Radium-223 is an alpha-emitting radionuclide used to treat advanced prostate cancer that has metastasized to the bone. It localizes rapidly in areas of new bone formation due to its similarity to calcium. Phase 3 trials showed Radium-223 improved overall survival by 3.6 months and delayed time to first skeletal-related event compared to placebo. Radium-223 also reduced bone pain symptoms with fewer side effects than beta-emitting radionuclides due to its short range in tissue.

1. Radionuclides in the treatment
of advanced prostate cancer
Dr Ioana Stoian
Department of Nuclear Medicine
Cliniques Universitaires St Luc
Brussels

2. What is Ra-223?
Ra-223 (Xofigo): alpha emitting radionuclide
Supplied by Algeta ASA in Norway
227
Ac ⇒
227
Th ⇒
223
Ra

3. Physical Properties of Ra-223
T
1/2
= 11.43 days
α energy : 5.78 MeV (93.5% emitted energy)
<4% as β particles
<2% as γ radiation

4. Distribution du Ra223
Model souris
Uptake osseux
tibia
femur
corps vértebraux
Localisation osseuse:
rapide à 1h post injection
pas de redistribution significative 4 et 24h
Localisation extra osseuse:
reins/vessie
intestins
rate

5. Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

6. Distribution du Ra223
Uptake extra osseux important (25% dose injectée)
?? En relation avec l’ostéopenie native connue des
differentes souches de souris?
Autre variable?
Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

7. Distribution du Ra223 et structure
osseuse
Souches souris
naturellement ostéopeniques (CD57)
densité osseuse normale (CD1)
Importance du phenotype osseux sur la
biodistribution Ra223?
Non, voire au contraire.
Oui: volume du tissu osseux est plus grand
Non: densité osseuse est similaire entre les 2 souches

8. Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

9. Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

10. Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

11. a, b – cellules cartilagineuses
c, d – os
e – osteoblastes
f – osteoclasts (cellules géantes)
Atlas of Histology Klein and Noble Smith

12. Whole body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer
Metastasis. Diane Abou et al. JNCI J Natl Cancer Inst (2016) 108: 1-9

13. Transition to Advanced Prostate
Cancer: a Major Shift in Tumor Burden
Time
INITIAL
DIAGNOSIS
& THERAPY ADT
PSA/TumorBurden
DEATH
SREs
METASTASES
CRPC/ APC
ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer;
PSA, prostate-specific antigen; SRE, skeletal-related event.
Scher H, et al. Urology 2000;55(3):323-327.

14. The bone as a metastatic niche
SITE OF METASTASES1,2
<5%
5%-10%
~90%
Bone ± lymph node/visceral
Lymph node only
Visceral only
Bone metastasis occurs in most
prostate cancer patients during the
natural course of their disease and
typically targets the lumbar spine,
vertebrae, and pelvis3
1. de Bono J, et al. N Engl J Med. 2011;364:1995–2005.
2. Scher H, et al. N Engl J Med. 2012;367:1187–1197.
3. Goh P, et al. Curr Oncol. 2007;14:9–12.

15. High morbidity and mortality
Bone pain
Skeletal related events (SREs)
Bone marrow insufficiency
HyperCa/ Rarely hypoCa
Spinal cord compression
Use of analgesics/opioids
Decreased QoL
Survival at 5 yrs 30% vs 100% if localized disease
From prostate to bone: Key players in prostate cancer bone metastasis. MN Thobe et al. Cancers 2011 (3): 478-493

16. The bone as a metastatic niche
Migration of metastatic cells
Trabecular metaphysis bone
Permissive environment
Fenestrated capillaries (sinusoids)
Rich and slow blood supply
Adhesion proteins (VCAM-1)
In vitro observation
Metastatic lesions develop at sites of blood
supply by sinusoids.
Radium revisited. Targeting of skeletal metastases by the alpha emitter Radium223.Roy H Larsen,Oyvind Bruland.
http://www.bruland.info/PDF/195-202.pdf

17. Bone remodeling and metastatic
growth
Highly dynamic tissue. Constant turnover
Osteoblasts
mesenchymal origin
bone marrow areas
generate collagen matrix
Osteoclasts
monocytic lineage
bone resorption
release of growth factors - osteoblasts

18. The vicious circle of bone
metastatic spread
1. Osteoclastic bone resorption
release of growth factors – coopted by tumor cells
limits active immune reconnaissance (hypothesis)
2. Tumor cells secrete growth factors: bone resorption
3. Interleukines/growth factors secreted by adipocytes.

19. Osteomimicry
How to fully benefit the bone metastatic niche?
Acquire a bone like phenotype
Gene expression of osteoblast and osteoclast activity
Metastatic phenotype
Gene expression for parathyroid hormone
GFs common for other tissues: “homing” possible.

20. Targeting of osseous sites with
radionuclides

21. Targeting of osseous sites with
radionuclides
β particle emitting therapies
significant palliation of painful bone metastases
no overall survival
high risk of myelosuppression
low LET (Linear Energy Transfer)
89Sr (Metastron)
153Sm (Quadramet)
Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate
cancer with symptomatic bone metastases. Seth Blacksburg et al. Curr Treat Options in Oncol 2015 (16): 11-20

22. Targeting of osseous sites with
radionuclides
α particle emitting therapies
223Ra
high LET
DNA double strands breaks
✓not reparable
high mass short distance in tissues
particle range 100μ
minimize marrow toxicity
Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate
cancer with symptomatic bone metastases. Seth Blacksburg et al. Curr Treat Options in Oncol 2015 (16): 11-20

24. Short Range of α-Emitters Reduces Bone
Marrow Exposure
Range of β-particle:
(long range – 10 to 1000 cell diameters2)
β-emitter
Marrow
Bone
Range of α-particle:
(short range – 2 to 10 cell diameters2)
Ra 223
Bone
Marrow
1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

25. Radionuclides targeting osteoclasts - Biphosphonates
153Sm
186/188Re
Radionuclides targeting osteoblasts – Calcium analogues
223Ra (alpha emitter)
89Sr ( beta emitter)

26. Short range of alpha emitter
reduces bone marrow exposure
Long range of beta emitters
may increase bone marrow exposure
and associated toxicities
Alpha Emitter
(OS benefit + impact on pain)*
Beta Emitters
(Pain palliation only)
Marrow
Bone
Radium-223
Marrow
Bone
Strontium-89
and
Samarium-153
1. Henriksen G, et al. Cancer Res. 2002;62:3120-3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-28. 3. Nilsson S, et
al. Eur J Cancer 2012;48(5):678-686. 4. Parker C, et al. N Engl J Med. 2013;369(3):213-23.
Mechanism of Action: Alpha vs Beta
emitters

27. 223Ra
Independent
cell cycle
tumor type
surface markers
Winning combination
short half life
bone seeking
high LET
short range
Least attractive but most important feature – potent and
irreversible DNA double strand damage.
Fighting prostate cancer with Radium-223 – Not your Madame’s Isotope. NEJM 2013 (369): 276-278

28. Radium is a calcium-mimetic element
28
Ra
88
20
Ca
 Radium belongs to
the same group of
elements as Calcium
 Radium is a calcium-
mimetic element
 Radium (Ra-223) is
quickly taken up in
newly forming bone

29. Radium-223 preferentially targets areas of increased bone turnover
Radium-223
Phosphate
Calcium
• Hydroxyapatite, an inorganic mineral primarily consisting of calcium and
phosphate (Ca10(PO4)6(OH)2), is the principal inorganic component of bone.
• As a bone-seeking agent, Ra223 is incorporated in place of calcium into new
hydroxyapatite deposits within the microenvironement of blastic lesions.
• Ra223 rapidly and selectively accumulates in multiple areas of new bone
formation, in and around metastases, making it highly localized and targeted.

30. Histological section of a osteoblastic bone metastasis in a patient with
prostate cancer. Note the presence of abundant woven bone
distributed as a mesh in between cords of tumour cells.
Radium 223 as a bone-seeking
radionuclide
Bruland OS et al. Clin Cancer Res 2006;12:6250s–7s
Target: hydroxyapatite Ca10(PO4)6(OH)2

31. Phase II studies with Ra223
pain reduction
reduction of biomarkers
PSA
total/bone alkaline phosphatase
Suggested improved survival
Cancer death is due to bone disease and complications
Bone targeting therapies
palliation of pain
no benefit on survival

32. Drug indication
Xofigo® is indicated for
the treatment of adults with
castration-resistant prostate cancer (CRPC),
symptomatic bone metastases
and no known visceral metastases.
Xofigo is the first and only alpha particle-emitting radioactive therapeutic agent
that has demonstrated improvement in overall survival (OS) and delay in time to
first symptomatic skeletal related event (SRE) compared to placebo, as shown in
the pivotal Phase III ALSYMPCA trial.
Or lymph nodes < 30mm short axis.

33. Phase 3 ALSYMPCA trial design
Primary endpoint: OS
Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total
ALP normalization, time to PSA progression, safety and QoL
ALP, alkaline phosphatase; mCRPC, metastatic CRPC; QoL, quality of life.
Parker C et al. J Clin Oncol 2012;30(suppl.): abstr LBA4512 and accompanying presentation. clinicaltrials.gov NCT00699751
Placebo + best
standard of care
FOLLOW-UP PHASETREATMENT PHASE
6 injections at 4-week intervals
3616 24120 286 20 328 10
Month
Stratification factors
• Total ALP < 220 U/L vs ≥ 220 U/L
• Bisphosphonate use (Yes vs No)
• Prior docetaxel (Yes vs No)
Key inclusion criteria
• Confirmed symptomatic CRPC
• ≥ 2 bone metastases
• No known visceral metastases
• Post-docetaxel or unfit for docetaxel
Assessments
Randomization
2:1
Radium 223 +
best standard of
care
n=921
mCRPC

34. 0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Survival(%)
Phase 3 ALSYMPCA: improved overall
survival
Radium 223 Placebo
Median OS, months 14.9 11.3
HR 0.695
95% CI 0.581–0.832
p value <0.0001
Radium 223
Placebo
Month
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
Median OS Δ: 3.6 months
Patients(%)
Parker C et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512 and accompanying presentation. clinicaltrials.gov NCT00699751.

35. Bottom line223Ra reduced by 30% the risk of death.
Increase of time to first SRE.
Benefit across all subgroups.
No significant difference with BoC in myelotoxicity.
Liberal definition of best of care,
reflecting the day to day clinical practice.

37. What about SREs?
SRE
Use of radiotherapy to relieve skeletal symptoms
Symptomatic vertebral fracture/spinal compression
Tumor related orthopedic surgery
Decrease in QoL
Use of analgesics/opioids
Neurologic damage

38. Phase 3 ALSYMPCA: bone pain
50
62
0
10
20
30
40
50
60
70
80
90
Radium 223
(n=600)
Placebo
(n=301)
Post-hoc analysis
AE, adverse event
Bone pain as an AE
(all grades)
Patients(%)
Parker C et al. N Engl J Med 2013;369:213–23; Nilsson S et al. ASCO GU 2013 abstract 19
36
50
0
10
20
30
40
50
60
70
80
90
Radium 223
(n=600)
Placebo
(n=301)
Patients(%)
Opioid use for bone pain

39. 1st SRE
11.8 months 223Ra
8.4 months placebo
Risk for subsequent SRE
41% 223Ra
46% placebo
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration resistant prostate cancer and bone metastases: results of a
phase 3, double blind, randomised trial. O Sartor et al. Lancet Oncol 2014 (15): 738-746

40. Effects maintained
Across subgroups
Docetaxel use
PSA levels
Bone/Total AF
Effect not maintained when adjusted to superscan
status at bone scintigraphy.
Note:
Effect may be overestimated due to concomitant use of
biphosphonates.
Biphosphonates correlate strongly with low incidence of bone pathologic
fracture.
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration resistant prostate cancer and
bone metastases: results of a phase 3, double blind, randomised trial. O Sartor et al. Lancet Oncol 2014 (15): 738-746

41. Ra223 et Docetaxel
Patients avec et sans traitement anterieur par Docetaxel
921 patients
57% avec traitement antérieur par Docetaxel
43% pas de Docetaxel
Ra223 prolonge la survie independamment Docetaxel +/-
9% Docetaxel antérieur + Ra223 – thrombopénie
3% Ra223 seul – thrombopénie
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration resistant prostate cancer and
bone metastases: results of a phase 3, double blind, randomised trial. O Sartor et al. Lancet Oncol 2014 (15): 738-746

42. Abiraterone + Enzalutamide : inhibiteurs androgens. Retard apparition SRE.
Controle maladie vs action sur os
Cabozantinib + Ra223 : Anti VEGFR. Stabilisation maladie osseuse. PFS 29 semaines…..
Denosumab + Biphosphonates : anti osteoclasts.
Managing bone metastases and reducing skeletal related events in prostate cancer. Nature Reviews Clinical Oncology (2016)

43. • Phase 3 ALSYMPCA study in mCRPC reported no clinically meaningful differences
in the frequency of haematological adverse events between Radium 223 and
placebo
• Clinically observed bone marrow toxicity with Ra 223 has been inconsistent with
that predicted by dosimetric calculations
• New dosimetric models are needed for alpha emitters because they have a much
shorter range than the considered anatomical features
Radium 223 bone metastases dosimetry
Parker C et al. N Engl J Med 2013;369:213−23; 2. Hobbs R et al. Phys Med Biol 2012;57:3207–22
Adverse event
Radium 223 (N=600) Placebo (N=301)
All
grades
Grade 3 Grade 4 Grade 5
All
grades
Grade 3 Grade 4 Grade 5
Number of patients (%)
Haematological
Anaemia 187 (31) 65 (11) 11 (2) 0 92 (31) 37 (12) 2 (1) 1 (<1)
Thrombocytopenia 69 (12) 20 (3) 18 (3) 1 (<1) 17 (6) 5 (2) 1 (<1) 0
Neutropenia 30 (5) 9 (2) 4 (1) 0 3 (1) 2 (1) 0 0

44. Rare phenomenon
Described only in phase I of ALSYMPCA
Flare of pain usually 1 week after treatment
Can lead to decrease in performance status
1 case report
75yrs old patient with advanced prostate cancer
Androgen deprivation since 2008
Subsequent therapy with 223Ra due to bone PD
Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with
radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378

45. Of flare phenomenon and
the evolution of biomarkers
Increase of bone pain at multiples sites
Decrease of performance status lasting for 10 days
After 1st dose
Subsequent doses minimal or no pain flare
Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with
radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378

46. Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with
radium-223. A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378

47. Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with
radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378

48. Slight flare phenomenon between 1st and 2nd Ra injection 1.
Other authors suggest a steady PSA reduction is rather the exception than the rule. 2
1. EC Etchebehere et al. Eur J Nucl Med Mol Imaging 2015.
2. R Nome et al. Scandinavian Journal of Urology 2015 (49): 211-217

49. EC Etchebehere et al. Eur J Nucl Med Mol Imaging 2015.

50. Baseline and FU checkups
Before every 223Ra injection:
Hb levels
Kidney and liver function
Alkaline phosphatase levels
PSA
Clinical exam. Remind radioprotection measures.
Before 1st treatment:
check testosterone levels
exclude visceral PD
if nodal disease : < 30mm short axis
Anemia: day prior / morning of injection: blood transfusion.

51. Bottom line
Remember the pain + PSA flare phenomenon
Total/bone AF levels steadily decrease
Demonstrates response
Differentiates flare from true PD
Reassure your patient
PSA reduction is rather the exception than
the rule
QoL improves. Bone pain will decrease
Exclude true bone or visceral PD
Changes in prostate specific antigen,markers of bone metabolism and bone scans after treatment with Radium-223.
R Nome et al. Scandinavian Journal of Urology 2015 (49): 211-217

52. Bottom line
!! Small tumor deposits may not lead to osteoblastic response
No 223Ra binding
PD during 223Ra therapy
!! Missed at baseline bone scan
!! “Mixed” response at FU bone scan
Novel FACBC PET/CT
Classic NaF PET/CT
FACBC
Leucine analogue
Target:background ratio > 11C-choline PET/CT
PET investigates metabolism rather than indirect bone response to insult
Check for PD when AFs increase during 223Ra therapy !

53. Facteurs influençant la réponse au
Ra223
Facteurs de mauvais pronostique
Hb < 10mg/dL
PSA > 10ng/mL
ALP > 146 U/L
SRE (Skeletal Related Events) +
Age
Metas viscerales
ECOG et score douleur

54. 1. Sélection patients pouvant beneficier du traitement
par Ra223?
1. Moment introduction Ra223 par rapport aux autres
traitements?
1. Timing des injections Ra223?
réserve médullaire réduite
recuperation avant suivant Ra223??
4. Impact des autres traitements sur distribution Ra223?

56. 110 patients 553 injections Ra223
53% traitement complet
44% interruption
Maladie progressive et
Toxicité hématologique
Augmentation du score ECOG
Apparition SREs
OS 11.7 mois
PFS 4.7 mois
Factors affecting 223Ra therapy: clinical experience after 532 cycles from a single institution.Elba Etchebehere et al.
Eur J Nucl Med Mol Imaging (2016) 43: 8-20

57. 92 patients long FU – 35% insuffisance médullaire
Chimiothérapie concomittante
pas de risque significatif pour IM
Radiotherapie concomittante
risque significatif p = 0.009
facteur de risque independant
IM post Ra223 – elle meme facteur pronostique de survie
Survie moyenne non atteinte pour patients sans IM
vs 6.9 mois pour patients avec IM. 88% décedés.

61. Monitoring du PSA n’a pas de valeur pronostique.
> 30% diminution de la FA : marqueur prédictif de réponse.
Kritische Betrachtung der Empfehlungen zur Diagnostik und Therapie des Metastasierten Prostatakarzinomas durch ein
Deutsches Expertengremium. C Thomas et al. Der Urologe (2016).

62. Facteurs de risque pour IM

63. Factors affecting 223Ra therapy: clinical experience after 532 cycles from a single institution.
Elba Etchebehere et al. Eur J Nucl Med Mol Imaging (2016) 43: 8-20

64. Conclusions
1. Radionuclide therapy with α emitters has the
advantage of high potency and specificity owing to a
high energy deposition and short range.
2. α particles cause double-stranded DNA breaks that
are almost completely unrepairable.
3. Small number of tracks through a cell nucleus can
sterilize a cell.
4. The biological effects of α particles are 3−7 times
greater than the damage caused by β emitters.

65. Conclusions
5. Significant survival increase for pts treated with 223Ra.
30% decrease of risk of death vs placebo + BoC.
6. Significantly decreased incidence of SREs, particularly if
combined with biphosphonates.
7. Increased quality of life and decrease of analgesics use.
8. Clinically observed bone marrow toxicity with 223Radium
has been lower than predicted by dosimetric calculations.


66. Thank you!