Bone Metastases and Mortality: Can We Be Doing More?

Leonard G. Gomella, MD Chairman, Department of Urology President Society of Urologic Oncology Sidney Kimmel Cancer Center Thomas Jefferson University Hospital

Economic  Burden  of  CaP  to  Bone  

Bone  Health  Issues  In  Prostate  Cancer  

•  Use  of  ADT  and  osteoporosis  risk  – Epidemiology  – Preven@on  strategies  

•  Morbidity  and  mortality  of  bone  metastasis  and  prostate  cancer  – Epidemiology  and  physiology  of  bone  metastasis  – Basis  of  new  bone  targeted  agents  – Minimizing  risk  of  bone  metastasis  – Prac@cal  aspects  of  radium  223  

Bone  Health  Issues  In  Prostate  Cancer  

•  Use  of  ADT  and  osteoporosis  risk  – Epidemiology  – Preven9on  strategies  

•  Morbidity  and  mortality  of  bone  metastasis  and  prostate  cancer  – Epidemiology  and  physiology  of  bone  metastasis  – Basis  of  new  bone  targeted  agents  – Minimizing  risk  of  bone  metastasis  – Prac@cal  aspects  of  radium  223  

Propor@on  of  Pa@ents  with  Fractures  1  to  5  Years  AKer  CaP  Diagnosis  

Shahinian et al. N Engl J Med. 2005;352:154-164.

0

3

6

9

12

15

18

Any Fracture

Fracture Resulting in Hospitalization

Freq

uen

cy (

%)

+2.8%; P < 0.001

+6.8%; P < 0.001 ADT (n = 6650)

No ADT (n = 20,035)

12.6  

21

5.2  

19.4  

2.4  

Survival  AKer  Hip  Fracture  

6  Trombetti A et al. Osteoporos Int. 2002;13:731-737

Hip fractured Women

Hip fractured Men

Women

Men

Expected survival in the general population

2 4 6 8 10 0.00

0.25

0.50

0.75

1.00

Surv

ival

pro

babi

lity

Time after hip fracture (years) 0

Prevalence  of  Osteoporosis  Increases  with  ADT  Dura@on  

Morote J, et al. Urology. 2007;69:500-504.

Diagnosing  Osteoporosis  

•  In  clinical  prac@ce,  Bone  Mineral  Density  (BMD)  remains  the  gold  standard.    

•  BMD  is  one  of  the  best  determinants  of  bone  strength  

•  Correlates  with  fracture  risk  

•  BMD  predicts  fracture  as  reliably  as  blood  pressure  predicts  stroke  

US Dept of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General 2004. Marshall et al. BMJ 1996: 312: 1254-1258

WHO  Criteria  for  Osteoporosis  by  DXA  

9  Kanis JA et al. J Bone Miner Res. 1994;9:1137-1141

   T-­‐Score Normal      -­‐1  and  above  

Low  bone  mass      -­‐1  to  -­‐2.5  

Osteoporosis      <  -­‐2.5  

Established  osteoporosis      <  -­‐2.5    and  one  or  more  fractures

WHO/FRAX® Risk Assessment

https://www.shef.ac.uk/FRAX/tool.jsp Accessed December 22, 2016.

Osteoporosis  and  Bone  Metastasis  Preven@on  and  Treatment  

•  Vitamin  D  supplementa9on  –  20%-­‐35%  decrease  fracture  risk  with  >480  IU  Vitamin  D  – Maximum  bone  density  achieved  with  Vitamin  D  levels  >  40,  lowers  risk  of  fracture  

–  The  spine  is  not  affected  by  Vitamin  D  –  Calcium  absorp@on  in  the  gut  is  directly  dependent  of  Vitamin  D.  If  deficient,  need  3000  mg  Calcium  to  get  absorbed,  if  sufficient  (>32)  only  need  1000  mg  calcium  

•  Recommend  1000  IU  –  1200  IU  daily  –  Obtain  a  25(OH)D  (only  accurate  way  to  evaluate)  not  1,25(OH)D  which  is  normal/elevated  in  Vit.  D  deficiency.  

Bischoff-Ferrari HA et al. JAMA .2005;293:2257. Dawson-HughesB, et al. Osteoporosis Int. 2005;16:713. Heaney RP. J Am Coll Nutr. 2003;22:142-146Holick MF Mayo Clin Proc. 2006;81:353-73.

Osteoporosis  and  Bone  Metastasis  Preven@on  and  Treatment  

 Calcium  Supplementa9on  

•  Recent  data:  calcium  supplementa@on  of  >1000  mg  increased  risk  of  CVD  mortality  by  20%  in  men.  

•  Some  now  recommend:  obtain  most  of  calcium  through  diet,  supplement  if  needed  with  calcium  600  mg  daily  – Not  widely  promoted  

•  My  OTC  Choice:  Caltrate  600+D3    –  (800  IU  cholecalciferol)  

Larson S. JAMA InterMed.2013;173(8):647-648.

Bisphosphonates  •  Inhibits  osteoclast  ac@vity,  reducing  bone  resorp@on  and  turnover  

•  Increase  BMD:  spine  by  5-­‐8%;  hip  3-­‐6%  aKer  3  years.  

•  Reduced  incidence  of  vertebral  fractures  by  40-­‐70%  •  Do  not  give  if  GFR  <30  •  Need  dental  exam  before  star@ng  and  every  6  months  

Black DM, et al. J Clin Endocrinol Metab. 2000;85:4118-4124. Harris ST et al. JAMA. 1999;282:1344-52. Chesnut CH et al. J Bone Min Res. 2004;19:1241-1249. Black DM, et al. N Eng J Med. 2007;356:1809-1818.

Common  Bisphosphonate    Side  Effects  

•  Dysphagia  •  Esophagi@s,  ulcera@on  •  Nausea,  dyspepsia  •  Uvei@s  •  Osteonecrosis  jaw  •  Hypocalcemia  •  Renal  impairment  •  Musculoskeletal  pain  •  Class  Warnings:  

–  Infrequent  bone,  joint  and/or  muscle  pain  –  Osteonecrosis  of  the  jaw  –  Atypical  fractures  of  femoral  shaV.  

14  

Denosumab  •  Monoclonal  an@body  that  binds  to  RANK  ligand  to  inhibit  forma@on,  func@on,  and  survival  of  osteoclasts  therefore  reducing  bone  resorp@on  

•  Increases  bone  density  by  6.7%  at  the  spine  aKer  2  years  

•  Decreased  incidence  of  vertebral  fractures  by  68%,  hip  by  40%  

 Cummings SR, et al. N Eng J Med. 2009;361: 751. Smith, MR et al. N Eng J Med 2009; 361:745.

Common  Osteoporosis  Agents  in  Men  

Two  Forms/Indica@ons  for  Denosumab  

• Prolia®:  Men  on  ADT  or  osteoporosis  • 60  mg  SC  Q  6  mo  

Denosumab  

• Xgeva®  :  Men  w/mets  ,  not  men  w/  osteoporosis  

• 120  mg  SC  Q  mo  Denosumab  

Na@onal  Osteoporosis  Founda@on  Fracture  Preven@on  Guidelines  for  Men  

•  Consider  FDA-­‐approved  medical  therapies  based    on  the  following  –  A  vertebral  or  hip  fracture  –  Femoral  neck  or  spine  T-­‐score  ≤  -­‐2.5  –  FRAX  10-­‐yr  probability  of  a  hip  fracture  ≥  3%  or  10-­‐yr  probability  of  any  major  fracture  ≥  20%  

National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2010.

Healthy  Bone  Program:  ADT  hip  fracture  reduced  >70%  

•  DEXA  scans  for  all  men  aged  >  70  years    •  Men  aged  >50  years  undergo  screening  if  addi@onal  risk  factors  are  present,  including  ADT.    

•  DEXA  repeated  every  5  years.    –  T-­‐score  from  -­‐2.0  to  -­‐2.5:  low  bone  mineral  density    –  T-­‐score  of  <  -­‐  2.5  for  a  diagnosis  of  osteoporosis.  –   T-­‐scores  >  -­‐  2.5  are  advised  on  smoking  cessa@on,  regular  exercise,  adequate  calcium  intake  (1200  mg/d),  and  adequate  vitamin  D  intake  (400-­‐800  IU/d).    

–  T-­‐scores  <  -­‐2.5  are  treated  with  pharmacologic  interven@on;  

•  the  first-­‐line  treatment  is  a  bisphosphonate,  and  the  pa@ent  is  followed  up  by  an  endocrinologist.  

 Zhumkhawala  AA,    Urology.  2013  May;  81(5):1010-­‐7.  

Bone  Health  Issues  In  Prostate  Cancer  

•  Use  of  ADT  and  osteoporosis  risk  – Epidemiology  – Preven@on  strategies  

•  Morbidity  and  mortality  of  bone  metastasis  and  prostate  cancer  – Epidemiology  and  physiology  of  bone  metastasis  – Basis  of  new  bone  targeted  agents  – Minimizing  risk  of  bone  metastasis  – Prac9cal  aspects  of  radium  223  

Skeletal-­‐Related  Events  and  Clinical  Consequences  of  Bone  Metastases  

Skeletal-­‐Related  Events  •  Pathologic  fractures*  •  Spinal  cord  compression*  

•  Radia@on  therapy  to  bone*  

•  Surgery  to  bone*  •  Hypercalcemia  •  Change  in  an@neoplas@c  therapy  

 

Other  Clinical  Symptoms  •  Bone  pain    •  Analgesic  usage  •  Quality-­‐of-­‐life  deteriora@on  

•  Shortened  survival  

*Universally  accepted  skeletal-­‐related  events;  Modified  from  Clinical  Care  Op@ons  in  Oncology  clinicalop@ons.com  

Impact  of  PCa  Bone  Metastasis  on  Survival  

Norgaard  J  Urol  2010;  184  (1);  162  

Site  of  Pca  Metastasis  and  Survival  

CaP  And  Bone  Metastasis  •  >  90%  of  pa@ents  with  mCRPC  have  bone  metastases  and  experience  skeletal-­‐related  events  (SRE)    

•  SREs  include  spinal  cord  compression,  pathological  fracture,  and  need  for  surgery  or  radiotherapy    

•  Bone  metastases  are  a  major  cause  of  death,  disability,  decreased  quality  of  life,  and  increased  treatment  cost    

•  The  an@-­‐resorp@ve,  bone-­‐targeted  therapies  (zoledronic  acid  and  denosumab)    –  do  not  improve  survival    –  Do  not  delay  metastasis  –  In  some  studies  may  delay  or  prevent  SREs  and  others  have  not  shown  an  advantage  

J  Clin  Oncol.  2014  Apr  10;32(11):1143-­‐50  

CaP  And  Bone  Metastasis  

•  About  50%  of  men  with  CRPC  will  develop  metastasis  within  2  years  of  CRPC  diagnosis  

•  Median  survival  with  mCRPC  varies  from  9  to  30  months  on  average  

•  More  than  30%  of  men  with  CRPC  thought  to  be  M0  (non  metasta@c)  actually  harbor  mets  and  are  actually  M1  – Based  on  ENTHUSE  (endothelin  trial)  

RADAR  Study  

Crawford  ED  Urology  2014  83(3):664  

Alk  Phos  and  PSA:  Predict  risk  of  Bone  Mets  

Bone  an9resorp9ve  therapy  with  MI  disease  

Fizazi K, et al. Lancet. 2011;337:813-822.

Phase  3  Study  of  Zoledronic  Acid  Versus  Denosumab:  Time  to  First  SRE  

•  Common  side  effects  that  are  similar  between  treatment  groups:  anemia,  bone  pain,  nausea,  decreased  appe@te,  cons@pa@on  

•  More  hypocalcemia  with  denosumab  (13%  vs  6%)  –  Calcium  and  Vitamin  D  will  decrease  likelihood    –  No  fatal  episodes  

•  Osteonecrosis  of  jaw  (ONJ)  incidence  low  –  2%  denosumab  vs  1%  zoledronic  acid,  P=0.09  

•  Acute  phase  reac@ons  –  8%  denosumab  vs  18%  zoledronic  acid  

Fizazi K, et al. Lancet. 2011;337:813-822.

Zoledronic  Acid  Versus  Denosumab:  Adverse  Events  

St.  Galen  Advanced  CaP  Consensus  

Annals  of  Oncology  26:  1589–1604,  2015  

St  Galen  Advanced  CaP  Consensus  

Annals  of  Oncology  26:  1589–1604,  2015  

The Curies and their Discovery of Radium

The Curies informed the l'Académie des Sciences, on December 26, 1898, that they had come upon an additional very active substance that

behaved chemically almost like pure barium. They suggested the name of radium for the new element.

1903 Mme. Curie shared the Nobel Prize with her husband

(and Henri Becquerel)

Radium Targets Osteoblastic Bone Metastases by Acting as a Calcium Mimetic

McDevitt et al. Eur J Nucl Med. 1998;25:1341-1351.

Calcium Strontium

Radium Barium

Radium Is a Bone-Seeking Calcium Mimetic That Binds to Hydroxyapatite [Ca10(PO4)6(OH)2]

Bruland et al. Clin Cancer Res. 2006;12:6250s-6257s.

Hydroxyapatite is intertwined with osteoid and cancer cells in the osteoblastic lesion

Cancer Cells

New Bone

Alpha  vs  Beta  radioisotope  therapy  

1.  Robinson  et  al  Radiographics  1989  2.  Serafini  et  al  J  Clin  Oncol  1998  3.  Parker  et  al  New  Engl  J  Med  2013  

Critical Differences in Alpha- and Beta-Particles

α β Relative particle mass 7300 1 Initial energy (MeV) per particle 3-8 0.01-2.5 Range in tissue (µm) 40-100 50-5000 LET (KeV/µm) 60-230 0.015-0.4 DNA hits to kill cells 1-10 100-1000

LET = linear energy transfer. Henriksen et al. J Nucl Med. 2003;44:252-259.

Alpha Beta

Lethality of Alpha-Particles Is due to DNA Double-Strand Breaks

More Repairable

Bruland et al. Clin Cancer Res. 2006;12:6250s-5627s.

Single-strand breaks

Double-strand breaks

Lethal, more difficult to repair

Alpha radiation

Beta and gamma radiation

Bottom Line: Radium-223 Is Short Range But Deadly

•  Highly localized cell killing with minimal damage to surrounding hematopoietic tissueα-particles cause double-strand DNA breaks in nearby tumour cells

•  Limited penetration of α emitters (~ 2-10 cell diameters) results in highly localized killing of tumor cells with minimal collateral damage to normal tissue in surrounding area

2-10 cell diameter range of alpha-particle

Radium-223

Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007

Choline PET Images Before and After Radium-223

Miyazaki et al. Nuc Med Mol Imag 49:314, 2015

Before Radium-223 After Radium-223

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

R A N D OM I S E D

2:1

N = 922

PATIENTS

• Confirmed symptomatic CRPC

• ≥ 2 bone metastases

• No known visceral metastases

• Post-docetaxel or unfit for docetaxel

ALSYMPCA Phase III Study Design

•  Total ALP: < 220 U/L vs ≥ 220 U/L •  Bisphosphonate use: Yes vs No •  Prior docetaxel: Yes vs No

STRATIFICATION

Parker et al. N Engl J Med. 2013;369:213-223. 43

ALSYMPCA Overall Survival in mCRPC

Radium-223 Median OS: 14.9 months

Placebo Median OS: 11.3 months

HR = 0.70 95% CI, 0.581, 0.832 P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

%

0

10

20

30

40

50

60

70

80

90

100

Parker et al. N Engl J Med. 2013;369:213-223. 44

ALSYMPCA Time to First Symptomatic Skeletal Event in mCRPC

0

10

20

30

40

50

60

70

80

90

100

Pat

ient

s w

ithou

t Ske

leta

l Eve

nt (%

)

Months since Randomization 0 3 6 9 12 15 18 21 24 27 30

Radium-223

Placebo

Radium-223 (N = 614)

Placebo (N = 307)

Hazard Ratio (95% CI)

Median time to first SRE

15.6 months

9.8 months

0.66 ( 0.52-0.83)

Parker et al. N Engl J Med. 2013;369:213-223. 45

ALSYMPCA Adverse Events of Interest

All Grades Grade 3 or 4 Patients with AEs n, (%)

Radium-223 n = 600

Placebo n = 301

Radium-223 n = 600

Placebo n = 301

Hematologic

Anemia 187 (31) 92 (31) 77 (13) 39 (13)

Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)

Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2)

Non-hematologic

Bone pain 300 (50) 187 (62) 125 (21) 77 (26)

Diarrhea 151 (25) 45 (15) 9 (2) 5 (2)

Nausea 213 (36) 104 (35) 10 (2) 5 (2)

Vomiting 111 (19) 41 (14) 10 (2) 7 (2)

Constipation 108 (18) 64 (21) 6 (1) 4 (1)

Parker et al. N Engl J Med. 2013;369:213-223. 46

ALSYMPCA Conclusions

In CRPC patients with bone metastases:

•  Radium-223 significantly prolonged Overall Survival by 3.6 mo –  P value = 0.00185; HR = 0.695; 95% CI, 0.552-0.875

•  Radium-223 significantly prolonged time to first SRE by 5.8 mo –  P value = 0.00046; HR = 0.610; 95% CI, 0.461-0.807

•  Radium-223 was very well tolerated

Radium-223: Survival after 1-4 injections versus 5-6 injections in

Early Access Program

Sartor et al. ASCO 2015, #5063

Radium-223 and Bisphosphonates: No combined effect on survival in ALSYMPCA

but positive effect on Symptomatic SRE’s

Sartor et al. Lancet Oncology 15:738, 2014

ALP  and  PSA  as  Ra-­‐223  Markers  

•  PSA  not  reliable;  may  only  slow  increase  •  ALP  (alkaline  phosphatase)  shows  u@lity  •  Phase  3b  study  696  men  (ESMO  2016)  

– 298  men  43%  no  decline  – 398  men  57%  ALP  decline  

•  70%  decreased  death    •  53%  decreased  SRE  

Annals  of  Oncology  (2016)  27  (6):  243-­‐265.  10.1093/annonc/mdw372  

Ra-­‐223  for  M1  DISEASE  

Radium-­‐223  Label  INDICATIONS  AND  USAGE  

•  Xofigo  is  an  alpha  par@cle-­‐emiwng  radioac@ve  therapeu@c  agent  indicated  for  the  treatment  of  pa@ents  with  castra@on-­‐resistant  prostate  cancer,  symptoma@c  bone  metastases  and  no  known  visceral  metasta@c  disease.    

DOSAGE  AND  ADMINISTRATION  •  The  dose  regimen  of  Xofigo  is  55  kBq  (1.49  microcurie)/kg  BW,  

given  at  4  week  intervals  for  6  injec@ons.    DOSAGE  FORMS  AND  STRENGTHS  

•  Single-­‐use  vial  at  a  concentra@on  of  1,100  kBq/mL  (30  microcurie/mL)  at  the  reference  date  with  a  total  radioac@vity  of  6,600  kBq/vial  (178  microcurie/vial)  at  the  reference  date  

CONTRAINDICATIONS  •  Pregnancy    

2016  Dosing  Change  

•  The  Na@onal  Ins@tute  of  Standards  and  Technology  (NIST)  revised  the  standards  for  radium-­‐223  in  2015  

•  The  numerical  value  of  the  radioac@vity  (in  Bq/mL)  contained  in  vials  of  radium  Ra  223  and  hence  the  pa@ent  dose  in  Bq/kg  body  weight  increase  by  ~10%:  

•  Result:  increase  of  the  radioac@vity  from  1000  kBq/mL  to  1100  kBq/mL  at  the  reference  date.    

•  Increase  in  pa9ent  dose,  from  50  kBq/kg  body  weight  to  55  kBq/kg  body  weight  (increase  from  1.35  uCi  (microcurie)/kg  BW  to  1.49  uCi  /kg  body  weight)  

hyps://hcp.xofigo-­‐us.com/downloads/PP-­‐600-­‐US-­‐2066_Xofigo_NIST_Update_Dear_HCP_Leyer.pdf  

Can  J  Urol.  2016  Jun;23(3):8301-­‐5  

Ra-­‐223  Protocol  (cont.)  

Can  J  Urol.  2016  Jun;23(3):8301-­‐5  

Ra-­‐223  Lab  parameters  

Can  J  Urol.  2016  Jun;23(3):8301-­‐5  

Conclusions  •  In  pa@ents  on  ADT  consider  monitoring  DEXA;  start  with  basic  management  strategies  before  Rx  

•  Strongly  consider  an@resorp@ve  therapy  with  M1  – Many  consider  it  standard  with  mCRPC  

•  Radium  223  useful  in  mCRPC  with  symptoms  and  significant  bone  mets  –  Sequencing  of  mCRPC  agents  under  study  –  Combina@ons  w/other  mCRPC  agents  appears  safe  

•  Ins@tu@onal  programma@c  support  to  u@lize  Radium-­‐223  in  the  clinic