Bisphosphonates Can Prevent Skeletal Complications From Prostate Cancer and Renal Cell Carcinoma

1
Bisphosphonates Can Prevent Skeletal
Complications From Prostate Cancer and Renal
Cell Carcinoma

• Fred Saad MD FRCS
• Professor of Surgery/UrologyDirector of Urologic
  OncologyChair in Prostate cancer
  researchUniversité Montréal

2
Bone Metastasis A Significant Complication of
Cancer

• Approximately 70 of patients with advanced
  prostate cancer are diagnosed with bone
  metastases
• Up to 30 of patients with renal cell carcinoma
  will develop bone metastases

Coleman, RE. Cancer Treat Rev. 200127165-176.
3
Patients With Bone Metastases May Suffer
Potentially Lethal Skeletal-Related Events
1. Gainor BJ, et al. Clin Orthop Relat Res.
1983178297-302 2. Cree M, et al. J Am Geriatr
Soc. 200048283-288 3. QOL and SRE Schulman et
al 20054. Jacofsky et al. J Orthop Trauma.
200418459-469 5. Coleman RE. Cancer.
1997801588-1594 6. Abrahm JL. J Support
Oncol. 20042377-388, 391.
4
The Goals of Therapy

• Preserve patients functional independence and
  quality of life by . . .
• Preventing skeletal-related events (SREs)
• Prevent the first SRE
• Delay the onset of the first SRE
• Prevent the recurrence of SRE
• Palliating and controlling bone pain
• Reduce the need for analgesics and palliative
  radiotherapy

5
Approved Indications for Different Bisphosphonates
? European registration
? Global registration
6
Randomized Trial of Zoledronic Acid Versus
Placebo in Patients With Prostate Cancer
R A N DO M I Z E D
Zoledronic acid 4 mg q 3 wk daily oral vitamin
D 400 IU and calcium 500 mg
n 214
n 208
Placebo q 3 wk daily oral vitamin D 400 IU and
calcium 500 mg
15 monthsCore analysis1
24 months Final analysis2
0
1. Saad F, et al. J Natl Cancer Inst.
2002941458-1468. 2. Saad F, et al. J Natl
Cancer Inst. 200496879-882.
7
Zoledronic Acid Consistently Reduced All Types
of SREs at 2 Years in HRPC Patients
PERCENT OF PATIENTS
HRPC Hormone-refractory prostate cancer. Saad
F, et al. J Natl Cancer Inst. 200496879-882.
8
Incidence of Radiation to Bone for Pain
Reduced by 33
80
Placebo
4 mg Zoledronic acid
60
P 0.034
Cumulative incidence of radiotherapy (n) per
100 patients
40
20
0
3
6
9
12
15
18
21
24
Time since randomization, months
Major PP, et al. Supp. Cancer Ther
20052237-238.
9
Reduced Risk of Bone Complication
Reduced by 35
Placebo Zoledronic acid 4 mg
120
P 0.002
100
Cumulative expected Bone Complications (n) per
100 patients
80
60
40
20
0
3
6
9
12
15
21
18
24
27
Months since randomization
Major PP, et al. ASCO Prostate Cancer
symposium. 2005 Abstract 282.
10
Delayed Time to First SRE by gt 5 Months
Median, days P value ZOL 4 mg 488 .009 Placebo 32
1
Percent without event
167 days
Saad F, et al. J Natl Cancer Inst.
200496879-882.
11
When should zoledronic acid treatment be
initiated?
12
Early Treatment to Prevent SREsIs Important
Because

• Patients who experience a first SRE are 2-fold
  more likely to experience subsequent SREs
• Pathologic fractures are associated with reduced
  survival

Saad F, et al. Presented at ECCOThe European
Cancer Conference October 30-November 3, 2005
Paris, France. Abstract 1265.
13
Early Treatment May be More Effective
80
70
39 relative reduction
18 relativereduction
60
49
49
50
40
Proportion of patients with an SRE,
40
30
30
20
10
0
Patients with no pain at baseline
Patients with pain at baseline
Saad F, et al. Eur Urol Suppl. 20054145.
14
Early Treatment May be More Effective
39 relative reduction
49 relative reduction
1.6
1.45
1.2
1.07
0.88
Mean annual incidence of SREs
0.8
0.55
0.4
0
Patients with no pain at baseline
Patients with pain at baseline
SMR Skeletal morbidity rate.Saad F, et al. Eur
Urol Suppl. 20054145.
15
Is zoledronic acid effectiveafter an SRE?
16
Benefit in patients with pre treatment SREs
Riskreduction
P value
Before study entry
0.670
.027
33
No prior SRE
0.603
.028
40
Prior SRE
0.640
Overall trialpopulation
.002
36
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0
0.2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favor of zoledronic acid
In favor of placebo
Data from Saad F, et al. J Natl Cancer Inst.
200496879-882.
17
Benefit in patients with post treatment SREs

• Zoledronic acid reduced the risk of SREs after
  the first on-study SRE by 40

Riskreduction
P value
0.601
Risk of subsequent SREs
.011
40
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0
0.2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favor of zoledronic acid
In favor of placebo
Saad F, et al. Eur Urol Suppl. 2006558.
18
For how long should zoledronic acid be
administered?
19
Long term benefit
Riskreduction
P value
0.640
Overall (Months 1 - 24)1
.002
36
0.643
.004
36
Months 1 - 152
0.467
Months 16 - 241
.022
53
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favor of placebo
In favor of zoledronic acid
1. Saad F, et al. J Natl Cancer Inst.
200496879-882 2. Saad F, et al. J Natl Cancer
Inst. 2002941458-1468.
20
Incidence of Adverse Events
Zoledronic acid 4 mg Placebo n 214 n
() n 208 n () Bone pain 114 (53.3) 134
(64.4) Nausea 82 (38.3) 81
(38.9) Constipation 79 (36.9) 80
(38.5) Fatigue 75 (35.0) 56
(26.9) Anemia 66 (30.8) 42
(20.2) Myalgia 56 (26.2) 42
(20.2) Weakness 51 (23.8) 44
(21.2) Vomiting 50 (23.4) 47
(22.6) Anorexia 49 (22.9) 39
(18.8) Pyrexia 46 (21.5) 31
(14.9) Dizziness (except vertigo) 44 (20.6)
27 (13.0) Edema lower limb 44 (20.6)
32 (15.4) Diarrhea 42 (19.6) 36
(17.3) Weight decreased 41 (19.2) 28
(13.5) Dyspnea 34 (15.9) 33
(15.9) Appetite decrease 33 (15.4) 25
(12.0) Arthralgia 31 (14.5) 31
(14.9) Insomnia 25 (11.7) 39 (18.8)
Regardless of study drug relationship.
21
Serum Creatinine Increase
Patients without increase,
Hazard ratio P value Zoledronic acid 4
mg 1.137 0.752 Placebo
Time, days
After start of study drug.Saad et al. AUA 2003.
Poster 1472.
22
Osteonecrosis of the Jaw Background

• Spontaneous reports primarily in patients with
  advanced malignancies and skeletal metastases
• Etiology and pathogenesis poorly characterized
• Relative contribution of multiple factors?
• Underlying cancer and cancer treatment
• Dental pathology and procedures (eg, extractions)
• Infections
• Local ischemia
• Bisphosphonates

23
ONJ MDACC Review

• Working definition
• No evidence of healing after 12 weeks and no
  evidence of metastatic disease in the jaw or
  osteo-radionecrosis
• 33 cases of ONJ identified in 4000 cancer
  patients (16 breast, 15 myeloma, 1 prostate, 1
  thyroid)
• Overall frequency 33/4000 (0.83)
• Breast cancer 16/1340 (1.2)
• Multiple myeloma 15/550 (2.8)
• 90 could possibly have been prevented

MDACC MD Anderson Cancer Center ONJ
osteonecrosis of the jaw 1. Hoff AO, et al.
Presented at 27th ASBMR September 23-27
Nashville, Tenn. Abstract 1218.
24
Prevention and Management of ONJ

• Prior to treatment with bisphosphonates
• Dental exam with appropriate preventive dentistry
• During treatment
• Avoid invasive dental procedures if possible
• In case of ONJ
• Reassess benefit/risk of continued bisphosphonate
  therapy
• Conservative management

25
Is zoledronic acid efficacious in other
genitourinary cancers?
26
Randomized Trial of Zoledronic Acid Versus
Placebo in Patients With Solid Tumors
R A N DO M I Z E D
n 257
Zoledronic acid 4 mg q 3 weeks Daily oral
vitamin D 400 IU and calcium 500 mg
n 250
Placebo q 3 weeks Daily oral vitamin D 400 IU
and calcium 500 mg
0
9 monthsCore analysis
21 months Final analysis

• Stratification based on non-small cell lung
  cancer (NSCLC) versus other solid tumors

27
Patient Demographics by Tumor Type
Lipton A, et al. Cancer. 200398962-969.
28
Zoledronic Acid Reduces the Percentage of RCC
Patients With Any SRE
Patients with any SRE,
n 27 n 19
SMR Skeletal morbidity rate, in events per
year RCC Renal cell carcinoma SRE
Skeletal-related event.Lipton A, et al.
Presented at What Is New in Bisphosphonates?
Seventh Workshop on BisphosphonatesFrom the
Laboratory to the Patient March 24-26, 2004
Davos, Switzerland. Poster 28.
29
Zoledronic Acid Prolongs the Time to First SRE in
Renal Cell Carcinoma
Median, days P value Zol 4 mg 424 .007 Placebo
72
Patients without event,
Zol 4 mg 27 12 7 4 2 1 Placebo 19 4 1 1 0 0
After start of study drug. Lipton A, et al.
Presented at What Is New in Bisphosphonates?
Seventh Workshop on BisphosphonatesFrom the
Laboratory to the Patient March 24-26, 2004
Davos, Switzerland. Poster 28.
30
Zoledronic Acid Reduces the Risk SREs by 58 in
Patients With RCC
Riskreduction
P value
0.418
Renal cell cancer
58
.010
0.693
Overall trialpopulation
.003
31
0.8
0
0.2
0.4
0.6
1
1.2
1.8
1.4
1.6
2
Risk ratio (zoledronic acid 4 mg versus placebo)
In favor of placebo
In favor of zoledronic acid
Lipton A, et al. Presented at What Is New in
Bisphosphonates? Seventh Workshop on
BisphosphonatesFrom the Laboratory to the
Patient March 24-26, 2004 Davos, Switzerland.
Poster 28.
31
Does Zoledronic Acid affect the Course of
Disease?
32
Zoledronic Acid Increases Survival by 2.6 Months
In Patients with HRPC (P .103)
Median P value ZOL 4 mg 18.2 mo. .103 Placebo 1
5.6 mo.
ZOL 4 mg 214 162 113 56 10Placebo 208 148 94
40 5
After start of study drug.Saad F, et al.
Presented at American Urological Association
Annual Meeting April 26-May 1, 2003Chicago,
Illinois. Abstract. 1472.
33
Zoledronic Acid Increases Survival by 131 Days In
Patients with RCC (P .104)
100
80
60
Patients without event,
40
20
0
0
120
240
360
480
Days
Zol 4 mg 27 23 15 11 8 Placebo 19 14 8 5 2
After start of study drug. Lipton, et al.
Presented at What Is New in Bisphosphonates?
Seventh Workshop on BisphosphonatesFrom the
Laboratory to the Patient March 24-26, 2004
Davos, Switzerland. Poster 28.
34
Zoledronic Acid Increases Time to Bone Lesion
Progression in Patients with RCC (P .014)
Days
Zol 4 mg 27 13 7 Placebo 19 3 0
After start of study drug. Lipton, et al.
Presented at What Is New in Bisphosphonates?
Seventh Workshop on BisphosphonatesFrom the
Laboratory to the Patient March 24-26, 2004
Davos, Switzerland. Poster 28.
35
Conclusions

• Zoledronic acid delays the onset and incidence of
  SREs in patients with bone metastases from HRPC
• Effective when administered after the onset of
  SRE
• Continues to provide benefits after patients
  experience an SRE
• Zoledronic acid has also provided significant
  delays in the onset and reduces the incidence of
  SREs in patients with bone metastases from renal
  cell carcinoma
• Zoledronic acid may provide additional benefits
  to patients, possibly including effects on
  disease course