1. Osteoclast Inhibitors in Malignancy
Joel Brothers
10/4/2016

2. Objectives
Understand the indications and benefits of bisphosphonates in metastatic disease:
Breast Cancer
Prostate Cancer
Multiple Myeloma
Other Solid Malignancies
2) Understand the role of bisphosphonates/denosumab in non-metastatic disease
3) Bisphosphonates versus Denosumab

3. Bisphosphonates Nitrogen Containing Zoledronic acid (Zometa, Reclast)
Pamidronate
Alendronate (Fosamax)
Ibandronate (Boniva)
Risedronate (Actonel)
Inhibit osteoclast binding
Non-Nitrogen Containing
Etidrunate
Tiludronate
Clodronate
Induce osteoclast apoptosis
Uptodate.com

4. Denosumab (Xgeva, Prolia)
RANK Ligand inhibitor
Dovepress.com

5. Potency
Reaseachgate.com

6. Approximate Costs 1 month supply
Pamidronate (IV) - $70 (generic)
Zoledronic Acid (IV) - $ (generic)
Alendronate (PO) - $80 (generic)
Risedronate (PO) - $ (generic)
Ibandronate (PO or IV) - $400 (generic)
Denosumab (subQ) - $2,500 (brand: Xgeva)
Uptodate.com

7. Administration Pamidronate: Zoledronate Denosumab 90mg IV over 2 hours
4 mg IV over 15 minutes
Denosumab
120mg SubQ injection

8. Breast Cancer
Bisphosphonates indicated for any patient with bony metastases
Skeletal related event (SRE)
Fracture
Cord Compression
Need for surgery or radiation
Hypercalcemia (+/-)

9. Bisphosphonates in Breast Cancer
1993 Clodronate PO v. placebo N=173
reduces SRE rate by 86/100 person years v. placebo. (Paterson et al, JCO)
1996: Pamidronate IV monthly for 1 year v. Placebo. N=382
13.1 v 7 month time to SRE. (Hortobagyi et al, NEJM)
2003 Ibandronate IV 6mg v. 2mg v placebo. N=466
Improvement in skeletal morbidity period rate and QOL with 6mg dose (Body et al, Ann Oncol)
SMPR number of 12 week periods with no SRE
Int. J. Cancer: 137, 753–764 (2015)

10. Bisphosphonates in Breast Cancer
2005: Zoledronate monthly v. placebo x1 year. N=228
39% RRR in SRE with zoledronate. 20% absolute reduction. (Kohno et al, JCO)
2004: Zoledronate q3-4w v. pamidronate q3- 4w for 1 year. N=1,130
Prevalence of SRE similar (43 v 45%) but longer time to SRE with zoledronic acid (310 v 174 days) (Rosen et al, Cancer)
2014: ZICE trial: Ibandronate PO daily inferior to zoledronate q3-4w. N=1,326 (Barrett-Lee et al, Lancet Oncol)
Int. J. Cancer: 137, 753–764 (2015)

11. Bisphosphonates in Breast Cancer Dosing Interval
OPTIMIZE-2:
Zoledronate q12w v q4 week. N=403. Non-inferiority.
No difference in SREs (23.2% v 22%) and similar time to SRE (HR 1.06). Less AEs in q12w group (but not significant). (Hortobagyi, 2014 ASCO)
ZOOM:
Previously completed months Zoledronate randomized to q4w or q12w dosing. N=425
No difference in SMR (26% v 22%), pain (Amadori, Lancet, Oncol 2013)
CALGB (Alliance):
Randomized to q4w or q12 Zoledronate for 2 years. (breast, prostate, myeloma, other). N=1822.
No difference in proportion of patients with SRE (ASCO 2015)

12. Bisphosphonates in Breast Cancer Summary
Zoledronate 4mg IV v. Pamidronate 90mg IV
Zoledronate is probably better
4 week v. 12 week dosing interval
In patients at high risk for SRE:
consider monthly for 1-year, then q3 months (Optimize-2)
In patients at low risk:
Consider q3 months (CALGB)

13. Zoledronate v. Denosumab in metastatic breast cancer
Randomized. Placebo controlled double blind study. N=1,026
Median time to SRE:
26.4 month v. not reached
HR 0.82 ( )
Similar OS, PFS, AEs
(Stopeck et al. JCO. 2010)

14. Denosumab versus Zoledronate
(Stopeck et al. JCO. 2010)

15. Renal Toxicity Denosumab: No dose adjustment necessary Zoledronate:
Increase in hypocalcemia if CrCl <30
Zoledronate:
CrCl:
>60: 4 mg
50-60: 3.5 mg
40-49: 3.3 mg
30-39: 3 mg
<30 do not use
Pamidronate: Do not use in severe renal impairment or AKI.
May consider use with longer infusion time if renal disease due to myeloma

16. Dosing Interval Denosumab
Insufficient data to reduce dosing interval
Small study (N=111) of 12w v. 4w dosing. No difference with 6 months follow up (Fizazi et al. JCO 2009)
Awaiting results of SAKK 96/12 (REDUSE) trial. (still recruiting)
Phase III breast and prostate cancer. Non inferiority. Expected completion date 2022.

17. Osteoclast Inhibitors as Adjuvant Therapy
Clodronate
Diel et al.
In patients with micrometastatic bone marrow disease 13% v. 29% DM at 3 years
Not replicated in two other studies
Saarto et al
Improved DFS
Powels et al
No difference

18. Osteoclast Inhibitors as Adjuvant Therapy
Clodronate
NSABP B-34
Placebo controlled
No difference in DFS
Subset (>50 years) with improved: recurrence free interval, BM free interval, non BM free interval
Ibandronate
GAIN trial
No difference in OS or PFS

19. Osteoclast Inhibitors as Adjuvant Therapy
Zoledronic Acid
ABCSG-12:
q6 month, premenopausal, HR positive early breast cancer
Disease progression: 3.2% ARR, 36% RRR
AZURE:
Zoledronate (19 doses over 5 years) in Stage II and III breast cancer
No difference in DFS
Pre-planned subgroup showed survival benefit in post-menopausal women
More chemo in Azure, did not suppress ovarian function

20. Osteoclast Inhibitors as Adjuvant Therapy
Zoledronic Acid
Q6 month Zometa. Patients on AI. Early, versus delayed (fracture or BMD drop). 5 year duration.
ZO-FAST (N=1065)
Advantage in DFS with upfront therapy
Z-Fast (N=602)
No difference in DFS between arms
Studies looking at role of bisphosphonates in postmenopausal women on AI. Designed to loos at BMD. Similar design. Geographically diverse

21. Osteoclast Inhibitors as Adjuvant Therapy
EBCTCG Meta Analysis (SABCS 2014, Lancet)
26 randomized trials. 18,766 women.
Any bisphosphonate versus placebo
No effect in pre-menopausal women.
In post-menopausal women:
34% reduction bone recurrence
17% reduction in breast cancer death
Borderline significance in overall population
Note: other meta-analyses with negative results

22. Osteoclast Inhibitors as Adjuvant Therapy
SWOG S0307: (ASCO 2015)
Clodronate v. Ibandronate v. Zoledronate
N=6, years.
No difference in DFS, OS.
No control arm.
Patients preferred oral treatment.

23. Osteoclast Inhibitors as Adjuvant Therapy
ABCSG-18
Denosumab 60mg q6 month v. placebo
N=3,420. Post-menopausal, HR receptor positive.
Helps prevent fractures
Preliminary trend toward improved DFS (HR p=0.051) (SABCS 2015 )
D-CARE Study
Adjuvant denosumab in stage II-III breast cancer
Primary outpoint: BM free survival
Secondary outcomes: OS, DFS, Distant recurrence free
Completed accrual. Results 2022.

24. Osteoclast Inhibitors as Adjuvant Therapy- Conclusions
Conflicting data on bisphosphonates
May consider zoledronate q6 month in post- menopausal patients
Awaiting results of randomized trials for denosumab
Currently no recommendation in NCCN guidelines for or against
NCCN guidelines do not address

25. Osteoclast Inhibitors and Bone Mineral Density
Premenopausal
Tamoxifen decreases BMD
AI +/- GnRH agonist or oophorectomy
Effects of chemotherapy (amenorrhea v. direct bone effect)
Postmenopausal
Increasing age
AIs
Chemotherapy

26. Osteoclast Inhibitors and Bone Mineral Density
Other risk factors:
Vit D deficiency
Chronic Steroid use
Smoking, drinking
Low BMI
Secondary (hyperparathyroid, Cushing’s, celiac, liver disease, RA, hypercalciuria)

27. Osteoclast Inhibitors and Bone Mineral Density- The Data
ABCSG-18:
Denosumab 60mg q6 month v. placebo
N=3,420. Post-menopausal, HR receptor positive.
Only trial to demonstrate decrease risk of fracture (92 v 176 fractures, HR 0.5 [95% CI ])
Bisphosphonates:
trials not powered to detect fracture difference
Primary outcome is BMD
never compared head to head with denosumab

28. Osteoclast Inhibitors and Bone Mineral Density- The Data
ABCSG-12
Premenopausal women: Goserelin plus either AI/Tamoxifen with or without zoledronate.
11.3% decrease w/o zoledronate; 0.4% increase with zoledronate
Z-FAST, ZO-FAST, E-ZO-FAST
Post-menopausal women on AI +/- zoledronate
Early v. late (after fracture or T score <-2.)
5-10% difference in BMD at 1 year f/u
SABRE Trial
Postmenopausal women on anastrozole
medium risk randomized to risedronate or placebo
Risedronate weekly improved BMD at 24 months

29. Osteoclast Inhibitors and Bone Mineral Density- Approach
Screen all women for risk factors for osteoporosis
Lifestyle modifications/ Ca / Vit D
DEXA for:
All post-menopausal women on AIs
Pre-menopausal women with treatment related amenorrhea (ASCO guidelines)
FRAX score: treatment if
T score < (-1.5 if significant loss due to cancer therapies)
10-year hip fracture risk >3%
10-year fracture risk >20% (NCCN guidelines)
NCCN repeat dexa every 24 months

31. Osteoclast Inhibitors and Bone Mineral Density- Treatment
Bisphosphonates:
Zoledronate 4 mg q6 month v. 5mg yearly
Alendronate, risendronate, ibandronate
Denosumab 60 mg q6 month
Do not use:
Raloxifene (SERM)
Teriparatide (sarcoma risk with XRT)

32. Prostate Cancer Metastatic Disease
Lower risk of fractures due to “- blastic”lesions
No role of osteoclast inhibitors in hormone sensitive disease
CALGB 90202: Zoledronate v. placebo. N=645
No difference in time to first SRE (32 v. 30 months). No difference in OS
Denosumab: No data in castrate sensitive disease

33. Prostate Cancer Metastatic Disease
Castrate Resistant:
Saad et al
Zoledronate 4mg v. 8mg v. placebo (N=643) q3w
Reduce SRE by 11% (38 v. 49%)
Reduce time to SRE (488 v. 321 days)
Improved pain scores
No difference in PFS, PS, QOL
Clodronate equivocal
Pamidronate no benefit

34. Prostate Cancer Metastatic Disease
Dosing Interval:
- Zoledonate
Q12 week dosing supported by CALBG 70604
Included 674 patients with prostate cancer
- Denosumab
Insufficient data to support less frequent dosing

35. Prostate Cancer Metastatic Disease
Castrate Resistant:
Fizazi et al. Lancet. 2011
Denosumab v. zoledronate monthly
Decreased time to SRE (20.7 v 17.1) with denosumab
No difference in OS, PFS
Increase in ONJ (non significant) and hypocalcemia (significant) with denosumab

36. Prostate Cancer Metastatic Disease
Hoskin et al. J Natl Cancer Inst
470 patients with pain from bone mets
Single dose RT v. ibandronate 6mg IV x1
30% crossover in each direction (allowed at 4 weeks)
No difference in pain response at 4 and 12 weeks
More rapid response with RT

37. Prostate Cancer Adjuvant Therapy
Bisphosphonates
ZEUS trial
High risk prostate cancer (Gleason 8-10, PSA >20, or node positive)
Zoledronate v. placebo q3 month for 4 years
No difference in incidence of bone mets (14.7 v 13.2%)
Clodronate trial also negative

38. Prostate Cancer Adjuvant Therapy
Denosumab
Smith et al. Lancet 2012
Non-metastatic CR high risk (PSA >8 or doubling time <10 months) prostate cancer
Denosumab 120mg monthly v. placebo
N=1432
Increased bone met free survival (29.5 v months)
No difference in OS
5% incidence ONJ
7 month delay in time to bone mets with doubling time <6 months

39. Prostate Cancer Bone Mineral Density
ADT:
Increase in fracture risk (21-54% RR)
Decrease in BMD 2-3% per year
Check DEXA scan at baseline and then at some interval thereafter with ADT
Ca/Vit D (1,200 mg/800 units)
FRAX score
20% fracture risk
3% hip fracture risk
Nccn.org

40. Prostate Cancer Bone Mineral Density
No trials demonstrate decrease in fracture rate
Primary outcome is BMD
Benefits in BMD:
Pamidronate 60mg q3 mo v. placebo (Smith et al. NEJM 2001)
Zoledronate 4mg q3 mo v. placebo (Smith et al J Urol 2008)
Alendronate 70mg q wk v. placebo (Greenspan Ann intern Med 2007; Klotz Eur Urol. 2013)
Risedronate v. placebo (RT and ADT) (Choo Int J Radiat Oncol Biol Phys 2013)
Denosumab 60mg q6 mo v placebo (Smith NEJM 2009, J Urol 2009)

41. Prostate Cancer Summary
Either denosumab or zoledronate in bone metastatic castrate-resistant prostate cancer
Denosumab may be slightly better
Zoledronate may be given q12 weeks
No role for adjuvant osteoclast inhibitors
Denosumab may delay time to bone mets in high risk patients
DEXA scan in patients on ADT
Bisphosphonates with high FRAX risk

42. Other Solid Tumors Rosen JCO 2003 Henry JCO 2011 CALBG 70604:
Excluded breast and prostate cancer
Zoledronic Acid reduced SRE (38 v 47%; 230 v. 163 days)
N=773
Henry JCO 2011
Denosumab noninferior to zoledronate in preventing SREs.
Trend toward superiority.
excluded breast and prostate
N=1776 (781 NSCLC, 200 myeloma, 1,005 other)
CALBG 70604:
Insufficient data (n=45) to recommend 12 week dosing interval

43. Multiple myeloma
85% of patients have lytic lesions, fracture, or osteopenia
Fracture rate 20-50%
60% Myeloma patients with lytic lesion at diagnosis

44. Multiple Myeloma 2012 Cochrane Review 20 randomized trials N=6692
16 placebo controlled
4 with different bisphosphonate as comparator
N=6692
Results:
No difference in OS, PFS, non-vertebral fractures
Improvement in:
Vertebral fractures; RR 0.74 [ ] (7 studies)
SREs; RR 0.80 [ ] (7 studies)
Pain; RR 0.80 [ ] (8 studies)
Zoledronate better than placebo or etidronate in OS, but not other bisphosphonates?

45. Multiple Myeloma 2 trials comparing pamidronate to zoledronate
Rosen et al. Cancer
N=1,648. Breast or Myeloma
Zoledronate 8mg v 4 mg v pamidronate
Similar proportion of patients SRE
Zoledronate better time to SRE in breast cancer, similar in myeloma

46. Multiple Myeloma Zoledronate versus clodronate (Myeloma IX)
Very complicated trial design

48. Multiple Myeloma Zoledronate versus clodronate (MRC Myeloma IX)
Very complicated trial design
Zoledronate reduced mortality 16% and improved median survival by 5.5 months
Improved PFS by 12% and median PFS by 2 months
Basis for NCCN recommendation:
all myeloma patients should receive bisphosphonates (Category 1)

49. Multiple Myeloma Denosumab
Denosumab is not approved for use in multiple myeloma
Henry JCO 2011
N=1,776. Denosumab versus zoledronate
In exploratory analysis of myeloma patients (n=180), denosumab appeared to increase mortality
HR 2.26 ( ; p=0.014)
Hypothesized to be differences in patient characteristics (Raje Blood Cancer Journal 2016)

50. Multiple Myeloma Denosumab
NCT
Ongoing phase 3 trial with 1718 patients enrolled
Sponsored by Amgen
Primary outcome: Time to SRE (non-inferiority)
Secondary: Time to SRE (superiority), Time to first and subsequent SRE (superiority)
Estimated completion March, 2019

51. MGUS, Smoldering Myeloma
Zoledronade v. placebo (Mustro. Cancer. 2008)
No difference in PFS. Lower SREs in Zoledronate group
Same with pamidronate (D’Arena. Leuk Lymphoma. 2011)
Zometa q 6 months improves BMD (Berenson. Clin Cancer Res )
Use not recommended unless high fracture risk (at osteoporosis dosing)

52. Multiple Myeloma Summary
Most (if not all) patients with myeloma should receive a bisphosphonate
Zometa 4mg monthly or Pamidronate 90mg monthly are reasonable options
Decrease SRE, pain. (Probably not survival)
Denosumab is not approved in myeloma
Awaiting results of phase III trial
No role for bisphosphonates in MGUS, smoldering myeloma

53. Risks of Treatment Notes: All patients on trials received Ca/Vit D
ASCO/NCCN recommend baseline dental exam

54. Risks of Treatment Osteonecrosis of the Jaw (ONJ)
Duration of therapy increases risk
1-2% risk in first year of treatment. Increases thereafter.
Higher potency osteoclast inhibitors increase risk
Poor dentition (h/o tooth extraction)
Dental surgery
Anti-angiogenic therapy
Dental-tribune.com

55. Risks of Treatment Hypocalcemia (greater with denosumab)
Atypical fractures
Bisphosphonates only
AKI (Zoledronate, pamidronate) Proteinuria (pamidronate -> FSGS?)
Acute phase reaction
Flu-like syndrome lasting several days
Usually does not recur
Ocular toxicity?

56. Conclusions Bone Metastatic Disease Adjuvant Therapy
Breast and Prostate: Zoledronate q3 months v. denosumab monthly
Myeloma: Zoledronate v. pamidronate monthly
Awaiting results of phase III denosumab trial
Adjuvant Therapy
Conflicting data on bisphosphonates in breast
Awaiting trials on denosumab
No real role in prostate cancer or myeloma

57. Conclusions 3. Bone mineral density 4) Denosumab v. bisphosphonates
Patients with breast, prostate, and myeloma at risks for osteoporosis and should be screened
Treat for osteoporosis according to fracture risk
4) Denosumab v. bisphosphonates
Denosumab marginally better but way more expensive
Can be used in renal insufficiency