3 238,000 188 92

After 4 cycles of

Radium-223

111 4.9 244,000 155 113

After 5 cycles of

Radium-223

115 5.5 212,000 121 119

After 6 cycles of

Radium-223

108 4.7 198,000 99 126

• Oct 2014: Patient completed radium-223 treatment

• Dec 2014: Pain progressed, PSA 260 ng/mL

• What would you suggest at this point?



• Dec 2014: Patient started docetaxel (7 cycles)

• April 2015:

– No unexpected side effects or myelosuppression beyond what was expected

– Patient not on G-CSF

Patient Case – Overview

AA = Abiraterone acetate; ALP = Alkaline phosphatase;

BIC = Bicalutamide; BM = Bone metastases, DXT = Docetaxel;

LEU = Leuprolide; TT = Testosterone

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