Managing Bone Lesions in Cancer

Managing Skeletal-Related Events in Patients With Cancer:
A Master Class in Breast Cancer, Prostate Cancer, and Multiple Myeloma

Matthew Raymond Smith, MD, PhD
Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts
This program is supported by an educational donation provided by
Managing Skeletal-Related Events in Patients With Cancer

clinicaloptions.com/oncology
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Faculty
Matthew Raymond Smith, MD, PhD Allan Lipton, MD
Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Professor of Medicine and Oncology Milton S. Hershey Medical Center Penn State Cancer Institute Hershey, Pennsylvania
Noopur Raje, MD
Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Boston, Massachusetts
Mitigating Bone Complications in Multiple MyelomaWhats Current and on the Horizon

Bone Involvement in Different Tumor Types

Disease Prevalence (US) (in Thousands) Myeloma Lung Breast Prostate 49.6[1] 327[1] 2051[1] 1477[1] Incidence of Bone Metastases in Patients With Advanced Disease, % 84[2] 30-40[3] 65-75[3] 65-75[3] Median Survival of Patients With Bone Metastases, Mos 37-58[4] 8-10[5] 19-25[6] 30-35[7]
1. National Cancer Institute. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. 3. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 4. Palumbo A, et al. Blood. 2004;104:3052-3057. 5. Smith W, et al. Semin Oncol. 2004;31(suppl 4):11-15. 6. Lipton A. J Support Oncol. 2004;2:205-213. 7. Tu SM, et al. Cancer Treat Res. 2004;118:23-46.

Factors Increasing Osteoclast Activity in Bone Metastasis

RANK ligand
OPG MIP-1 alpha

OPG RANKL
1,25(OH)2D3
Prevents Promotes
PTHrP
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
Increased osteoclastic activity and decreased OPG

Prevalence of Skeletal Complications in Myeloma

Total Pathologic Fracture Radiation to Bone Hypercalcemia of Malignancy Surgery to Bone Spinal Cord Compression 0
* *
10 20 30 40 Patients With SREs (%) 50 60
*9-mo data. Placebo arm of pamidronate randomized trial. Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593602.

Current Treatment of MM Bone Disease

Bisphosphonates Surgical procedures
Vertebroplasty Balloon kyphoplasty
Radiotherapy Treatment of myeloma
Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.

Pamidronate Decreases SREs in Patients With Myeloma

P = .015 51 41 24 38 Placebo Pamidronate
60 50
P < .001
Patients (%)
40 30 20 10 0 9
Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593602.
Mos
21

Zoledronic Acid vs Pamidronate in Multiple Myeloma
Patients With SRE (%)
13-month follow-up: zoledronic acid was shown to be effective compared with pamidronate across all clinical endpoints The proportion of patients requiring radiation therapy to bone was significantly lower in the zoledronic acid 4 mg group than in the pamidronate group (15% vs 20%, respectively, P = .031) Zoledronic acid not inferior to pamidronate in reducing the risk of skeletal complications
60 46% 40 44%
20
Pamidronate 90 mg
Zoledronic acid 4 mg
All SREs
Rosen LS, et al. Cancer J. 2001;7:377-387.

MRC Myeloma IX: Analysis Schematic for Zoledronic Acid vs Clodronate

Zoledronic acid 4 mg IV q 3-4 wks* + intensive or nonintensive chemotherapy (n = 981) Patients with newly diagnosed MM (stage I, II, III) (N = 1960) Treatment continued until disease progression
Clodronate 1600 mg/day PO + intensive or nonintensive chemotherapy (n = 979)
Endpoints (zoledronic acid vs clodronate) Primary: PFS, OS, and ORR Secondary: time to first SRE, SRE incidence, and safety
*Dose-adjusted for patients with impaired renal function, per the prescribing information.
Morgan G, et al., Lancet. 2010;376:1989-1999

MRC Myeloma IX: ZOL SREs* vs CLO Regardless of Bone Lesions at Baseline
Bone Lesions at Baseline
0.5
No Lesions at Baseline
0.5 0.4
CLO ZOL
SREs/Patient
0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Mos From Randomization
0.3 0.2 0.1 0 0 Pts at Risk, n 6 12 18 24 30 36 42 48 54 60 66 72 Mos From Randomization
CLO ZOL
Pts at Risk, n
Zoledronic acid 668 415325 250 189 136 100 69 50 35 Clodronate 682 402297 212 164 117 75 50 37 24 18 6 12 4 0
0 Zoledronic acid 302 241185 135 92 63 38 28 18 11 Clodronate 276 212159 118 91 56 37 24 18 12
8 7
5 4
0 0
Highlights the importance of treating all patients regardless of skeletal morbidity at presentation Morgan GJ, et al. ASH 2010. Abstract 311. Reprinted with permission. Morgan G, et al. Lancet. 2010;376:1989-1999.

MRC Myeloma IX: Zoledronic Acid Improved OS and PFS vs Clodronate

Zoledronic acid significantly reduced the relative risk of death by 16% vs clodronate (HR: 0.842; 95% CI: 0.736-0.963; P = .0118)
Risk Reduction P Value .0118
OS
0.842
16%
PFS
0 0.2 0.4
0.883
12%
.0179 1.8 2
0.6 0.8 1 1.2 1.4 1.6 HR (Zoledronic Acid vs Clodronate)

In favor of ZOL In favor of CLO
Reprinted from The Lancet, 376(9757), Morgan GJ, Davies FE, Gregory WM, et al., First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.989-1999, Copyright 2010, with permission from Elsevier.

Z-MARK Study Design

Prospective, single-arm, open-label, multicenter study
Patients with MM who received IV bisphosphonate therapy 52-104 wks before first zoledronic acid dose on study* (N = 121) Bone marker-directed ZOL dosing x 96 wk uNTx 50 ZOL 4 mg q4wk
uNTx < 50
ZOL 4 mg q12wke
SRE, PD, or uNTX 50
ZOL 4 mg q4wk
*Patient had to receive 4 doses of IV bisphosphonate; last previous IV bisphosphonate dose must have been administered 3 wks before initial zoledronic acid dose on study. nmol/mmol creatinine. Patients will remain on zoledronic acid q 4 wks for remainder of the study. All patients were reminded to take supplemental oral calcium ( 500 mg) and vitamin D ( 400 IU) daily. Dose adjusted for patients with mild to moderate renal impairment at study entry.
Raje N, et al. ASH 2010. Abstract 2971.

Results
SREs by end of Year 1
2 patients receiving zoledronic acid q12wk
Spinal cord compression (1 patient) Radiation therapy to bone x 4 (1 patient)
uNTX
Baseline uNTX
Median: 17 nmol/mmol Cr Range: 7-71 nmol/mmol Cr
Median % change from baseline in uNTX

Wk 12-36: 0% 11.7% (range, -80.5% 344.4%) Wk 48: 0% (range, -67.5%188.9%)
0 patients receiving zoledronic acid q4wk
Raje N, et al. ASH 2010. Abstract 2971.

Summary of Bisphosphonates in MM
Inhibit bone resorption Pamidronate better than placebo Pamidronate and zoledronic acid equivalent Zoledronic acid has a survival advantage

Denosumab: Inhibiting RANK in Bone Disease

High affinity human monoclonal antibody that binds RANKL Administered via subcutaneous injection Specific: does not bind to TNF-, TNF-, TRAIL, or CD40L Inhibits formation and activation of osteoclasts

Phase II Study of Denosumab in Relapsed and Plateau-Phase MM

Effective for myeloma bone disease Median changes in bone resorption markers were -70% and -52% for relapsed and plateau-phase patients
Vij R, et al. Am J Hematol. 2009;84:650-656.

Denosumab vs Zoledronic Acid

Phase III trial in 1776 patients with solid tumors (not breast or prostate) or myeloma
Primary endpoint: median time to first SRE
Denosumab was noninferior to zoledronic acid in delaying time to first on-study SRE (HR: 0.84; 95% CI: 0.71-0.98; P = .0007) Serious adverse events were similar ONJ infrequent and similar (10 vs 11 patients)
Henry D, et al. J Clin Oncol. 2011;29:1125-1132.

Bortezomib/Lenalidomide in MBD
Myeloma cells Lenalidomide
OAFs Bortezomib
OCL precursor
OCL Osteoblasts
Bone
BMP-2
Runx-2
MSCs
Roodman GD. J Clin Invest. 2008;118:462-464.

CCR1 Inhibition Decreases Osteoclastogenesis

CCR1 and Osteoclastogenesis/Osteoclasts Function Menu: On Murine OC BX4471 Is a Potent Inhibitor of Osteoclastogenesis TRAP + multinucleated cells Resorbed area on dentine slices MLN3897 10 nM MLN3897 10 nM
140 120 100 80 60 40 20 0
TRAP + MN Cell (% of connect)
Cathepsin K expression
PB1 0 0.2 2 10 100 MLN3807(nM) Pro-cathepsin K Cathepsin K C-tubulin
PB2 + +
MLN3807 10 nM MLN3807 10 nM
Pct Area as % of Total Area
P < .05
12 10 8 6 4 2 0
P < .05
0.2
10
MLN3807(nM)
This research was originally published in Blood. Vallet S, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. 2007 Nov 15;110(10):3744-52. the American Society of Hematology.

DKK1 and sFRP-2 in Myeloma Bone Disease

Inhibitors of the WNT signaling pathway WNT signaling is a critical pathway for OBL differentiation Secreted by myeloma cells Marrow plasma from patients with high levels of DKK1 or sFRP-2 inhibit murine OBL differentiation DKK1 gene expression levels correlated with extent of bone disease in MM patients
Tian E, et al. N Engl J Med. 2003;349:2483-2489. Oshima T, et al. Blood. 2005;106:3160-3165.

Anti-DKK1 BHQ880 Reverses Inhibitory Effect of MM Cells on Osteoblastogenesis

A
No Isotype Control BHQ880, 1 g/mL - BHQ880 + BHQ880
Calcium Deposition (% of control)
MM Cells
150 100 50 0
P = .08
P = .0001
With MM Cells
P = .0001 No MM Cells With MM Cells
B
huIL-6 ng/mL
8 6 4 2 0
P = .002 P = .0002 - BHQ880 + BHQ880 P = .0003 No MM Cells With MM Cells
This research was originally published in Blood. Fulciniti M, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. 2009;114:371-379. the American Society of Hematology.

Activin and Bone Growth

Osteoclast
Activin stimulates osteoclasts Activin inhibits osteoblasts
Osteoblast
Activin
Activin
Activin receptor type IIA Reduced bone formation Activin decreases bone mineral density and strength
Activin receptor type IIA
Increased bone resorption

Activin A Levels Are Elevated in Patients With MM and Osteolytic Disease

Activin A Levels Are Increased in Bone Marrow Plasma of Patients With MM NS 150 * * Activin A Is Produced by the Microenvironment, Notably BMSCs and Osteoclasts 3500 3000 2500 2000 1500 1000 500 0 NS Mean 1884
pg/mL
100
pg/mL
50 0 MM 0-1 OL MM > 1 OL Non MM
Mean 1300
Average Levels of Activin A MM 0-1 OL: 28.62 6.2 pg/mL MM > 1 OL: 112.07 30.4 pg/mL Non-MM: 30.6 7.9 pg/mL
Mean Mean 299 8.2 OC BMSC OB MM
*P < .05; P < .01
Vallet S, et al. Proc Natl Acad Sci U S A. 2010;107:5124-5129. Copyright 2010 National Academy of Sciences, U.S.A.

Phase II Study of hActRIIA-IgG1 in Patients With Osteolytic Lesions of MM

Randomized, double blind, placebo controlled Dose ranging, multiple dose, parallel assignment N = 30 All patients receiving backbone MPT regimen 0.1 mg/kg ACE-011, SQ monthly x 4 (n = 8) 0.3 mg/kg ACE-011, SQ monthly x 4 (n = 8) 0.5 mg/kg ACE-011, SQ monthly x 4 (n = 8) Placebo, SQ monthly x 4 (n = 6)
ClinicalTrials.gov. NCT00747123.

Results
28 patients had at least 1 previous treatment 13 patients receiving bisphosphonates 75% of patients had Hb increase of 1.5 gm/dL vs 17% of patients receiving placebo Increased BSAP and slightly decreased S-CTX levels among BP-naive patients
Abdulkadyrov KM, et al. ASH 2009. Abstract 749
Optimal Management of Bone Metastases in Patients With Breast Cancer

Scope of the Problem

400,000 new patients/yr in the United States develop bone metastases

Incidence of Skeletal-Related Events

Breast Cancer* Multiple Myeloma Prostate Cancer* Lung Cancer/Others 0 20 40 51 49 48 60
68
80
Patients With SREs (%) *24 mos. 21 mos. Placebo arm of pamidronate or zoledronic acid randomized trials.
Coleman RE. Oncologist. 2004;9(suppl 4):14-27.

Patients With Bone Lesions Are at High Risk for Skeletal Complications
60 52 Placebo Arms of Large Randomized Studies
Patients With SRE (%)
50 40 30 20 10 0
43 33 25 37 34
Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression 34 22
11 3 Breast[1] 24 mos 4 Prostate[2] 24 mos
Multiple myeloma*[3,4] NSCLC + other 21 mos solid tumors[5] 21 mos Cancer Type *21-mo data except for surgical intervention and spinal cord compression, for which only 9-mo data are available.
1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F, et al. AUA 2003. Abstract 1472. 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. 4. Berenson JR, et al. N Engl J Med. 1996;334:488-493. 5. Rosen LS, et al. Cancer. 2004;100:2613-2621.

Skeletal-Related Events and OS

Median Time to a Skeletal-Related Event and Median Survival Lung[1,2] Breast[3] Myeloma[4,5] Prostate[6,7] 0
5.1 12 9 11
12.3 26.7
Skeletal-related event Survival
44.8 53.0 20 Mos 40 60
As advances are made in cancer treatment, survival is increasedand with it, the risk of skeletal-related events
1. Rosen LS, et al. Cancer. 2004;100:2613-2621. 2. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 4. Berenson JR, et al. N Engl J Med. 1996;334:488493. 5. Kumar SK, et al. Blood. 2008;111:2516-2520. 6. Saad F, et al. J Natl Cancer Inst. 2004;96:879892. 7. Coleman RE. Cancer. 1997;80(8 suppl):1588-1594.
Pamidronate, Zoledronic Acid, and Denosumab

Zoledronic Acid Significantly Delays Time to First SRE Compared With Placebo
Proportion of Patients With Bone Metastases Without an SRE
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 50
P = .004
Zoledronic acid 4 mg Placebo
100 150 200 250 300 Days After Start of Study Drug
350
400
Kohno N, et al. SABCS 2004. Abstract 3060. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Reprinted with permission.

Zoledronic Acid Reduces SRE Risk vs Pamidronate in Breast Cancer

Zoledronic acid reduced SRE risk by 16% overall vs pamidronate (N = 417*) and by over 30% in patients in the breast carcinoma hormonal therapy stratum
Multiple Event Analysis Total Breast carcinoma hormonal therapy stratum Breast carcinoma chemotherapy stratum Multiple myeloma stratum
Risk Ratio 0.841 0.693 0.955 0.932
P Value .030 .009 .749 0.593
*Patients who entered the extension study in the 4 mg zoledronic acid or pamidronate groups.
Rosen LS, et al. Cancer. 2003;98:1735-1744.

International, Randomized, Double-Blind, Active-Controlled Study

Primary endpoint: time to first on-study SRE (noninferiority)
Patients with advanced breast cancer and confirmed bone metastases (N = 2046)

Denosumab 120 mg SC + Placebo IV* q4w (n = 1026)
Zoledronic acid 4 mg IV* + Placebo SC q4w (n = 1020)
Secondary endpoints: time to first on-study SRE (superiority); time to first and subsequent on-study SRE (multiple event analysis) Current or previous IV bisphosphonate administration not permitted
*IV agent dose adjusted for creatinine clearance at baseline and subsequent dosing intervals determined based on serum creatinine levels according to zoledronic acid label. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

Time to First On-Study SRE

1.00 HR: 0.82 (95% CI: 0.71-0.95; P < .001 noninferiority; P = .01 superiority*)
Proportion of Subjects Without SRE
0.75
0.50 0.25 KM Estimate of Median Mos Not reached Denosumab 26.4 Zoledronic acid 0 3
829 839
6
676 697
9
584 602
12
498 514
Patients at Risk, n Zoledronic acid 1020 Denosumab 1026 *Adjusted for multiplicity.
15 Mos
427 437
18
296 306
21
191 189
24
94 99
27
29 26
30
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. 2010 American Society of Clinical Oncology. All rights reserved.

Time to First and Subsequent SRE*: Multiple Event Analysis

1.5 Denosumab Zoledronic acid
Cumulative Mean Number of SREs
1.0
0.5 Rate ratio: 0.77 (95% CI: 0.66-0.89; P = .001) 0 3 6 9 12 15 Mos 18 21 24 27 30
*Events that occurred at least 21 days apart. Adjusted for multiplicity.


Time to Experiencing Mod or Severe Pain (Worst Pain Score > 4 Pts/Brief Pain Inv)
1.00
Proportion of Subjects
0.75
KM Estimate of Median Days Denosumab 88 Zoledronic acid 64
0.50 0.25
HR: 0.87 (95% CI: 0.79-0.97; P = .009)
12 Mos
15
18
21
24
27
Patients at Risk, n Zoledronic acid 1020 Denosumab 1026
463 511
318 378
250 312
209 256
172 214
126 159
93 109
56 59
17 27
Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted.

Disease Progression
Proportion of Subjects Without Disease Progression
1.00 0.75 HR: 1.00 (95% CI: 0.89-1.11; P = .93)
0.50 0.25
Denosumab Zoledronic acid 0 3

842 858
6
686 693
9
563 567
12
462 453
15 Mos
370 351
18
240 241
21
148 128
24
65 65
27
17 20
30

Overall Survival
1.00 HR: 0.95 (95% CI: 0.81-1.11; P = .49)
Proportion of Subjects Survived
0.75
0.50 0.25
Denosumab Zoledronic acid 0 3

962 984
6
897 916
9
834 849
12
757 771
15 Mos
699 690
18
515 511
21
352 336
24
184 177
27
54 57
30

Adverse Events
Adverse Event, % Overall Serious Acute phase reactions (first 3 days) Renal toxicity Zoledronic Acid (n = 1013) 97.2 46.5 27.3 8.5 1.5 1.4 Denosumab (n = 1020) 95.8 44.4 10.4 4.9 0.2 2.0
Overall Serious
ONJ*
*P = .39
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

Skeletal Complication Risk: Incremental Benefits in Breast Cancer

No bisphosphonate Pamidronate 64% risk at 2 yrs ~ 20% risk reduction Zoledronic acid Additional ~ 20% risk reduction Denosumab Additional 18% risk reduction
64%
51%
34%
27%
Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
Novel Strategies for BoneDirected Therapy in Prostate Cancer

Spectrum of Bone Disease in Prostate Cancer

Treatment-Related Fractures New Bone Metastases Disease-Related Skeletal Complications
Castrate sensitive, nonmetastatic
Castrate resistant, nonmetastatic
Castrate resistant, metastatic

Clinical Complications of Osteoblastic Metastases

Pain Fractures Spinal cord compression Myelophthisis

Markers of Osteoblast (BAP) and Osteoclast (NTx) Activity in Men With PC

25% 75%
4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 0 200 Correlation coefficient = 0.67
BAP (U/L)
75% 50% 25%
400 600 800 1000 1200 1400 NTx (nmol/mmol creatinine) Reproduced and adapted with permission from the American Association for Cancer Research: Cook RJ, et al. Clin Cancer Res. 2006;12:3361-3367. Figure 1B. Normal

Zoledronic Acid in Hormone-Refractory Prostate Cancer

Eligibility Criteria Patients with prostate cancer Hormone refractory Bone metastases (N = 643) Zoledronic acid 4 mg q3w (n = 214) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (n = 208)
Patients on the 8-mg arm reduced to 4 mg because of renal toxicity Primary outcome: proportion of patients having 1 SRE Secondary outcomes: time to first on-study SRE; proportion of patients with SREs, and TTP
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Zoledronic Acid vs Placebo: Time to First On-Study SRE

100
Patients Without Event (%)
90 80 70 60 50 40 30 20 10 0 0 Zoledronic acid 4 mg Zoledronic acid 8/4 mg Placebo 90 163 155 149 180 270 360 Days After the Start of Study Drug 113 102 103 92 68 69 70 46 43 450 5 4 1 540 0 0 0
Patients at Risk, n Zol acid 4 mg 214 Zol acid 8/4 mg 221 Placebo 208
Saad F, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468, by permission of Oxford University Press.

Denosumab vs Zoledronic Acid to Prevent SREs

Prospective, double-blind, placebo-controlled phase III trial
Denosumab 120 mg SC + Placebo IV q4w (n = 950)
Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901)
Zoledronic Acid 4 mg IV + Placebo SC q4w (n = 951)
Primary endpoint SREs: fracture, radiation or surgery to bone, spinal cord compression
Fizazi K, et al. Lancet. 2011;377:813-822.

Denosumab vs Zoledronic Acid: Time to First On-Study SRE

1.00 Denosumab Zoledronic acid Median Mos (95% CI) 20.7 (18.8-24.9) 17.1 (15.0-19.4)
Proportion of Patients Without an SRE
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 3 758 733 6 582 544 9 472 407 12 15 Study Mo 361 299 259 207 18 168 140 21 115 93 24 70 64 27 39 47
Patients at Risk, n Denosumab 950 Zoledronic acid 951
Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castrationresistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier

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

2.0
Cumulative Mean Number of SREs per Patient
1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 0
Rate ratio: 0.82 (95% CI: 0.71-0.94; P = .004; adjusted P = .008)
Events Denosumab (n = 950) 494 Zoledronic acid (n = 951) 584 3 6 9 12 15 18 21 Study Mo 24 27 30 33 36
*Events occurring at least 21 days apart.
Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier

Results
Denosumab was superior to zoledronic acid
Delay time to first SRE on study Reduce the rate of multiple SREs
Rates of adverse events similar (infection) ONJ infrequent and no statistical difference between arms Hypocalcemia more frequent in denosumab arm
Fizazi K, et al. Lancet. 2011;377:813-822.

Conclusions
Disease-related skeletal complications are common in men with metastatic prostate cancer Zoledronic acid decreases risk of SREs in men with castrate-resistant disease and bone metastases Denosumab is superior to zoledronic acid for delay in first SREs and rate of SREs in this setting


Metastasis Prevention

PSA and PSADT Are Associated With Shorter Bone Metastasis-Free Survival
1.0
Incidence of Bone Mets or Death
Incidence of Bone Mets or Death
0.8 0.6 0.4 0.2 0
PSA < 7.7 ng/mL PSA 7.7-24.0 ng/mL PSA > 24.0 ng/mL
1.0 0.8 0.6 0.4 0.2 0
PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos
0.5
1.0 1.5 2.0 2.5 3.0 Yrs Since Randomization
0.5 1.0 1.5 2.0 2.5 Yrs Since Randomization
3.0
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. 2005 American Society of Clinical Oncology. All rights reserved.

Denosumab to Prevent Metastases

Denosumab 120 mg monthly
Patients with CRPC and no bone metastases; PSA > 8 or PSADT < 10 mos (N = 1435)
Placebo monthly
Primary endpoint: bone metastasis-free survival
Smith MR, et al. 2011 AUA. Plenary. ClinicalTrials.gov. NCT00286091.

Primary Endpoint: Bone Metastasis-Free Survival

Proportion of Patients With Bone MetastasisFree Survival
1.0 0.8 0.6 0.4 0.2 0 Median Mos Placebo 25.2 Denosumab 29.5 0 3 6 9 12 15 18 21 24 Study Mo 27 30 33 36 39 42 36 35 HR: 0.85 (95% CI: 0.73-0.98; P = .028)
Patients at Risk, n Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59
Smith MR, et al. 2011 AUA. Plenary.

Time to Symptomatic Bone Metastasis

Proportion of Patients Without Symptomatic Bone Metastasis
1.0 0.8 0.6 0.4 0.2 0 HR: 0.67 (95% CI: 0.49-0.92; P = .01)
Placebo Denosumab 0 3 6 9 12 15 18 21 24 Study Mo 27 30 33 36 39 51 47
Patients at Risk, n Placebo 716 667 565 474 411 368 347 293 242 189 142 130 94 Denosumab 716 683 603 503 441 385 360 308 260 200 160 143 96
Note: Symptomatic bone metastases before or coinciding with imaging diagnosing. Smith MR, et al. 2011 AUA. Plenary.

ZEUS: Zoledronic Acid to Prevent Metastases

Patients with high-risk prostate cancer: Gleason sum 8-10, pN+, or PSA > 20 ng/mL at diagnosis; no bone metastases (N = 1433) Zoledronic acid q3m for 48 mos
Placebo q3m for 48 mos
Primary endpoint: first bone metastasis
Study does not control for ADT 1. Some men will develop bone metastases prior to ADT 2. Dramatic variation in duration of response to ADT
Wirth M, et al. ASCO GU 2008. Abstract 184.

Conclusions: Metastasis Prevention

Prevention of bone metastases is an important unmet clinical need Failure of previous studies is related, at least in part, to previously poorly defined natural history of castrationresistant nonmetastatic disease In men with high-risk CRPC, denosumab significantly increased bone metastasis-free survival, time to bone metastasis, and time to symptomatic bone metastasis


Treatment-Related Fractures

Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis

+6.8%; P < .001 21 18 19.4 ADT (n = 6650) No ADT (n = 20,035)
Frequency (%)
15 12 9 6 3 0 2.4 Any Fracture Fracture Resulting in Hospitalization 5.2 12.6 +2.8%; P < .001
Shahinian VB, et al. N Engl J Med. 2005;352:154-164.

GnRH Agonists Decrease BMD in Men With Prostate Cancer

2 1 Control GnRH agonist P < .001 for each comparison
Percent Change
0 -1 -2 -3 -4 -5 Lumbar Spine Total Hip
12-mo data
Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

6 Placebo 4 Zoledronic acid
BMD Percent Change
2 0 -2 -4 -6 Lumbar Spine Total Hip Final 12-mo data
Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.

Alendronate Increases BMD During GnRH Agonist Therapy

5 4 Placebo Alendronate P < .005 for each comparison
BMD Percent Change
3 2 1 0 -1 -2 -3 Lumbar Spine Total Hip
12-mo data
Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.

Denosumab Fracture Prevention Study

Current androgen deprivation therapy for patients with prostate cancer who are older than 70 yrs of age or with T score < -1.0 (N = 1468)
for 3 yrs
for 3 yrs
Primary endpoints: BMD, new vertebral fractures
ClinicalTrials.gov. NCT00089674.

Denosumab to Increase BMD in Patients With Prostate Cancer Receiving ADT

Denosumab Lumbar Spine 10 Placebo Total Hip 10
Percent Change in BMD From Baseline
Percent Change in BMD From Baseline
8 6 4 2 0 -2 -4 -6 Difference at 24 mos: 6.7 percentage points
8 6 4 2 0 -2 -4 -6 01 3 6 12 Mos 24 36 Difference at 24 mos: 4.8 percentage points
01 3 6
12
Mos
24
36
Smith MR. N Engl J Med. 2009;361:745-755. Copyright 2009 Massachusetts Medical Society. All rights reserved.

Denosumab to Prevent Fractures

10
New Vertebral Fracture (%)
Denosumab Placebo P = .004 P = .004 P = .006 3.9 1.5
8 6 4 2 0 1.9 0.3 12 13 2 1.0 24 Mos 22 7 36 26 10 3.3
Patients, n
Smith MR. N Engl J Med. 2009;361:745-755. Copyright 2009 Massachusetts Medical Society. All rights reserved.

Summary: Prevention of TreatmentRelated Fractures

Androgen deprivation therapy increases fracture risk Bisphosphonates increase BMD during androgen deprivation therapy Denosumab increases BMD and decreases fractures during androgen deprivation therapy
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Managing Bone Lesions in Cancer

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Managing Skeletal-Related Events in Patients With Cancer:

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Managing Skeletal-Related Events in Patients With Cancer

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0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Mos From Randomization

0.3 0.2 0.1 0 0 Pts at Risk, n 6 12 18 24 30 36 42 48 54 60 66 72 Mos From Randomization

0 Zoledronic acid 302 241185 135 92 63 38 28 18 11 Clodronate 276 212159 118 91 56 37 24 18 12

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CCR1 Inhibition Decreases Osteoclastogenesis

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