Dr Peter Harper Leaders in Oncology Care London

Dr Peter Harper Leaders in Oncology Care London
Bone and Lung Cancer Dr Peter Harper Leaders in Oncology Care London

WHAT UNITES TORINO AND LIVERPOOL?

WHAT UNITES TORINO AND LIVERPOOL?
Prof Giorgio Vittorio Scagliotti & Prof Pieter Edsge Postmus

WHAT UNITES TORINO AND MANCHESTER?

31 people died in the crash.
TORINO 4th MAY 1949 The Superga air disaster occurred on 4 May 1949 when the Fiat G.212 of Avio Linee Italiane (Italian Airlines),carrying the Entire Torino football team crashed into the retaining wall at the back of the Basilica of Superga, which stands on the hill of Turin. 31 people died in the crash.

Torino itself would not claim another title until 1976.
After refuelling at Barcelona, the plane carrying the team flew into a thunderstorm on the approach to Turin and encountered conditions of low cloud and poor visibility. They were forced to descend to be able to fly visually.. The emotional impact of the crash on Italian sports fans was profound, as it claimed the lives of the players of a team which had won five successive Serie A titles, tying the all-time record, and seriously weakened the Italian national team, which had included up to 10 Torino players. Torino itself would not claim another title until 1976.

Manchester United February 6th 1958
On that day in 1958, the darkest day in United's history, 23 people - including eight players and three members of the club's staff - suffered fatal injuries in the Munich air crash. Flying back from a European Cup tie against Red Star Belgrade, the team plane stopped in Germany to refuel. The first two attempts to take off from Munich airport were aborted; following a third attempt, the plane crashed. Twenty-one of the people on board died instantly. Aeroplane captain Kenneth Rayment died a few weeks later from the injuries he sustained while Duncan Edwards - one of the eight victims from the team - passed away 15 days after the crash. The tragedy is an indelible part of United's history, as is Sir Matt Busby overcoming his injuries to build another great team which won the European Cup 10 years later.

Bone Metastases Have Debilitating Consequences ‘Skeletal Related Events’ (SREs)
Disease Skeletal-related events Consequences Fracture Loss of autonomy Radiation to bone Significant morbidity Bone mets Spinal cord compression Bone pain Hypercalcemia Increased healthcare costs and resources Surgery to bone Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31. 8

Bone Metastases Have Debilitating Consequences
Ultimate consequence Disease Skeletal-related events Consequences Fracture Loss of autonomy Radiation to bone Significant morbidity Bone metastases Decreased survival Spinal cord compression Bone pain Hypercalcemia Increased healthcare costs and resources Surgery to bone Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31. 9

Bone Remodeling Osteoclast Osteoblasts 10

Phases of Bone “Metastasis”
B) Tumour cell proliferation and bone metastasis progression A) Tumour cell colonisation of bone Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence Tumour cell proliferation Re-circulation to other metastatic sites HSC Stimulation of bone resorption HSC niche Tumour cell Hematopoietic stem cell (HSC) Osteoblast Osteoclast Development of bone lesions

Phases of Bone “Metastasis”
B) Tumour cell proliferation and bone metastasis progression A) Tumour cell colonisation of bone Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence Tumour cell proliferation Onward Dissemination HSC Stimulation of bone resorption HSC niche Tumour cell Hematopoietic stem cell (HSC) Osteoblast Osteoclast Development of bone lesions

Molecular Mechanisms Associated With the Formation of OSTEOLYTIC Lesions
LPA Bone marrow Tumor cell SMAD COX2 Ca2+ DKK-1 Noggin IGF PTHrP, IL-6, IL-8, IL-11, PGE2, CTGF, MG-CSF TGF RANK RANKL Osteoclast Osteolytic lesion Osteoblast Bone Clézardin P. Rev Rhum. 2008;75(4):

Molecular Mechanisms Associated With the Formation of OSTEOBLASTIC Lesions
Bone Bone `marrow Tumor Cell ET-1, VEGF, BMP-6, Wnt, … BMP IGF Ca2+ ET-1 Osteoclast Osteoblast RANKL OPG PSA PTHrP PTHrP(1-23) Osteoblastic lesion LPA Clézardin P. Rev Rhum. 2008;75(4):

Clinical Priorities Across the Spectrum of Bone Disease
Prevention of Treatment Induced Bone Loss Metastasis Prevention Prevention of Skeletal Morbidity 15

Clinical Priorities Across the Spectrum of Bone Disease
Prevention of Treatment Induced Bone Loss Metastasis Prevention (ie ‘do something’) Prevention of Skeletal Morbidity (ie ‘do something’) 16

Approved bone-targeted agents in the oncology setting
Bisphosphonates14 Zoledronic acid Clodronate Pamidronate Ibandronate RANK Ligand inhibitor5 Denosumab Radiopharmaceuticals69 Radium-223† Strontium-89‡ Samarium-153 1. Zometa SmPC, Novartis; 2. Bonefos SmPC, Bayer; 3. Aredia SmPC, Novartis; 4. Bondronat SmPC, Roche; 5. XGEVA SmPC, Amgen; 6. Xofigo PI, Bayer and Algeta; 7. Metastron PI, GE Healthcare; 8. Quadramet SmPC, CIS Bio International; 9. Quadramet PI, EUSA Pharma. †Positive CHMP opinion for CRPC with symptomatic bone metastases; ‡Not approved in EU.

Bisphosphonates High affinity for bone1
Rapidly absorbed onto bone surface1 Induce apoptosis of activated osteoclasts1 Long half-life in bone (110 years)2 Excreted unchanged by the kidneys2 1. Green JR. Oncologist 2004;9(Suppl 4):3–13; 2. Lin JH. Bone 1996;18:7585.

RANK Ligand Member of the tumour necrosis factor (TNF) cytokine family1 Binds to receptor RANK1 Key factor for osteoclast differentiation and activation1 Physiological roles also observed beyond the bone211 1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523; 3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772; 5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150; 7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102; 9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998; 11. Brown JM, et al. Urology 2001;57:611–6. RANK, receptor activator of nuclear factor kappa-B.

Metastatic Bone Disease Is Common
5-year world prevalence, thousands1 Proportion developing metastases Incidence of bone metastases in advanced cancers2 Median survival, months2-3 Renal 586 60% 12 Melanoma 643 20% 6 Bladder 1,100 40% 40 15 Thyroid 475 10% 60 48 Lung 1,362 90% 6 - 7 Breast 4,406 40% Prostate 2,369 35% 1. Ferlay J et al. GLOBOCAN 2002: 2. Coleman RE. Cancer Treat Rev. 2001;27: 3. Coleman RE. Cancer. 1997;80:

Frequency of Skeletal Morbidity (SREs) in Advanced Cancer with Bone metastases
Data are from the placebo arms of 3 major trials of placebo vs. IV bisphosphonate in different tumour types Mean number of SREs per patient per year Percentage of patients developing SREs Percentage of patients Mean number of SREs/patient/year Breast1 (24 months fup) Prostate2 (24 months fup) Lung and other solid tumours3 (21 months fup) Breast1 Prostate2 Lung and other solid tumours3 1. Lipton A, et al. Cancer 2000;88:108290; 2. Saad F, et al. J Natl Cancer Inst 2004;96:87982; 3. Rosen LS, et al. Cancer 2004;100:261321. 21

ZOL in Patients With Bone Metastases From NSCLC and Other Solid Tumors
Zoledronic acid 4 mg q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg n = 266 8-mg dose reduced to 4 mg for renal safety n = 250 Placebo q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg 9 months Core analysis 21 months Final analysis Stratification based on non-small cell lung cancer (NSCLC) versus other solid tumors Rosen LS, et al. Cancer. 2004;100(12):

Rosen LS, et al. Cancer. 2004;100(12):2613-2621.
Tumour Types Enrolled: Randomized, Placebo-Controlled Trial of ZOL in Patients With Solid Tumours Tumor type n % NSCLC 244 49 Small-cell lung cancer (SCLC) 36 7 Renal cell carcinoma 46 9 Colon/rectum/intestinal 37 Cancer unknown primary 35 Bladder 26 5 Esophagus/gastroesophageal 12 2 Head and neck 10 Melanoma Thyroid 6 1 Other tumor types (n = 11) 39 8 Rosen LS, et al. Cancer. 2004;100(12):

Disease Progression and Survival in the Overall Trial Population
Median time to, [days] ZOL 4 mg (n = 257) Placebo (n = 250) Bone lesion progression 145days 109 P = .415 Overall disease progression 89days 84 P = .089 Death 203days 183 P = .929 Rosen LS, et al. Cancer. 2004;100(12):

are all bone metastases the same????

Coleman et al – J Clin Oncol 2005
Bone Resorption Rates Prior to Bisphosphonate Treatment as reflected in NTX excretion (nmol/mmol creatinine) % 40% 30% 30% NTX excretion (nmol/mmol creatinine) Coleman et al – J Clin Oncol 2005

NSCLC/OST (NTX ≥ 100 versus NTX < 100 nmol/mmol creatinine)
Elevated NTX Levels (high levels of bone turnover)Are Associated With an Increased Risk of ‘BAD’ Clinical Outcomes [from the control arm of the trial] NSCLC/OST (NTX ≥ 100 versus NTX < 100 nmol/mmol creatinine) P value 1.79 .010 SREs 1.91 Disease progression .011 2.67 <.001 Death 1 2 3 4 NTX < 100 NTX ≥ 100 Relative risk NTX= n-telopeptide

Remain Elevated 3-month NTX (E-E)
Zoledronic Acid Normalized NTX Levels in a Majority of Patients With Elevated Baseline NTX 90 Normalized 3-month NTX (E-N) 80 Remain Elevated 3-month NTX (E-E) 70 60 Patients, % 50 40 30 20 10 (n =) 70 11 38 8 NSCLC/OST NSCLC Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type l collagen; OST, other solid tumors. Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

Normalization of NTX Levels With ZOL Improved Survival
NSCLC/OST (n = 87) Risk reduction, % P value 0.39 Bone progression-free survival 61 .023 0.43 Death 57 .012 NSCLC (n = 49) 0.48 Bone progression-free survival 52 .174 0.54 Death 46 .142 0.5 1.0 1.5 2.0 Relative risk Reduced risk for E to N Reduced risk for E to E Abbreviations: NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; OST, other solid tumors; ZOL, zoledronic acid. Comparison is throughout the study for patients with elevated baseline NTX that normalized within 3 months of zoledronic acid (E-N group) versus patients whose NTX levels remained elevated at 3 months (E-E group). Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

Survival in Patients With NSCLC and Normal Baseline NTX
Normal NTX 100 Zoledronic acid (81 at risk, 68 died) Placebo (37 at risk, 26 died) 80 RR = 1.33 CI = (0.84, 2.09) P = 0.223 60 Proportion alive, % 40 20 3 6 9 12 15 18 21 Time since randomization, months Abbreviations: CI, confidence interval; NSCLC, non-small cell lung cancer; NTX = N-telopeptide of type I collagen; RR = Relative risk. Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3):

Time since randomization, months
Survival in Patients With NSCLC and High Baseline NTX (> 64 nmol/mmol Cr) Who Received ZOL or Placebo Elevated NTX (> 64 nmol/mmol Cr) 100 Zoledronic acid (102 at risk, 91 died) Placebo (42 at risk, 41 died) 80 RR = 0.65 60 CI = Proportion alive, % P = .025 40 20 3 6 9 12 15 18 21 Time since randomization, months Abbreviations: CI, confidence interval; Cr, creatinine; NSCLC, non-small cell lung cancer; NTX, N-telopeptide of type I collagen; RR, relative risk. Adapted from Hirsh V, et al. J Thorac Oncol. 2008;3(3): 31

Kaplan-Meier Estimates of Survival by 3-Month NTX Status
NSCLC and OST 100 80 E-E 60 E-N Proportion deceased, % patients 40 P = .0116 20 3 6 9 12 15 18 21 Time on study, months (starting at month 3) Abbreviations: E-E = Patients whose NTX levels remained elevated at 3 months; E-N = Patients whose NTX levels normalized at 3 months from elevated baseline levels; NSCLC = Non-small cell lung cancer; NTX = N-telopeptide of type I collagen; OST = Other solid tumors. Hirsh V. Presented at: 12th World Conference on Lung Cancer; September 2-6, 2007; Seoul, Korea. Abstract D5-07.

ZOL Significantly  Survival in NSCLC Patients With High Baseline NTX in a Multivariate Analysis
P value 0.565 ZOL vs placebo .0047 43%  risk of death Other significant variables 0.569 No narcotics use .016 0.515 . 019 Excellent/good ECOG 0.977 Lymphocytes (per % ) .011 0.2 0.4 0.6 0.8 1.0 1.2 Risk ratio Reduced risk of death for variable Increased risk of death Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; ZOL, zoledronic acid. Hirsh V, et al. J Thoracic Oncol. 2008:3(3):

Coleman et al. J Bone Oncology 2013 : 2, 70-76.
Potential Survival Benefits With Zoledronic Acid in Metastatic Bone Disease; META-ANALYSIS Coleman et al. J Bone Oncology 2013 : 2, QUESTION was; ‘Is survival improved by bisphosphonates in patients with a high rate of bone turnover?’

Coleman et al. J Bone Oncology 2013 : 2, 70-76.
Potential Survival Benefits With Zoledronic Acid in Metastatic Bone Disease; META-ANALYSIS Coleman et al. J Bone Oncology 2013 : 2, QUESTION was; ‘Is survival improved by bisphosphonates in patients with a high rate of bone turnover?’ Independent individual patient level meta-analysis of placebo controlled trials of zoledronic acid 1642 patients Prostate cancer – 643 patients Breast cancer – 227 patients Lung and other solid tumours – 772 patients Overall survival RR, 0.939; 95% CI, to 1.064,

Coleman et al. J Bone Oncology 2013:2, 70-76.
Survival Benefits With Zoledronic Acid Seen in Patients With Increased Bone Resorption (n = %) (n = %) Coleman et al. J Bone Oncology 2013:2,

RANK Ligand Member of the tumour necrosis factor (TNF) cytokine family1 Binds to receptor RANK1 Key factor for osteoclast differentiation and activation1 Physiological roles also observed beyond the bone211 1. Lacey DL, et al. Nat Rev Drug Discov 2012;11:40119; 2. Kong YY, et al. Nature 1999;397:31523; 3. Dougall WC, et al. Genes Dev 1999;13:241224; 4. Rossi SW, et al. J Exp Med 2007;204:126772; 5. Hanada R, et al. Nature 2009;462:5059; 6. Fata JE, et al. Nature 2000;103:4150; 7. Ock S, et al. Cardiovasc Res 2012;94:10514; 8. Schramek D, et al. Nature 2010;468:98102; 9. Gonzáles-Suárez E, et al. Nature 2010;468:1037; 10. Chen G, et al. Cancer 2006;107:28998; 11. Brown JM, et al. Urology 2001;57:611–6. RANK, receptor activator of nuclear factor kappa-B.

Three Identical Randomized Trials ; Zoledronic Acid vs Denosumab ; (each ‘arm’ Placebo Controlled)
Adults with breast, prostate, or other solid tumors and bone metastases, or multiple myeloma No current or previous IV bisphosphonate administration for treatment of bone metastases (N = 5723) Denosumab 120 mg SC + Placebo IV* q4w (n = 2862) Supplemental calcium and vitamin D recommended Zoledronic Acid 4 mg IV* + Placebo SC q4w (n = 2861) 1° Endpoint Time to first on-study SRE (noninferiority) 2° Endpoints Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine. Lipton A, et al. ESMO Abstract 1249P. 38 38

Primary Endpoint: Time to First On-Study SRE n=5,723pts
17% 1.0 0.8 0.6 0.4 0.2 HR 0.83 (95% CI: 0.76, 0.90) P<0.001 (Superiority) Risk Reduction Proportion without SRE KM Estimate of Median Months Denosumab 27.66 Zoledronic Acid 19.45 Month Patients at Risk: Denosumab Zoledronic Acid Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;

Risk of First On-study SRE by Solid Tumor Type
Risk Reduction, % P Value (Superiority) HR (95% CI) Integrated Analysis 0.82 ( ) 18 < .0001 Tumor Type Breast 0.82 ( ) 18 .0101 Prostate 0.82 ( ) 18 .0085 Lung and other Solid tumors 0.81 ( ) 19% .0168 0.6 1.0 1.4 2.0 HR Favors Denosumab Favors Zoledronic Acid Richardson G, et al. Clinical Oncological Society of Australia Annual Meeting Abstract 296.

Denosumab Trial Results: Effects on First and Subsequent SREs
1.6 Time to first and subsequent SREs (n = 5723) RR = 0.82 (95% CI, 0.75–0.89) P < (superiority) 1.4 18% Risk Reduction 1.2 1.0 Cumulative mean number of SREs per patient 0.8 0.6 0.4 Total SREs: Denosumab: 1360 0.2 Zoledronic acid: 1628 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study month Lipton A et al. Poster presented at ESMO 35; Milan, Italy; 8–12 October, 2010 [Abstract 1249P]. Events occurring at least 21 days apart (multiple event analysis) RR, rate ratio

QoL: FACT-G Mean Change From Baseline
1 From Baseline Mean Change in FACT-G Score -1 -2 Denosumab Zoledronic acid -3 1 3 6 9 12 15 18 Mos Pts at risk, n Denosumab 913 878 787 709 640 575 460 Zoledronic acid 890 845 768 700 640 592 467 Health-related QoL higher with denosumab than zoledronic acid throughout study Fallowfield L, et al. ASCO Abstract 1025.

Denosumab Trials: Safety Results
Patient incidence, n (%) Zoledronic acid (n = 2836) Denosumab (n = 2841) Infectious adverse events (AEs) 1218 (42.9) 1233 (43.4) Infectious serious AEs 309 (10.9) 329 (11.6) Acute phase reactions (first 3 days) 572 (20.2) 246 (8.7) Cumulative rate of ONJ 37 (1.3) 52 (1.8) Year 1 15 (0.5) 22 (0.8) Year 2 28 (1.0) 51 (1.8) Hypocalcaemia 141 (5.0) 273 (9.6) New primary malignancy 18 (0.6) 572 (20.2%) 246 (8.7%) 141 (5.0) 273 (9.6) Lipton A et al. Poster presented at ESMO 35; Milan, Italy; 8–12 October, 2010 [Abstract 1249P].

Denosumab Phase III Bone Metastasis Programme - ONJ Summary
6 Zoledronic acid (n = 2836) Denosumab (n = 2814) 4 P = 0.13* Proportion of patients (%) 1.8 1.8 2 1.3 1.0 0.8 0.5 Year 1 Year 2 Year 3* Breast Other solid tumours & MM Prostate Brown J et al. Presented at CIBD, 2010 [Abstract OC-15]. Proportions are % of all patients treated with zoledronic acid or denosumab

Phase III Denosumab SRE Prevention Trial in Solid Tumours/MM: Exploratory Endpoint Overall Survival
0.25 1.00 0.50 0.75 0.00 HR = 0.95 (95% CI, 0.83–1.08) P = 0.43 Overall survival (proportion) Denosumab Zoledronic acid 3 6 9 12 15 18 21 24 27 Study month Subjects at risk: Zoledronic acid 890 727 540 410 343 232 176 118 64 26 Denosumab 886 726 557 420 340 247 181 127 66 15 Henry DH, et al. J Clin Oncol 2011;29:1125−32.

Post-hoc Analysis in Lung Cancer Subgroup of Study 244
Scagliotti GV, et al. J Thorac Oncol 2012;7:18239. Denosumab 120 mg SC Q4W + Placebo IV* Q4W Key inclusion Adults with lung cancer and bone metastases Key exclusion Current or prior IV bisphosphonate administration 1:1 Calcium and Vitamin D Supplementation Zoledronic acid 4 mg IV* Q4W + Placebo SC Q4W Lung cancer type, n (%) Zoledronic acid (n = 400) Denosumab (n = 411) NSCLC 352 (88) 350 (85) Adenocarcinoma 211 (60) 189 (54) Squamous cell 75 (21) 88 (25) Other 66 (19) 73 (21) SCLC 48 (12) 61 (15)

Proportion of patients surviving
Post-hoc Analysis  Overall Survival: Denosumab vs Zoledronic Acid in NSCLC 1.0 KM estimate of median, months Denosumab 9.5 Zoledronic acid 8.0 0.8 0.6 Proportion of patients surviving 0.4 0.2 HR = 0.78 (95% CI, 0.65–0.94) P = 0.0 3 6 9 12 15 18 21 Study month Patients at risk: Zoledronic acid Denosumab 352 350 275 278 185 203 123 148 91 110 40 66 23 39 12 24 Scagliotti GV, et al. J Thorac Oncol 2012;7:18239.

What is the Mechanism of the Observed Survival Benefit in the Denosumab Lung Cancer Subgroup?
Mechanism currently unknown Possible explanations: Direct or indirect anticancer effect of denosumab NFkB modulation through RANK in cancer cells Impact on micro-environment? Secondary consequence of SRE reduction Spurious result

SPLENDOUR A Randomised Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC Sponsor: European Thoracic Oncology Platform (ETOP) Trial Coordinators: European Organization for Research and Treatment of Cancer (EORTC) Central European Cooperative Oncology Group (CECOG) Pharma Partner: Amgen PI: Solange Peters Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy (SPLENDOUR)

SPLENDOUR Study Design
Screening, Eligibility and Enrollment Trial Treatment RANDOMI SE 46 Cycles Chemotherapy q. 3 Weeks + BSC A Stratify: - Bone Mets - Region - ECOG PS - Histology First-line Stage IV NSCLC 46 Cycles Chemotherapy q. 3 Weeks + Denosumab 120 mg q. 3 (4) Weeks s.c. B Sample size: 1000

Objectives and Endpoints
Primary Objective Overall survival Secondary Objectives Progression free survival (PFS) (RECIST 1.1) Toxicity profile of denosumab (CTCAE v 4) Determination of biomarkers for translational research

Translational Mandatory FFPE tissue (slides or block), serum and urine samples will be collected at baseline (prior to the start of chemotherapy), on day 1 of cycle 3 and at progression Serum analyses by ELISA include: Osteopontin (OPN); bone sialoprotein (BSP); RANK Ligand by ELISA kit designed for the quantitative determination of total (free RANK Ligand and RANK Ligand complexed to osteoprotegerin [OPG]) soluble RANK Ligand in serum and OPG levels Urine samples: Will be analysed for NTX FFPE tumour samples: Will be accessed for correlative research whenever possible. Evaluations will include: IHC for RANK Ligand and RANK; NFkB pathway components, and potentially BSP and OPN levels in primary tumour may correlate with tumour aggressiveness

Radium-223 Targets Bone Metastases
Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Ca Sr Ba Ra

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT 6 injections at 4-week intervals PATIENTS STRATIFICATION Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel R A N D OM I Z E D 2:1 Radium-223 (50 kBq/kg) + Best standard of care Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care N = 921 Planned follow-up is 3 years

ALSYMPCA: Overall Survival
100 HR = 0.695; 95% CI, P = 90 80 70 % of Patients 60 50 Radium-223, n = 614 Median OS: 14.9 months 40 30 20 Placebo, n = 307 Median OS: 11.3 months 10 Month 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 7 1 Placebo 307 288 228 157 103 67 14 4 2 Parker C, et al NEJM 2013

Bone Metastases Have Debilitating Consequences
Ultimate consequence Disease Skeletal-related events Consequences Fracture Loss of autonomy Radiation to bone Significant morbidity Bone metastases Decreased survival Spinal cord compression Bone pain Hypercalcemia Increased healthcare costs and resources Surgery to bone Kinnane N. Eur J Oncol Nurs. 2007;11(suppl):S28-S31. 57

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