Elderly men with prostate cancer + ADT

Background and Rationale

ADT and Osteoporosis

Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis +6.8%; P < .001 No ADT (n = 20,035)

21

ADT (n = 6650) 18

19.4

Frequency (%)

15

12

12.6

9

+2.8%; P < .001

6 5.2 3 2.4 0

Any Fracture Shahinian VB, et al. N Engl J Med. 2005;352:154-164.

Fracture Resulting in Hospitalization

Bone metastases

Bone metastases

• > 90% of patients with metastatic CRPC have radiologic evidence of bone metastases1 • Skeletal-related events (SREs) include spinal cord compression, pathological fracture, and need for surgery or EBRT2 • Bone metastases are a major cause of death, disability, decreased quality of life, and increased treatment cost3

1. Tannock et al. N Engl J Med. 2004;351:1502-1512. 2. Lipton. Semin Oncol. 2010;37:S15-S29. 3. Lange and Vasella. Cancer Metastasis Rev. 1999;17:331-336.

Lumbar spine MRI

Bone Metastases: The Clinical Problems • Replacement of hematopoietic tissues in the bone marrow by the prostate cancer cells may lead to – Anemia

– Increased susceptibility to infection

• Damage caused by bone metastases overgrowth may lead to – Pain – Fractures – Spinal cord compression that may lead to hemiparesis or paresis

Logothetis CJ, Lin S-H. Nat Rev Cancer. 2005;5(1):21-28.

Incidence of bone complications

Outcome Disease

Observation time, mos Total SREs, % Radiation to bone, % Pathologic fractures, % Hypercalcemia of malignancy, % Surgery to bone, % Spinal cord compression, %

Placebo Arms Pamidronate Trials ZA Trials Lung/ Breast[1] Myeloma[2] Prostate[3] Other[4] 24 21 24 21 64 51 49 46 43 34 33 34 52 37 25 22 13

9

1

4

11 3

5 3

4 8

5 4

1. Lipton A. Cancer. 2000;88:1082. 2. Berenson JR, et al. J Clin Oncol. 1998;16:593. 3. Saad F, et al. J Natl Cancer Inst. 2004;96:879. 4. Rosen LS, et al. Cancer. 2004;100:2613.

Patients (%)

Skeletal-related events in metastatic prostate cancer

Total SREs

Pathologic fracture

Radiation therapy

24-month data of the placebo arm of a randomized trial; n=208 Saad F, et al. J Urol, 2003. Abstract 1472.

Surgical intervention

Spinal cord compression

Bone lesions are associated with worse survival No bone lesions 6 bone lesions

1.0

Cumulative survival

0.8

0.6

0.4

0.2

0 0

20

40

60

80

Months Pezaro C et al. Eur Urology 2013. In press Attard G, Multidisciplinary approach to castration-resistant prostate cancer. Presented at ECC 2013.

MDT approach Urologist

Radiotherapist

Medical oncologist

Surgeon

Nuclear medicine physician

Normal Bone Remodeling Relies on the Balance Between the Activities of Osteoblasts and Osteoclasts

Normal bone remodeling Resting

Reversal Resorption New bone

Osteoblasts Osteoclasts Mononuclear cells

Mineralized bone matrix

Adapted from Coxon JP, et al. Prostate Cancer Prostatic Dis. 2004;7:99-104.

The “Vicious Cycle” of Bone Metastases in CRPC Prostate cancer cells Growth factors (ALP, PINP, Unknown GFs)

CTXI, ICTP, Bone-derived growth factors (TGF-β) Osteolytic factors (PTHrP/IL-6)

Osteoblastic factors (ET-1, BMP, IGFs, FGF, uPA, TGF-β) RANKL RANKL RANKL

New bone Osteoblasts Osteoclasts

Mineralized bone matrix

CRPC bone metastases are predominantly osteoblastic

ET, endothelin; ICTP, C-terminal telopeptides of type I collagen; PTHrP, parathyroid hormone–related protein; uPA, urokinase-type plasminogen activator. Adapted from Kingsley LA, et al. Mol Cancer Ther. 2007;6:2609-2617.

The Ability of CRPC Cells to Induce Bone Formation is Essential for Metastatic Growth Osteoblastic factors secreted from tumor cells • Promote osteoblast proliferation • Stimulate osteoblasts to produce factors that trigger proliferation of prostate cancer cells • Promote the secretion of growth factors that trigger deposition of new bone matrix

1. Logothetis CJ, Lin S-H. Nat Rev Cancer. 2005;5(1):21-28. 2. Loriot Y, et al. Ann Oncol. 2012;23(5):1085-1094. 3. Adapted from Kingsley LA, et al. Mol Cancer Ther. 2007;6:2609-2617.

Bone Metastasis–Targeted Therapies: Capitalizing on the Altered Microenvironment Existing therapies for bone metastasis γ-Rays: EBRT

Bisphosphonates

β-Emitters: Strontium-89, samarium-153

Denosumab

α-Emitter: Radium 223

Interfere with deregulated signaling pathways to/from the bone

Target the bone and actively kill the tumor cells

1. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 2. Saad F, et al. J Natl Cancer Inst. 2004;96(11):879-882. 3. Horwich A, et al. Ann Oncol. 2013;Jun 27[Epub ahead of print].

Radium-223 Has a Targeted Mechanism of Action

Tumor cells

Bone marrow

Osteoblast Radium-223 deposition

Osteoclast

α-particle radiation

Newly formed bone

Targets new bone, e.g. bone metastases

Irradiates adjacent tumor cells leading to highly localized tumor cell killing

Bruland et al. Clin Cancer Res 2006;12:6250s.

Therapies That Interfere With Deregulated Signaling Pathways to/From the Bone Denosumab

Bisphosphonates Bisphosphonates

RANKL

Denosumab RANK

Binds to RANKL and prevents it from binding to RANK on the surface of cells

Bind to bone mineral and are taken up by mature osteoclasts at sites of bone resorption

Loss of osteoclast formation, function, and survival

Loss of resorptive function

Baron R, et al. Bone. 2011;48(4):677-692.

•

Provides palliative effect

•

No survival benefit has been demonstrated

Elderly men with prostate cancer

Pamidronate vs Placebo in Metastatic Prostate Cancer Skeletal Event by Study Week 27, n (%)

Pamidronate (n = 169)

Placebo (n = 181)

Any SRE

42 (25)

46 (25)

Radiation to bone for pain relief

25 (15)

29 (16)

Radiation to bone to prevent fracture

8 (5)

7 (4)

Nonvertebral fractures

14 (8)

12 (7)

Vertebral fractures

11 (7)

10 (6)

Spinal cord compression

5 (3)

3 (2)

Surgery to bone

5 (3)

6 (3)

Hypercalcemia

1 (< 1)

2 (1)

Small EJ, et al. J Clin Oncol. 2003;21:4277-4284.

ZA vs Placebo: Time to First On-Study SRE

Patients Without Event (%)

100 90 80 70 60 50 40 30

ZA 4 mg

ZA 8/4 mg

20

Placebo

10 0 0

Patients at Risk, n ZA 4 mg 214 ZA 8/4 mg 221 Placebo 208

90

163 155 149

180 270 360 Days After Start of Study Drug 113 102 103

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

92 68 69

70 46 43

450

540

5 4 1

0 0 0

Denosumab vs ZA: Time to First On-Study SRE Median Mos (95% CI) Denosumab 20.7 (18.8-24.9) ZA 17.1 (15.0-19.4)

Proportion of Patients Without SRE

1.00

0.75

0.50

0.25 HR: 0.82 (95% CI: 0.71-0.95; P = .0002 for noninferiority analysis; P = .008 for superiority analysis) 0 0

Patients at Risk, n Denosumab 950 ZA 951

3

6

9

758 733

582 544

472 407

Fizazi K, et al. Lancet. 2011;377:813-822.

12 15 18 Number of Months 361 299

259 207

168 140

21

24

27

115 93

70 64

39 47

Time to First and Subsequent On-Study SRE (Multiple Event Analysis)*

Cumulative Mean Number of SREs per Patient

2.0

Rate ratio: 0.82 (95% CI: 0.71-0.94; P = .004; adjusted P = .008)

1.8 1.6 1.4

1.2 1.0

0.8 0.6 0.4

Events, n Denosumab (n = 950) 494 ZA (n = 951) 584

0.2 0 0

3

6

9

12

15

18

21

24

Number of Months *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:813-822.

27

30

33

36

Comparison of First SRE After Starting BoneDirected Therapy Events, n (%)

ZA (n = 951)

Denosumab (n = 950)

Total confirmed events

386 (41)

341 (36)

Radiation to bone

203 (21)

177 (19)

Pathologic fracture

143 (15)

137 (14)

Spinal cord compression

36 (4)

26 (3)

Surgery to bone

4 (< 1)

1 (< 1)

Fizazi K, et al. Lancet. 2011;377:813-822.

Comparison of Bone-Directed Therapies

Zoledronic Acid

Denosumab

Intravenous

Subcutaneous

Acute phase reactions

Yes

No

Renal toxicity

Yes

No

Hypocalcemia

Rare

Not rare

ONJ

Yes

Yes

Survival benefit

No

No

Usually not

Regional

Route

Reimbursement concerns

Abiraterone and SRE

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

Beta emitters: long range increases bone marrow exposure Beta Range in tissue (μm)

50–12 000

Relative particle mass

1

DNA hits for cell kill

Marrow Bone

>1000

Beta emitter

Range of beta particle (10–1000 cell diameters2)

Henriksen G et al. Cancer Res 2002;62:3120–5; Brechbiel M. Dalton Trans 2007;43:4918–28