Radium 223: when, where Orazio Caffo

Ra 88 56 Ba Sr 38 20 Ca

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.

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;62:3120-3125. 2. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

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

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

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

X Ra 223 Modified from Croucher et al Nat Rev Cancer 2016, 16, 373 Other sites colonization X Ra 223 L.IT.MA.03.2017.2325 Modified from Croucher et al Nat Rev Cancer 2016, 16, 373

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

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

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. 2016 , Baldari et al. Critical Review in Oncology and Hematology 2017

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

New agents mechanism of action AA CYP17 AR cAbA mit AR ENZ AR

New agents mechanism of action AA CYP17 AR cAbA mit AR ENZ AR -mediated Dna damage RA223

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

Pezaro et al Eur Urol 2014

Functional decline and pain AA ENZ CHEMO RA223 CRPC with Bone Metastasis Fatal Disease Visceral metastasis Functional decline and pain

The future landscape: combinations

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