Osteoclast Inhibitors in Malignancy - PowerPoint Presentation

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Osteoclast Inhibitors in Malignancy

Joel Brothers

10/4/2016

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Understand 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

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Bisphosphonates

Nitrogen Containing

Zoledronic

acid (

Zometa

,

Reclast)Pamidronate Alendronate (Fosamax)Ibandronate (Boniva)Risedronate (Actonel)Inhibit osteoclast binding

Non-Nitrogen ContainingEtidrunateTiludronateClodronateInduce osteoclast apoptosis

Uptodate.com

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RANK Ligand inhibitor

Denosumab

(Xgeva, Prolia)

Dovepress.com

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Potency

Reaseachgate.com

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Pamidronate (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

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Pamidronate:

90mg IV over 2 hours

Zoledronate4 mg IV over 15 minutesDenosumab120mg SubQ injectionAdministration

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Bisphosphonates indicated for any patient with bony metastases

Skeletal related event (SRE)

FractureCord CompressionNeed for surgery or radiationHypercalcemia (+/-)Breast Cancer

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1993 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)

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2005:

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)

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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 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

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Zoledronate

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

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Randomized. 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)

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Denosumab

versus

Zoledronate

(

Stopeck

et al. JCO. 2010)

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Denosumab

: 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

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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)Dosing IntervalDenosumab

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Clodronate

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

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Clodronate

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

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Zoledronic

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

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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 therapyZ-Fast (N=602)No difference in DFS between armsOsteoclast Inhibitors asAdjuvant Therapy

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EBCTCG 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

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SWOG 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

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ABCSG-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

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Conflicting 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

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Premenopausal

Tamoxifen decreases BMD

AI +/- GnRH agonist or oophorectomyEffects of chemotherapy (amenorrhea v. direct bone effect)Postmenopausal Increasing ageAIsChemotherapyOsteoclast Inhibitors and Bone Mineral Density

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Other risk factors:

Vit

D deficiencyChronic Steroid useSmoking, drinkingLow BMISecondary (hyperparathyroid, Cushing’s, celiac, liver disease, RA, hypercalciuria)Osteoclast Inhibitors and Bone Mineral Density

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ABCSG-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

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ABCSG-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

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Screen 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

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Bisphosphonates:

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

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Lower 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

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Castrate 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

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Dosing Interval:

-

ZoledonateQ12 week dosing supported by CALBG 70604Included 674 patients with prostate cancer- DenosumabInsufficient data to support less frequent dosingProstate CancerMetastatic Disease

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Castrate 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

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Hoskin

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

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Bisphosphonates

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

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Denosumab

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

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ADT:

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

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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)Prostate CancerBone Mineral Density

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Either 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

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Rosen 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

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85% of patients have lytic lesions, fracture, or osteopenia

Fracture rate 20-50%

60% Myeloma patients with lytic lesion at diagnosisMultiple myeloma

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2012 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

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2 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

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Zoledronate versus

clodronate

(Myeloma IX)Very complicated trial designMultiple Myeloma

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Zoledronate 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

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Denosumab

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

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NCT01345019

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

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Zoledronade 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

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Most (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

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Notes:

All patients on trials received Ca/

Vit DASCO/NCCN recommend baseline dental examRisks of Treatment

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Duration 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

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Hypocalcemia (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

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Bone 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

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3. 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