Bone Metastases and Mortality: Can We Be Doing More?

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1 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

2 Economic Burden of CaP to Bone

3 Bone Health Issues In Prostate Cancer Use of ADT and osteoporosis risk Epidemiology 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 aspects of radium 223

4 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 aspects of radium 223

Propor@on of Pa@ents with Fractures 1 to 5

5 of with Fractures 1 to 5 Years AKer CaP Diagnosis Frequency (%) %; P < Any Fracture ADT (n = 6650) No ADT (n = 20,035) +2.8%; P < Fracture Resulting in Hospitalization Shahinian et al. N Engl J Med. 2005;352:

6 Survival AKer Hip Fracture Survival probability Expected survival in the general population Women Men Time after hip fracture (years) Hip fractured Women Hip fractured Men Trombetti A et al. Osteoporos Int. 2002;13:

7 Prevalence of Osteoporosis Increases with ADT Morote J, et al. Urology. 2007;69:

8 Diagnosing Osteoporosis In clinical 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 Marshall et al. BMJ 1996: 312:

9 WHO Criteria for Osteoporosis by DXA T- Score Normal - 1 and above Low bone mass - 1 to Osteoporosis Established osteoporosis < < and one or more fractures Kanis JA et al. J Bone Miner Res. 1994;9:

10 WHO/FRAX Risk Assessment Accessed December 22, 2016.

11 Osteoporosis and Bone Metastasis 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: Holick MF Mayo Clin Proc. 2006;81:

12 Osteoporosis and Bone Metastasis and Treatment Calcium Supplementa9on Recent data: calcium 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):

13 Bisphosphonates Inhibits osteoclast reducing bone 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: Harris ST et al. JAMA. 1999;282: Chesnut CH et al. J Bone Min Res. 2004;19: Black DM, et al. N Eng J Med. 2007;356:

14 Common Bisphosphonate Side Effects Dysphagia Nausea, dyspepsia 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

15 Denosumab Monoclonal that binds to RANK ligand to inhibit and survival of osteoclasts therefore reducing bone 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.

16 Common Osteoporosis Agents in Men

17 Two for Denosumab 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

18 Osteoporosis Fracture Guidelines for Men Consider FDA- approved medical therapies based on the following A vertebral or hip fracture Femoral neck or spine T- score 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

19 Healthy Bone Program: ADT hip fracture reduced >70% DEXA scans for all men aged > 70 years Men aged >50 years undergo screening if risk factors are present, including ADT. DEXA repeated every 5 years. T- score from to - 2.5: low bone mineral density T- score of < for a diagnosis of osteoporosis. T- scores > are advised on smoking cessa@on, regular exercise, adequate calcium intake (1200 mg/d), and adequate vitamin D intake ( IU/d). T- scores < 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 May; 81(5):

20 Bone Health Issues In Prostate Cancer Use of ADT and osteoporosis risk Epidemiology 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

21 Skeletal- Related Events and Clinical Consequences of Bone Metastases Skeletal- Related Events Pathologic fractures* Spinal cord compression* therapy to bone* Surgery to bone* Hypercalcemia Change in therapy Other Clinical Symptoms Bone pain Analgesic usage Quality- of- life Shortened survival *Universally accepted skeletal- related events; Modified from Clinical Care in Oncology

22 Impact of PCa Bone Metastasis on Survival Norgaard J Urol 2010; 184 (1); 162

23 Site of Pca Metastasis and Survival

24 CaP And Bone Metastasis > 90% of 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 Apr 10;32(11):

25 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)

26 Crawford ED Urology (3):664 RADAR Study

27 Alk Phos and PSA: Predict risk of Bone Mets

28 Bone an9resorp9ve therapy with MI disease

29 Phase 3 Study of Zoledronic Acid Versus Denosumab: Time to First SRE Fizazi K, et al. Lancet. 2011;337:

30 Zoledronic Acid Versus Denosumab: Adverse Events Common side effects that are similar between treatment groups: anemia, bone pain, nausea, decreased 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:

31 St. Galen Advanced CaP Consensus Annals of Oncology 26: , 2015

32 St Galen Advanced CaP Consensus Annals of Oncology 26: , 2015

The Curies and their Discovery of Radium The Curies

1898, that they had come upon an additional very active

They suggested the name of radium for the new element.

33 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 Mme. Curie shared the Nobel Prize with her husband (and Henri Becquerel)

35 Radium Targets Osteoblastic Bone Metastases by Acting as a Calcium Mimetic Calcium Strontium Barium Radium McDevitt et al. Eur J Nucl Med. 1998;25:

intertwined with osteoid and cancer cells in the osteoblastic

36 Radium Is a Bone-Seeking Calcium Mimetic That Binds to Hydroxyapatite [Ca 10 (PO 4 ) 6 (OH) 2] Hydroxyapatite is intertwined with osteoid and cancer cells in the osteoblastic lesion New Bone Cancer Cells Bruland et al. Clin Cancer Res. 2006;12:6250s-6257s.

37 Alpha vs Beta radioisotope therapy 1. Robinson et al Radiographics Serafini et al J Clin Oncol Parker et al New Engl J Med 2013

38 Critical Differences in Alpha- and Beta-Particles Alpha Beta α β Relative particle mass Initial energy (MeV) per particle Range in tissue (µm) LET (KeV/µm) DNA hits to kill cells LET = linear energy transfer. Henriksen et al. J Nucl Med. 2003;44:

39 Lethality of Alpha-Particles Is due to DNA Double-Strand Breaks Beta and gamma radiation Single-strand breaks More Repairable Double-strand breaks Lethal, more difficult to repair Alpha radiation Bruland et al. Clin Cancer Res. 2006;12:6250s-5627s.

Bottom Line: Radium-223 Is Short Range But Deadly 2-10 cell diameter range of

surrounding hematopoietic tissueα-particles cause double-strand DNA breaks in nearby

localized killing of tumor cells with minimal collateral damage to normal tissue in

40 Bottom Line: Radium-223 Is Short Range But Deadly 2-10 cell diameter range of alpha-particle Radium-223 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 Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007

41 Choline PET Images Before and After Radium-223 Miyazaki et al. Nuc Med Mol Imag 49:314, 2015 Before Radium-223 After Radium-223

ALSYMPCA Phase III Study Design PATIENTS STRATIFICATION

known visceral metastases Post-docetaxel or unfit for

use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S

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

43 ALSYMPCA Phase III Study Design PATIENTS STRATIFICATION TREATMENT Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Parker et al. N Engl J Med. 2013;369:

44 ALSYMPCA Overall Survival in mcrpc HR = % CI, 0.581, P = % Radium-223 Median OS: 14.9 months Placebo Median OS: 11.3 months 0 Month Radium Placebo Parker et al. N Engl J Med. 2013;369:

45 ALSYMPCA Time to First Symptomatic Skeletal Event in mcrpc Patients without Skeletal Event (%) Placebo Radium Parker et al. N Engl J Med. 2013;369: Median time to first SRE Radium-223 (N = 614) 15.6 months Months since Randomization Placebo (N = 307) 9.8 months Hazard Ratio (95% CI) 0.66 ( ) 45

46 ALSYMPCA Adverse Events of Interest Patients with AEs n, (%) Hematologic Radium-223 n = 600 All Grades Grade 3 or 4 Placebo n = 301 Radium-223 n = 600 Placebo n = 301 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:

47 ALSYMPCA Conclusions In CRPC patients with bone metastases: Radium-223 significantly prolonged Overall Survival by 3.6 mo P value = ; HR = 0.695; 95% CI, Radium-223 significantly prolonged time to first SRE by 5.8 mo P value = ; HR = 0.610; 95% CI, Radium-223 was very well tolerated

48 Radium-223: Survival after 1-4 injections versus 5-6 injections in Early Access Program Sartor et al. ASCO 2015, #5063

49 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

50 ALP and PSA as Ra- 223 Markers PSA not reliable; may only slow increase ALP (alkaline phosphatase) shows 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): /annonc/mdw372

51 Ra- 223 for M1 DISEASE

52 Radium- 223 Label INDICATIONS AND USAGE Xofigo is an alpha emiwng agent indicated for the treatment of with resistant prostate cancer, bone metastases and no known visceral 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

53 2016 Dosing Change The of Standards and Technology (NIST) revised the standards for radium- 223 in 2015 The numerical value of the (in Bq/mL) contained in vials of radium Ra 223 and hence the dose in Bq/kg body weight increase by ~10%: Result: increase of the 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 US- 2066_Xofigo_NIST_Update_Dear_HCP_Leyer.pdf

54 Can J Urol Jun;23(3):8301-5

55 Ra- 223 Protocol (cont.) Can J Urol Jun;23(3):8301-5

56 Ra- 223 Lab parameters Can J Urol Jun;23(3):8301-5

57 Conclusions In on ADT consider monitoring DEXA; start with basic management strategies before Rx Strongly consider 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 w/other mcrpc agents appears safe support to Radium- 223 in the clinic

Elderly men with prostate cancer + ADT

Elderly men with prostate cancer + ADT Background and Rationale ADT and Osteoporosis Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis 21 18 +6.8%; P