Ponencia en el marco del 4to Congreso ACHO, Barranquilla, 29/10/2016.

1. Bifosfonatos Vs. Denosumab para el
manejo de enfermedad metastásica
ósea
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Barranquilla, 29.10.2016

2. Bifosfonatos Vs.
Denosumab para el manejo
de enfermedad metastásica
ósea
Mauricio Lema Medina

3. @onconerd

4. Conflict of interest: I own a (smaller than I would
like) part of an infusional center. Therefore, non-IV
agents put me out-of-business
Mauricio Lema Medina

5. The Majority of Patients With Advanced Breast and
Prostate Cancer Are Likely to Get Bone Metastases

6. SREs Are Clinically Significant and Serious
Consequences of Bone Metastases

7. SREs Are Both a Common and Frequent Problem
for Patients With Advanced Cancer Untreated for
Bone Metastases
1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. 3. Rosen LS, et al. Cancer.
2004;100:2613-2621. 4. Saad F, et al. Clin Prostate Cancer. 2005;4:31-37

8. With Improvements in Survival, Patients Are More
Likely to Experience an SRE
1. Lipton A, et al. Cancer 2000;88:1082-1090. 2. Miller K, et al. N Engl J Med. 2007;357:2666-2676. 3. Saad F, et al. J Natl
Cancer Inst. 2002;94:1458-1468. 4. Kantoff PW, et al. N Engl J Med. 2010;363;411-422. 5. Rosen LS, et al.
Cancer. 2004;100:2613-2621. 6. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

9. RANK Ligand Is an Essential Mediator of the Vicious
Cycle of Bone Destruction
Roodman, GD. N Engl J Med. 2004;350:1655-1664.

10. Denosumab: From Bench to Bedside
OPG = osteoprotegerin.
1. ClinicalTrials.gov. Available at: http://clinicaltrials.gov. Accessed Nov 20, 2010. 2. Anderson DM, et al. Nature.
1997;390:175-179. 3. Simonet WS, et al. Cell. 1997;89:309-319. 4. Lacey DL, et al. Cell. 1998;93:165-176. 5. Yasuda H,
et al. Proc Natl Acad Sci U S A. 1998;95:3597-3602. 6. Bekker, PJ, et al. J Bone Miner Res. 2004;19:1059-1066.

11. Denosumab
Denosumab: Targets and Inhibits RANK Ligand to
Break the Vicious Cycle of Bone Destruction and
Prevents SREs
Roodman, GD. N Engl J Med. 2004;350:1655-1664.

12. Is denosumab MORE effective
than bisphosphonates in
(relevant outcomes of bone
metastases) in solid tumors?

13. Is denosumab SAFER than
bisphosphonates metastatic
bone disease in solid tumors?

14. Is denosumab COST-EFFECTIVE
when compared to (active)
bisphosphonates in solid
tumors?

15. Three Identically Designed Head-to-Head Studies
Comparing Denosumab vs Zoledronic Acid Enables
a Prespecified Intregated Analysis
*Daily supplementation of calcium 500 mg and vitamin D 400 IU recommended.
1. XGEVATM (denosumab) prescribing information, Amgen. 2. Data on file, Amgen. 3. Lipton A, et al. Ann Oncol.
2010;21(suppl 8):382. Abstract 1249 and poster.
J Clin Oncol 28:5132-5139. © 2010
J Clin Oncol 29:1125-1132. © 2011
Lancet 2011; 377: 813–22

16. Three Identically Designed Head-to-Head Studies
Comparing Denosumab vs Zoledronic Acid Enables
a Prespecified Intregated Analysis
SREs in this study were defined as either pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression.
1. XGEVATM (denosumab) prescribing information, Amgen. 2. Data on file, Amgen. 3. Lipton A, et al. Ann Oncol. 2010;21(suppl
8):382. Abstract 1249 and poster.

17. J Clin Oncol 28:5132-5139. © 2010
J Clin Oncol 29:1125-1132. © 2011
Lancet 2011; 377: 813–22

18. J Clin Oncol 28:5132-5139. © 2010

19. SRE Rate: Denosumab vs ZA in Breast
Cancer Patients With Bone Metastases
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
Denosumab
0
1.2
SREsperPatientperYr
0.4
0.6
0.8
0.2
1.0
ZA
0.58
0.45
-22% (P = .004)

20. Time to First On-Study SRE:
Extended Analysis
Zoledronic acid 1020 831 675 584 498 429 356 265 186 111 38 4
Denosumab 1026 834 692 597 510 444 384 280 193 101 38 9
Patients at Risk, n
KM Estimate of
Median Mos
Denosumab
Zoledronic acid
32.7
27.4
HR: 0.82 (95% CI: 0.71-0.95;
P = .0096, superiority)
Study Mo
0
1.0
SubjectsWithoutSRE(%)
0.2
0.4
0.6
0 3 6 9 12 15 18 21 24 27 3330
0.8
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

21. Time to First and Subsequent On-Study
SRE* (Multiple Event Analysis)
0 3 6 9 12 15 18 21 24 27 30
0
0.5
1.0
1.5
CumulativeMeanNumberofSRE
Mos
Total No. of
Events
Denosumab
Zoledronic acid
474
608
Rate ratio: 0.77 (95% CI: 0.66-0.89;
P = .001†)
*Events that occurred at least 21 days apart. †Adjusted for multiplicity.
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

22. n = number of patients randomized
Lipton A, et al. ASCO 2010. Abstract 9015.
Pooled Analysis: Time to First On-Study
SRE by Previous SRE History
HR: 0.82 (95% CI: 0.70-0.96;
P = .015)
HR: 0.83 (95% CI: 0.72-0.97;
P = .021)
HR: 0.83 (95% CI: 0.74-0.92;
P < .001)
ProportionofPatients
WithoutOn-StudySRE
0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
0
With Previous SRE
Zoledronic acid (n = 819)
Denosumab (n = 818)
0 6 12 18 24 30
Without Previous SRE
Zoledronic acid (n = 1091)
Denosumab (n = 1094)
0 6 12 18 24 30
Overall
Zoledronic acid (n = 1910)
Denosumab (n = 1912)
Study Mo
Risk Set, n
ZA
Dmab
819
818
0
1
425
411
266
266
145
144
36
48
1910
1912
4
4
1052
1084
692
716
382
402
114
127
1091
1094
4
3
627
673
426
450
237
258
78
79

23. Skeletal Complication Risk: Incremental
Benefits in Breast Cancer
No bisphosphonate
64% risk at 2 yrs Pamidronate
~ 20% risk reduction
64% 51% 34%
Zoledronic acid
Additional ~ 20%
risk reduction
27%
Denosumab
Additional 18%
risk reduction
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.

24. Between-Group Differences in AEs With
Unadjusted P < .05
Favors denosumab Favors zoledronic acid
Hypocalcemia
Toothache
Renal failure acute
Blood urea increased
Bronchospasm
Hyperthermia
Skin hyperpigmentation
Metastases to spine
Hypercalcemia
Edema
Alanine aminotransferase increased
Lumbar vertebral fracture
Dyspepsia
Renal failure
Pain
Chills
Anemia
Arthralgia
Bone pain
Pyrexia
Risk Difference
-10 10-5 50
Zoledronic Acid,
n (%) (n = 1013)
Denosumab,
n (%) (n = 1020)
247 (24.4)170 (16.7)
238 (23.5)186 (18.2)
291 (28.7)250 (24.5)
232 (22.9)192 (18.8)
58 (5.7)29 (2.8)
97 (9.6)72 (7.1)
25 (2.5)2 (0.2)
74 (7.3)52 (5.1)
56 (5.5)35 (3.4)
47 (4.6)28 (2.7)
40 (3.9)22 (2.2)
35 (3.5)17 (1.7)
21 (2.1)9 (0.9)
19 (1.9)7 (0.7)
15 (1.5)4 (0.4)
10 (1.0)2 (0.2)
8 (0.8)0 (0.0)
7 (0.7)1 (0.1)
37 (3.7)57 (5.6)
34 (3.4)56 (5.5)
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

25. *P = .2861
†No cases of hypocalcemia were grade 5 (fatal).
‡In the first 3 days after initial treatment.
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.
Adverse Events: From Extended Analysis
Event, n (%) Zoledronic Acid
(n = 1013)
Denosumab
(n = 1020)
All adverse events 987 (97.4) 961 (96.2)
Serious adverse events 509 (50.2) 489 (47.9)
Adverse events related to renal toxicity 95 (9.4) 55 (5.4)
Osteonecrosis of the jaw* 18 (1.8) 26 (2.5)
Hypocalcemia (any) 37 (3.7) 62 (6.1)
 Hypocalcemia of grade 3 or 4† 12 (1.2) 18 (1.8)
Acute-phase reactions‡ 286 (28.2) 109 (10.7)

26. ONJ Associated With Bone-Targeted
Therapy in Patients With Bone Metastases
Saad F, et al. Ann Oncol. 2012;23:1341-1347.
Denosumab
(n = 52)
1.8%
Zoledronic acid
(n = 37)
1.3%
Positively adjudicated
for ONJ
(n = 89)
Potential ONJ
(n = 276)
All patients
(N = 5723)
Integrated analysis of pivotal
denosumab SRE prevention trials
No significant difference
between groups (P = .13)

27. Denosumab vs Zoledronic Acid Pivotal
Phase III SRE Prevention Trials
1. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 2. Fizazi K, et al. Lancet. 2011;377:813-822.
3. Henry DH, et al. J Clin Oncol. 2011;29:1125-1132.
Supplemental calcium and vitamin D
Denosumab 120 mg SC q4w
+
Placebo IV q4w†
Zoledronic Acid 4 mg IV q4w†
+
Placebo SC q4w
Study 136[1]
Breast cancer
(N = 2049)
Study 103[2]
Prostate cancer
(N = 1904)
Study 244[3]
Other solid tumors/MM
(N = 1779)
R
A
N
D
O
M
I
Z
A
T
I
O
N
In total, > 5700 patients with bone metastases

28. Prespecified Integrated Analysis: Baseline
Demographics
ECOG = Eastern Cooperative Oncology Group.
1. Data on file, Amgen. 2. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.

29. Denosumab Was Superior to Zoledronic Acid: 17%
Risk Reduction in First SRE
P value for superiority.
1. Data on file, Amgen. 2. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.
Denosumab 120 mg Q4W (n= 2862)
Zoledronic acid 4 mg Q4W (n= 2861)

30. Superior Efficacy Across Multiple Solid Tumor
Types: Reduction in Risk of First SRE
*P value for superiority. †Excluding breast and prostate.
1. XGEVATM (denosumab) prescribing information, Amgen. 2. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 3. Fizazi K, et al.
Denosumab 120 mg Q4W (n= 2862)
Zoledronic acid 4 mg Q4W (n= 2861)

31. Proven Efficacy in Multiple Solid Tumor Types: Reduction
in Risk in the Subanalysis of Other Solid Tumors
Henry D, et al. Presentation at: ASCO Annual Meeting. June 4-8, 2010; Chicago, IL
Denosumab
Zoledronic Acid
Excluding Multiple Myeloma (10% of the patients)

32. Increased Time to First SRE
1. Denosumab prescribing information, Amgen. 2. Lipton A, et al. Cancer 2000;88:1082-1090. 3. Saad F, et al. J Natl Cancer Inst.
2002;94:1458-1468.
Denosumab Zoledronic None Denosumab Zoledronic None

33. Increased Time to First SRE
1. Henry D, et al. Presentation at: ASCO Annual Meeting. June 4‐8, 2010; Chicago, ILL. 2 Rosen LS, et al. Cancer. 2004;100:2613-
2621.
Denosumab Zoledronic None

34. Denosumab Was Superior to Zoledronic Acid: 18% Risk
Reduction in First and Subsequent SREs
1. Henry D, et al. Presentation at: ASCO Annual Meeting. June 4‐8, 2010; Chicago, ILL. 2 Rosen LS, et al. Cancer. 2004;100:2613-
2621.
Denosumab
Zoledronic Acid

35. Denosumab Was Superior to Zoledronic Acid: 18% Risk
Reduction in First and Subsequent SREs
*P value for superiority. †Excluding breast and prostate. Study Month
1. Denosumab prescribing information, Amgen. 2. Stopeck A, et al. Presentation at: ECCO/ESMO Multidisciplinary Congress. Sept
20-24, 2009; Berlin, Germany. 3. Stopeck AT, et al. J Clin Oncol. 2010;28:5132- 5139. 4. Fizazi K, et al. Lancet. 2011;377:813-822. 5.
Henry D, et al. J Clin Oncol. [Epub ahead of print] doi: 10.1200/JCO.2010.31.3304.
Denosumab
Zoledronic Acid

36. Overal Survival
*Excluding breast and prostate.
1. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 2. Fizazi K, et al. Lancet. 2011;377:813-822. 3. Henry D, et al. J Clin Oncol.
[Epub ahead of print] doi: 10.1200/JCO.2010.31.3304. 4. XGEVATM (denosumab) prescribing information, Amgen.
Denosumab
Zoledronic Acid

37. Denosumab: Superior Efficacy
*Excluding breast and prostate.
1. Data on file, Amgen. 2. XGEVATM (denosumab) prescribing information, Amgen. 3. Henry D, et al. Presentation at: ASCO Annual
Meeting. June 4-8, 2010; Chicago, ILL. 4. Stopeck A, et al. Presentation at: ECCO/ESMO. Sept 20-24, 2009; Berlin, Germany.
Abstract 2LBA. 5. Fizazi K, et al. Lancet. 2011;377:813-822. 6. Henry D, et al. J Clin Oncol. [Epub ahead of print] doi:
10.1200/JCO.2010.31.3304. 7. Lipton A, et al. Ann Oncol. 2010;21(suppl 8):382. Abstract 1249 and poster.

38. Is denosumab SAFER than
bisphosphonates metastatic
bone disease in solid tumors?

39. Denosumab does not require dose adjustments,
regardless of renal function
1. Lewiecki EM. Biologics. 2008;2:645-653. 2. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. 3. Mould DR, Green B.
BioDrugs. 2010;24:23-39. 4. Data on file, Amgen. 5. Zometa® Prescribing Information, Novartis.
Zoledronic Acid Denosumab

40. Most Common Adverse Reactions Ocurring in More than
25% of Patients
*Laboratory-derived and below the central laboratory lower limit of normal (2.2–2.8 mg/dL [0.71–0.9 mmol/L] for phosphorus).
Zoledronic AcidDenosumab

41. Hypocalcemia
1. Data on file, Amgen. 2. XGEVA (denosumab) prescribing information, Amgen.
Zoledronic Acid Denosumab
Adverse events of hypocalcemia were predominantly
transient and generally not associated with clinical
consequences.
Most adverse events of hypocalcemia were single events
that resolved with oral calcium or no action taken.

42. Osteonecrosis of the Jaw (ONJ)
Denosumab: 1.8%
Zoledronic acid: 1.3% (NS)

43. Acute-Phase Reactions
Denosumab: 8.7%
Zoledronic acid: 20.2%
Acute phase reaction events occurred within the first 3
days of treatment, and the most common were pyrexia,
fatigue, bone pain, arthralgia, and chills.

44. Sun L, Am J Clin Oncol 2013;36:399–403

45. Sun L, Am J Clin Oncol 2013;36:399–403
Time to First SRE Time to Multiple SREs
Overall survival Disease progression

46. Sun L, Am J Clin Oncol 2013;36:399–403
This meta-analysis indicates that denosumab is
more effective than ZA in reducing morbidity for
patients with bone metastases. In addition, the
risk of relative serious AEs was not significantly
increased in patients receiving denosumab
compared with those given ZA

47. Is denosumab COST-EFFECTIVE
when compared to (active)
bisphosphonates in solid
tumors?

48. Carter JA, Botteman MF. Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic
prostate cancer. Expert Rev Pharmacoecon Outcomes Res. 2012;12:425–437

49. Can we SELECT who will reap a
greater benefit from
denosumab?

50. Lipton A. Eur Journal of Cancer 53 (2016) 75-83

51. Lipton A. Eur Journal of Cancer 53 (2016) 75-83

52. Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab

53. Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab

54. Lipton A. Eur Journal of Cancer 53 (2016) 75-83
Favors denosumab

55. Denosumab prior to bone events
in solid tumors

56. Smith MR, Lancet 2012; 379: 39–46
High-Risk Non-metastatic
castration-resistant prostate
cancer (PSA greater or equal
than 8 or PSA doubling time
less than 10 months)
R
Denosumab
Placebo
Composite endpoint determined by time to fi rst occurrence
of bone metastasis (symptomatic or asymptomatic) or death from any cause
n=716
n=716
120 mg q4wk

57. Smith MR, Lancet 2012; 379: 39–46

58. Smith MR, Lancet 2012; 379: 39–46
Bone-Metastasis-Free Survival

59. Smith MR, Lancet 2012; 379: 39–46
Time to bone metastases

60. Smith MR, Lancet 2012; 379: 39–46
Time to symptomatic bone metastases

61. Smith MR, Lancet 2012; 379: 39–46
Time to symptomatic bone metastases

62. Smith MR, Lancet 2012; 379: 39–46

63. Gnant M, Lancet Oncol 2015
Post-menopausal women
with HR+ Early-Stage Breast
Cancer and receiving AI
R
Denosumab
Placebo
Time from randomization to first fracture
n=1711
n=1709
60 mg Q6m

64. Gnant M, Lancet Oncol 2015

65. Gnant M, Lancet Oncol 2015

66. Is denosumab MORE effective
than bisphosphonates in
(relevant outcomes of bone
metastases) in solid tumors?
Yes

67. Is denosumab SAFER than
bisphosphonates metastatic
bone disease in solid tumors?
Probably, at least in
patients with renal
impairment

68. Is denosumab COST-EFFECTIVE
when compared to (active)
bisphosphonates in solid
tumors?
Maybe

69. Should YOU use it routinely in
your patients with solid tumors
?
…

70. @onconerd