Joel Brothers 1042016 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 ID: 812677
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Slide1
Osteoclast Inhibitors in Malignancy
Joel Brothers
10/4/2016
Slide2Understand the indications and benefits of bisphosphonates in metastatic disease:
Breast Cancer
Prostate CancerMultiple MyelomaOther Solid Malignancies2) Understand the role of bisphosphonates/denosumab in non-metastatic disease3) Bisphosphonates versus Denosumab
Objectives
Slide3Bisphosphonates
Nitrogen Containing
Zoledronic
acid (
Zometa
,
Reclast)Pamidronate Alendronate (Fosamax)Ibandronate (Boniva)Risedronate (Actonel)Inhibit osteoclast binding
Non-Nitrogen ContainingEtidrunateTiludronateClodronateInduce osteoclast apoptosis
Uptodate.com
Slide4RANK Ligand inhibitor
Denosumab
(Xgeva, Prolia)
Dovepress.com
Slide5Potency
Reaseachgate.com
Slide6Pamidronate (IV) - $70 (generic)
Zoledronic
Acid (IV) - $70-300 (generic)Alendronate (PO) - $80 (generic)Risedronate (PO) - $200-300 (generic)Ibandronate (PO or IV) - $400 (generic) Denosumab (subQ) - $2,500 (brand: Xgeva)
Approximate Costs
1 month supply
Uptodate.com
Slide7Pamidronate:
90mg IV over 2 hours
Zoledronate4 mg IV over 15 minutesDenosumab120mg SubQ injectionAdministration
Slide8Bisphosphonates indicated for any patient with bony metastases
Skeletal related event (SRE)
FractureCord CompressionNeed for surgery or radiationHypercalcemia (+/-)Breast Cancer
Slide91993 Clodronate
PO v. placebo
N=173reduces SRE rate by 86/100 person years v. placebo. (Paterson et al, JCO)1996: Pamidronate IV monthly for 1 year v. Placebo. N=38213.1 v 7 month time to SRE. (Hortobagyi et al, NEJM)2003 Ibandronate IV 6mg v. 2mg v placebo. N=466Improvement in skeletal morbidity period rate and QOL with 6mg dose
(Body et al, Ann
Oncol
)
Bisphosphonates in Breast CancerInt. J. Cancer: 137, 753–764 (2015)
Slide102005:
Zoledronate
monthly v. placebo x1 year. N=22839% RRR in SRE with zoledronate. 20% absolute reduction. (Kohno et al, JCO) 2004: Zoledronate q3-4w v. pamidronate q3-4w for 1 year. N=1,130Prevalence 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)Bisphosphonates in Breast CancerInt. J. Cancer: 137, 753–764 (2015)
Slide11OPTIMIZE-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 12-15 months Zoledronate randomized to q4w or q12w dosing. N=425No difference in SMR (26% v 22%), pain (Amadori, Lancet, Oncol
2013)
CALGB 70604 (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)Bisphosphonates in Breast CancerDosing Interval
Slide12Zoledronate
4mg IV v.
Pamidronate 90mg IVZoledronate is probably better4 week v. 12 week dosing intervalIn 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)
Bisphosphonates in Breast Cancer
Summary
Slide13Randomized. Placebo controlled double blind study. N=1,026
Median time to SRE:
26.4 month v. not reachedHR 0.82 (0.71-0.95)Similar OS, PFS, AEsZoledronate v. Denosumab in metastatic breast cancer
(
Stopeck
et al. JCO. 2010)
Slide14Denosumab
versus
Zoledronate
(
Stopeck
et al. JCO. 2010)
Slide15Denosumab
: No dose adjustment necessary
Increase in hypocalcemia if CrCl <30Zoledronate: CrCl:>60: 4 mg50-60: 3.5 mg40-49: 3.3 mg30-39: 3 mg<30 do not usePamidronate: Do not use in severe renal impairment or AKI.May consider use with longer infusion time if renal disease due to myeloma
Renal Toxicity
Slide16Insufficient 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)Dosing IntervalDenosumab
Slide17Clodronate
Diel et al.
In patients with micrometastatic bone marrow disease 13% v. 29% DM at 3 yearsNot replicated in two other studiesSaarto et alImproved DFSPowels et alNo difference
Osteoclast Inhibitors as
Adjuvant Therapy
Slide18Clodronate
NSABP B-34
Placebo controlledNo difference in DFSSubset (>50 years) with improved: recurrence free interval, BM free interval, non BM free intervalIbandronateGAIN trialNo difference in OS or PFSOsteoclast Inhibitors asAdjuvant Therapy
Slide19Zoledronic
Acid
ABCSG-12:q6 month, premenopausal, HR positive early breast cancerDisease progression: 3.2% ARR, 36% RRRAZURE:Zoledronate (19 doses over 5 years) in Stage II and III breast cancerNo difference in DFSPre-planned subgroup showed survival benefit in post-menopausal womenOsteoclast Inhibitors asAdjuvant Therapy
Slide20Zoledronic
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 therapyZ-Fast (N=602)No difference in DFS between armsOsteoclast Inhibitors asAdjuvant Therapy
Slide21EBCTCG Meta Analysis (SABCS 2014, Lancet)
26 randomized trials. 18,766 women.
Any bisphosphonate versus placeboNo effect in pre-menopausal women. In post-menopausal women:34% reduction bone recurrence17% reduction in breast cancer deathBorderline significance in overall populationNote: other meta-analyses with negative resultsOsteoclast Inhibitors asAdjuvant Therapy
Slide22SWOG S0307: (ASCO 2015)
Clodronate
v. Ibandronate v. ZoledronateN=6,000. 2.5 years.No difference in DFS, OS.No control arm. Patients preferred oral treatment. Osteoclast Inhibitors asAdjuvant Therapy
Slide23ABCSG-18
Denosumab
60mg q6 month v. placeboN=3,420. Post-menopausal, HR receptor positive. Helps prevent fracturesPreliminary trend toward improved DFS (HR 0.82 p=0.051) (SABCS 2015 )D-CARE StudyAdjuvant denosumab in stage II-III breast cancerPrimary outpoint: BM free survivalSecondary outcomes: OS, DFS, Distant recurrence freeCompleted accrual. Results 2022.
Osteoclast Inhibitors as
Adjuvant Therapy
Slide24Conflicting data on bisphosphonates
May consider
zoledronate q6 month in post-menopausal patientsAwaiting results of randomized trials for denosumabCurrently no recommendation in NCCN guidelines for or againstOsteoclast Inhibitors asAdjuvant Therapy-Conclusions
Slide25Premenopausal
Tamoxifen decreases BMD
AI +/- GnRH agonist or oophorectomyEffects of chemotherapy (amenorrhea v. direct bone effect)Postmenopausal Increasing ageAIsChemotherapyOsteoclast Inhibitors and Bone Mineral Density
Slide26Other risk factors:
Vit
D deficiencyChronic Steroid useSmoking, drinkingLow BMISecondary (hyperparathyroid, Cushing’s, celiac, liver disease, RA, hypercalciuria)Osteoclast Inhibitors and Bone Mineral Density
Slide27ABCSG-18:
Denosumab
60mg q6 month v. placeboN=3,420. Post-menopausal, HR receptor positive. Only trial to demonstrate decrease risk of fracture (92 v 176 fractures, HR 0.5 [95% CI 0.39-0.65])Bisphosphonates: trials not powered to detect fracture differencePrimary outcome is BMDnever compared head to head with denosumabOsteoclast Inhibitors and
Bone Mineral
Density-
The Data
Slide28ABCSG-12
Premenopausal women:
Goserelin plus either AI/Tamoxifen with or without zoledronate. 11.3% decrease w/o zoledronate; 0.4% increase with zoledronateZ-FAST, ZO-FAST, E-ZO-FASTPost-menopausal women on AI +/- zoledronateEarly v. late (after fracture or T score <-2.)
5-10% difference in BMD at 1 year f/u
SABRE Trial
Postmenopausal women on
anastrozolemedium risk randomized to risedronate or placeboRisedronate weekly improved BMD at 24 monthsOsteoclast Inhibitors and Bone Mineral Density-The Data
Slide29Screen all women for risk factors for osteoporosis
Lifestyle modifications/ Ca /
Vit DDEXA for:All post-menopausal women on AIs Pre-menopausal women with treatment related amenorrhea (ASCO guidelines)FRAX score: treatment if T score < -2.0 (-1.5 if significant loss due to cancer therapies) 10-year hip fracture risk >3%10-year fracture risk >20% (NCCN guidelines)
Osteoclast Inhibitors and
Bone Mineral
Density-
Approach
Slide30Slide31Bisphosphonates:
Zoledronate
4 mg q6 month v. 5mg yearlyAlendronate, risendronate, ibandronateDenosumab 60 mg q6 monthDo not use:Raloxifene (SERM)Teriparatide (sarcoma risk with XRT)
Osteoclast Inhibitors and
Bone Mineral Density-
Treatment
Slide32Lower risk of fractures due to “-
blastic”lesions
No role of osteoclast inhibitors in hormone sensitive diseaseCALGB 90202: Zoledronate v. placebo. N=645No difference in time to first SRE (32 v. 30 months). No difference in OSDenosumab: No data in castrate sensitive diseaseProstate CancerMetastatic Disease
Slide33Castrate Resistant:
Saad
et al. 2002.Zoledronate 4mg v. 8mg v. placebo (N=643) q3wReduce SRE by 11% (38 v. 49%)Reduce time to SRE (488 v. 321 days)Improved pain scoresNo difference in PFS, PS, QOLClodronate equivocalPamidronate no benefit
Prostate Cancer
Metastatic Disease
Slide34Dosing Interval:
-
ZoledonateQ12 week dosing supported by CALBG 70604Included 674 patients with prostate cancer- DenosumabInsufficient data to support less frequent dosingProstate CancerMetastatic Disease
Slide35Castrate Resistant:
Fizazi
et al. Lancet. 2011Denosumab v. zoledronate monthlyDecreased time to SRE (20.7 v 17.1) with denosumabNo difference in OS, PFSIncrease in ONJ (non significant) and hypocalcemia (significant) with denosumabProstate Cancer
Metastatic Disease
Slide36Hoskin
et al. J Natl Cancer Inst. 2015.
470 patients with pain from bone metsSingle dose RT v. ibandronate 6mg IV x130% crossover in each direction (allowed at 4 weeks)No difference in pain response at 4 and 12 weeksMore rapid response with RTProstate CancerMetastatic Disease
Slide37Bisphosphonates
ZEUS trial
High risk prostate cancer (Gleason 8-10, PSA >20, or node positive)Zoledronate v. placebo q3 month for 4 yearsNo difference in incidence of bone mets (14.7 v 13.2%)Clodronate trial also negativeProstate CancerAdjuvant Therapy
Slide38Denosumab
Smith et al. Lancet 2012
Non-metastatic CR high risk (PSA >8 or doubling time <10 months) prostate cancerDenosumab 120mg monthly v. placeboN=1432Increased bone met free survival (29.5 v. 25.2 months)No difference in OS5% incidence ONJ7 month delay in time to bone mets with doubling time <6 months
Prostate Cancer
Adjuvant Therapy
Slide39ADT:
Increase in fracture risk (21-54% RR)
Decrease in BMD 2-3% per yearCheck DEXA scan at baseline and then at some interval thereafter with ADTCa/Vit D (1,200 mg/800 units)FRAX score20% fracture risk3% hip fracture riskProstate CancerBone Mineral Density
Nccn.org
Slide40No 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)Prostate CancerBone Mineral Density
Slide41Either denosumab
or
zoledronate in bone metastatic castrate-resistant prostate cancerDenosumab may be slightly betterZoledronate may be given q12 weeksNo role for adjuvant osteoclast inhibitorsDenosumab may delay time to bone mets in high risk patientsDEXA scan in patients on ADTBisphosphonates with high FRAX risk
Prostate Cancer
Summary
Slide42Rosen JCO 2003
Excluded breast and prostate cancer
Zoledronic Acid reduced SRE (38 v 47%; 230 v. 163 days) N=773Henry JCO 2011Denosumab noninferior to zoledronate in preventing SREs. Trend toward superiority. excluded breast and prostateN=1776 (781 NSCLC, 200 myeloma, 1,005 other)CALBG 70604:
Insufficient data (n=45) to recommend 12 week dosing interval
Other Solid
T
umors
Slide4385% of patients have lytic lesions, fracture, or osteopenia
Fracture rate 20-50%
60% Myeloma patients with lytic lesion at diagnosisMultiple myeloma
Slide442012 Cochrane Review
20 randomized trials
16 placebo controlled4 with different bisphosphonate as comparatorN=6692Results:No difference in OS, PFS, non-vertebral fracturesImprovement in:Vertebral fractures; RR 0.74 [0.62-0.89] (7 studies)SREs; RR 0.80 [0.72-0.89] (7 studies)Pain; RR 0.80 [0.6-0.95] (8 studies)Zoledronate better than placebo or etidronate in OS, but not other bisphosphonates?
Multiple Myeloma
Slide452 trials comparing
pamidronate
to zoledronateRosen et al. Cancer. 2003.N=1,648. Breast or MyelomaZoledronate 8mg v 4 mg v pamidronateSimilar proportion of patients SREZoledronate better time to SRE in breast cancer, similar in myelomaMultiple Myeloma
Slide46Zoledronate versus
clodronate
(Myeloma IX)Very complicated trial designMultiple Myeloma
Slide47Slide48Zoledronate versus
clodronate
(MRC Myeloma IX)Very complicated trial designZoledronate reduced mortality 16% and improved median survival by 5.5 monthsImproved PFS by 12% and median PFS by 2 monthsBasis for NCCN recommendation: all myeloma patients should receive bisphosphonates (Category 1) Multiple Myeloma
Slide49Denosumab
is not approved for use in multiple myeloma
Henry JCO 2011N=1,776. Denosumab versus zoledronateIn exploratory analysis of myeloma patients (n=180), denosumab appeared to increase mortality HR 2.26 (1.13-4.50; p=0.014)Hypothesized to be differences in patient characteristics (Raje
Blood Cancer Journal 2016)
Multiple Myeloma
Denosumab
Slide50NCT01345019
Ongoing phase 3 trial with 1718 patients enrolled
Sponsored by AmgenPrimary outcome: Time to SRE (non-inferiority)Secondary: Time to SRE (superiority), Time to first and subsequent SRE (superiority)Estimated completion March, 2019Multiple MyelomaDenosumab
Slide51Zoledronade v. placebo
(
Mustro. Cancer. 2008)No difference in PFS. Lower SREs in Zoledronate groupSame with pamidronate (D’Arena. Leuk Lymphoma. 2011)Zometa q 6 months improves BMD (Berenson.
Clin
Cancer Res. 2008)
Use not recommended unless high fracture risk (at osteoporosis dosing)
MGUS, Smoldering Myeloma
Slide52Most (if not all) patients with myeloma should receive a bisphosphonate
Zometa
4mg monthly or Pamidronate 90mg monthly are reasonable optionsDecrease SRE, pain. (Probably not survival)Denosumab is not approved in myelomaAwaiting results of phase III trialNo role for bisphosphonates in MGUS, smoldering myelomaMultiple Myeloma Summary
Slide53Notes:
All patients on trials received Ca/
Vit DASCO/NCCN recommend baseline dental examRisks of Treatment
Slide54Duration of therapy increases risk
1-2% risk in first year of treatment. Increases thereafter.
Higher potency osteoclast inhibitors increase riskPoor dentition (h/o tooth extraction)Dental surgeryAnti-angiogenic therapyRisks of TreatmentOsteonecrosis of the Jaw (ONJ)
Dental-tribune.com
Slide55Hypocalcemia (greater with
denosumab
)Atypical fracturesBisphosphonates onlyAKI (Zoledronate, pamidronate) Proteinuria (pamidronate -> FSGS?)Acute phase reactionFlu-like syndrome lasting several daysUsually does not recurOcular toxicity?
Risks of Treatment
Slide56Bone Metastatic Disease
Breast and Prostate:
Zoledronate q3 months v. denosumab monthlyMyeloma: Zoledronate v. pamidronate monthlyAwaiting 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 myelomaConclusions
Slide573. Bone mineral density
Patients with breast, prostate, and myeloma at risks for osteoporosis and should be screened
Treat for osteoporosis according to fracture risk4) Denosumab v. bisphosphonatesDenosumab marginally better but way more expensiveCan be used in renal insufficiencyConclusions