1. Radium 223:
when, where
Orazio Caffo

2. Ra 88 56 Ba Sr 38 20 Ca

3. α-Particles Released by Radium Ra 223 Dichloride Cause Lethal Double-Strand DNA Breaks
b-emitters
Low-LET b-radiation produces single-strand DNA breaks1
Single-strand breaks are easily repaired using the opposite strand as a template1
Single-strand breaks are less likely to induce cell death1
a-emitters
High-LET a-particles produce double-strand DNA breaks1,2
Double-strand breaks are difficult to repair1,2
Failure to repair double-strand breaks leads to apoptosis (programmed cell death)1
Misrepaired double-strand breaks create chromosomal aberrations that result in mitotic cell death1
LET, linear energy transfer.
1. Hall E, Giaccia A. Radiology for the Radiologist. 6th Ed. Philadelphia: Lippincott William & Wilkins; 2006; 2. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

4. Short Range of α-Emitters Reduces Bone Marrow Exposure1
Range of α-particle (short range: 2-10
cell diameters2)
Radium Ra 223 dichloride
Bone
1. Henriksen G, et al. Cancer Res. 2002;62: Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

5. Best standard of care (BSoC) 50 kBq/kg
Radium-223 +
Best standard of care (BSoC) 50 kBq/kg
n=921 mCRPC patients
2:1
Randomisation
Placebo + BSoC
6 injections at 4 week intervals
Health-related quality of life (HRQOL) assessed using FACT-P questionnaire.
Inclusion criteria
Histologically confirmed, progressive castration-resistant prostate cancer (CRPC) with ≥2 bone metastases (on skeletal scintigraphy) and no known visceral metastases
Patients were receiving Best standard of care (BSoC)
Patients had either received docetaxel, were not fit enough or willing to receive docetaxel, or did not have docetaxel available
Symptomatic disease, defined as regular use of analgesic medication for cancer-related bone pain or treatment with external beam radiation therapy (EBRT) for bone pain within previous 12 weeks
Prostate-specific antigen (PSA) ≥5 ng/mL with evidence of progressively rising PSA values
Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 to 2
Life expectancy of ≥6 months
Adequate hematologic, renal, and liver function
Absolute neutrophil count (ANC) ≥1.5 × 109/L
Platelet count ≥100 × 109/L
Hemoglobin ≥10.0 g/dL (100 g/L; 6.2 mmol/L)
Total bilirubin level ≤1.5 institutional upper limit of normal (ULN)
Aspartate aminotransferase and alanine aminotransferase ≤2.5 ULN
Creatinine ≤1.5 ULN
Albumin >25 g/L
Exclusion criteria
Treatment with chemotherapy within the previous 4 weeks or failure to recover from adverse events (AEs) due to chemotherapy
Prior hemibody external radiation therapy
Systemic radiation therapy with radioisotopes within the previous 24 weeks
Malignant lymphadenopathy >3 cm in short-axis diameter
History or presence of visceral metastases
Imminent or established spinal cord compression
Blood transfusion or use of erythropoietin-stimulating agent within the previous 4 wks
Key inclusion criteria
Confirmed symptomatic CRPC
≥2 bone metastases
No known visceral metastases
Node mets ≤ 3 cm
Post docetaxel or unfit/unwilling for docetaxel
Stratification factors
Total ALP: <220 U/L vs ≥220 U/L
Bisphosphonate use: Yes vs no
Prior docetaxel: Yes vs no

9. Homing and growth of prostate tumor cells in the bone could occur
through factors produced or expressed in both bone and tumor.
From Jin et al Int J Cancer 2011, 128: 2545

10. From Croucher et al Nat Rev Cancer 2016, 16, 373

11. X Ra 223 Modified from Croucher et al Nat Rev Cancer 2016, 16, 373
Other sites
colonization X
Ra 223
L.IT.MA
Modified from Croucher et al Nat Rev Cancer 2016, 16, 373

12. Modified from Croucher et al Nat Rev Cancer 2016, 16, 373
Other sites
colonization
Modified from Croucher et al Nat Rev Cancer 2016, 16, 373

13. Criteria for response evaluation
Clinical criteria
Pain (clinical benefit)
PSA
Other biomarkers
Imaging criteria
Bone scan CT
PET
Focus PRIMA sulla clinica, poi sugli altri indicatori (markers e imaging); capacità di leggere e interpretare tutti i dati, all’interno del TMD

14. Imaging assessment Follow Up * 1
Bone scan and CT recommended at the baseline *
Bone scan and CT useful after treatment*
Bone scan and CT only in presence of clinical suspect of PD* 3 2 1 2 3
6x Radio 223
Follow Up *
PET-Ch if used as baseline assessment
3 Mos
6 Mos
Bombardieri et al. Eur J Nucl Med Mol Imaging ,
Baldari et al. Critical Review in Oncology and Hematology 2017

15. 2017 landscape HSPC CRPC Local treats Biochemical relapse metastases
ADT
AntiAndrogens
HSPC
CRPC
Docetaxel
Abiraterone
Enzalutamide
Abiraterone
Docetaxel
Cabazitaxel
Enzalutamide
Abiraterone
Ra 223

16. New agents mechanism of actionAA
CYP17 AR
cAbA
mit AR
ENZ AR

19. New agents mechanism of actionAA
CYP17 AR
cAbA
mit AR
ENZ AR
-mediated
Dna damage
RA223

21. Docetaxel efficacy Study Median OS Line Previous treatment TAX327 18.9
First NA
Mezynski et al.
12.5
Second HT
Aggarwal et al.
12.4
Azad et al.
11.7
Ueda et al.
14.4
Sartor
17.5
RA223

22. Pezaro et al Eur Urol 2014

23. Functional decline and painAA
ENZ
CHEMO
RA223
CRPC with Bone Metastasis
Fatal Disease
Visceral metastasis
Functional decline and pain

24. The future landscape: combinations

25. Thank you