MÉTASTASES OSSEUSES ET RADIUM PDF Free Download

MÉTASTASES OSSEUSES ET RADIUM 223 Marie-Laure Amram Service d oncologie Hôpitaux Universitaires de Genève Forome du 21.05.2015

Radium-22:3:mécanisme d action

Mécanisme d action

Radium-223 is a calcium mimetic and an alpha emitter Radium-223 is incorporated into the bone mineral hydroxyapatite in areas of increased bone turnover 1-2 Calcium Radium-223 High LET of alpha emitters leads to a high frequency of doublestrand DNA breaks in adjacent tumour cells, resulting in a potent local antitumour effect 3 Bone Drawings are not to scale. LET = Linear energy transfer. 1. Agency for Toxic Substances and Disease Registry, US Public Health Service. Toxicological profile for radium. (December 1990). http://www.atsdr.cdc.gov/toxprofiles/tp144.pdf. Accessed March 7, 2014. 2. Henriksen G, et al. Cancer Res. 2002;62:3120-3125. 3. Xofigo Swiss Professional Information. www.swissmedicinfo.ch. 5

Alpha Emitter Versus Beta Emitter Alpha Emitter Beta Emitter Bone marrow Bone marrow Radium-223 Bone Bone β emitter Short range of alpha emitters (5-10 cell diameters or 40-100 μm Long range of beta emitters (0.2-12 mm) Sofou S. Radionuclide carriers for targeting of cancer. International journal of nanomedicine 2008;3:181.. 6

½ vie: 11.4 jours Mécanisme d action

Données pratiques 18 centres en CH A Ge: 08-2013-04.2014 (early access programm) Depuis 11.2014 Administration ambulatoire, en médecine nucléaire 6 injections lente iv de dichlorure de radium- 223 de 50KBq/kg Intervalle: 1x/4 semaines

Administration pratique: bilan paraclinique

Administration pratique: posologie

mcrpc

Approved Therapies for Advanced CRPC in Switzerland OS Benefit Docetaxel 1,2 Abiraterone5,8 Radium-2237,8 Enzalutamide6,8 Cabazitaxel 3,8 2004 2011 2012 2013 2014 Denosumab 4,8 No OS Benefit 1. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 2. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 3. de Bono JS, et al. Lancet. 2010;376:1147-1154. 4. Fizazi K, et al. Lancet. 2011;377:813-822. 5. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 6. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197. 7. Parker C, et al. N Engl J Med. 2013;369(3):213-223. 8. https://www.swissmedic.ch/arzneimittel/00156/00221/00222/00230/index.html?lang=de 12

Rationale for Targeting Bone Metastases in Advanced Prostate Cancer ~90% of patients with CRPC develop bone metastases 1,2 Bone metastases are strongly associated with a higher risk of death and higher risk of SREs 3,4 SREs are associated with increased morbidity 3,4,5, higher treatment costs 6, and lower QoL 7 CRPC=castration-resistant prostate cancer. 1. Tannock IF, et al. N Engl J Med. 2004;351(15):1502-1512. 2. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 3. Norgaard, M, et al. J Urol. 2010; 184:162-167. 4. Sathiakumar, N, et al. Pros Canc and Pros Diseases. 2011; 14: 177-183. 5. Yong C, et al. Curr Opin Oncol. 2014(3):274-83. 6. Lage MJ, et al. Am J Manag Care. 2008;14(5):317-322. 7. Weinfurt KP, et al. Ann Oncol. 2005;16:579-584. 13

Bone metastases can have serious and debilitating consequences skeletal-related events (SREs) SREs are defined as: Radiation to bone Pathological fracture Spinal cord compression Surgery to bone SREs are associated with increased morbidity, higher treatment costs, and lower QoL

Radium-223 Phase III ALSYMPCA trial Parker C, et al. N Engl J Med. 2013;369(3):213 23.

ALSYMPCA: Study Design 16 PATIENTS (N=921) Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel, unfit for docetaxel, or refused docetaxel a STRATIFICATION Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R 2:1 Radium-223 (50 kbq/kg IV) 6 injections at 4-week intervals + best standard of care b Placebo (saline) 6 injections at 4-week intervals + best standard of care b 136 centers in 19 countries Planned follow-up is 3 years 136 centers in 19 countries Planned follow-up is 3 years ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castration-resistant prostate cancer. a. Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable. b. Best standard of care defined as a routine standard of care at each center, e.g., local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (e.g., stilbestrol), estramustine, or ketoconazole. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 23.

Patient Demographics and Baseline Characteristics (ITT Population)

ALSYMPCA: inclusion Criteria 18 Histologically confirmed, progressive CRPC a with 2 bone metastases (on skeletal scintigraphy) and no known visceral metastases Patients were receiving best standard of care 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 EBRT for bone pain within previous 12 weeks PSA 5 ng/ml with evidence of progressively rising PSA values b ECOG PS score of 0 to 2 c Life expectancy of 6 months Adequate hematologic, renal, and liver function CRPC, castration-resistant prostate cancer; EBRT, external beam radiation therapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PSA, prostate-specific antigen. a. Castration-resistant disease was defined as serum testosterone 50 ng/dl ( 1.7 nmol/l) after bilateral orchiectomy or during maintenance on androgen-ablation therapy with luteinizing hormone-releasing hormone agonist or polyestradiol phosphate throughout the study. b. Two consecutive increases over previous reference value. c. Score 0 denotes a patient fully active with no functional restriction, and increasing numbers denote greater functional compromise. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 23.

ALSYMPCA: exclusion Criteria 19 Treatment with chemotherapy within the previous 4 weeks or failure to recover from AEs due to chemotherapy Prior hemibody external radiation therapy Systemic radiation therapy with radioisotopes within the previous 24 weeks Blood transfusion or erythropoietin-stimulating agents within the previous 4 weeks Malignant lymphadenopathy >3 cm in short-axis diameter History or presence of visceral metastases Imminent or established spinal cord compression AE, adverse event. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 23.

ALSYMPCA Updated Analysis: Radium-223 Significantly Improved Overall Survival The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium-223 group compared with placebo.

ALSYMPCA Updated Analysis: Radium-223 Improved OS Across All Patient Subgroups

ALSYMPCA Updated Analysis: Radium-223 Significantly Improved All Secondary Efficacy Endpoints The significant improvement in all main secondary efficacy endpoints provided support for the benefit of radium-223 (+ BSoC) over placebo (+ BSoC).

ALSYMPCA Post Hoc Sensitivity Analysis: Radium-223 Significantly Improved Time to SSE

ALSYMPCA Safety Analysis The percentage of patients with treatment-emergent AEs was consistently lower in the radium-223 group compared with the placebo group for all grade AEs (93% vs. 96%), grade 3 or 4 AEs (56% vs. 62%), serious AEs (47% vs. 60%), and study drug discontinuation due to AEs (16% vs. 21%).

ALSYMPCA Safety Analysis 25 NUMBER OF PATIENTS WITH AEs OCCURRING IN 5% OF PATIENTS IN EITHER TREATMENT GROUP AE, adverse event. a. Only 1 grade 5 hematologic AE was considered possibly related to study drug: thrombocytopenia in 1 patient in the radium-223 group.

Conclusions 26 In ALSYMPCA, radium-223 significantly prolonged overall survival in patients who had castration-resistant prostate cancer and bone metastases, with a 30% reduction in the risk of death (HR=0.70), as compared with placebo All main secondary efficacy endpoints were significant and favored treatment with radium-223, including the clinically defined end point of the time to the first symptomatic skeletal event (SSE) The overall incidence of AEs (all grade, grade 3/4, SAEs) was consistently lower in the radium-223 group than in the placebo group

Conclusions Efficacité du traitement en fin de course? Administration plus précoce dans le stade de la maladie? Avant chimiothérapie? En combinaison? Administration à d autres tumeurs (sein)?

Cas cliniques 6 patients «cadre étude» 24 doses administrées 4 patients décédés (3 sans traitement complet) 1 traitement stoppé 1 traitement complet: patient en vie 2 patients avec diminution PSA (842 à 150, 23.7 à10.2) 2 patients hors étude 1 patient après 4 doses: insuffisance rénale (diminution transitoire PSA), DCD 1 patient après 2 doses: nette diminution de la douleur osseuse

Conclusions Efficacité du traitement en fin de course? Administration plus précoce dans le stade de la maladie? Avant chimiothérapie? En combinaison? Administration à d autres tumeurs (sein)?

ALSYMPCA: Safety of cytotoxic chemotherapy following radium-223 chloride (Ra-223) therapy In order to better understand the safety of administering chemotherapy following radium- 223 therapy, a post hoc analysis was conducted to evaluate the hematologic safety profile in ALSYMPCA patients receiving chemotherapy after completing treatment with the study drug Post hoc analysis of patients (n=147/921/15.9%) receiving chemotherapy after ALSYMPCA Radium-223 group, 15% (93/614); placebo group, 18% (54/307) Most common chemotherapy: docetaxel (n=105), mitoxantrone (n=23), and cyclophosphamide (n=19) Radium-223 (n=93) Placebo (n=54) Median time to chemotherapy after study drug, days (range) 80.0 (1-667) 64.5 (2-448) Median duration of chemotherapy, days (range) 120.0 (1-809) 112.5 (1-863) Median OS from start of chemotherapy, months 15.6 14.6 Hematologic safety profiles for patients receiving chemotherapy after radium-223 were similar to those for patients receiving chemotherapy after placebo Sartor O, et al. Safety of cytotoxic chemotherapy following radium-223 chloride (Ra-223) therapy in the phase 3 ALSYMPCA study in patients with castration-resistant prostate cancer (CRPC) with bone metastases. Ann Oncol. 2012;23(suppl 9). Abstract 936P. Presented at ESMO 2012. 31

Conclusions Efficacité du traitement en fin de course? Administration plus précoce dans le stade de la maladie? Avant chimiothérapie? En combinaison? Administration à d autres tumeurs (sein)?

Combination studies with radium-223 in CRPC ERA223 (n = 800; phase III) 1 Asymptomatic or mildly symptomatic chemonaive with bone-predominant mcrpc double-blind, placebo-controlled trial of Radium-223 in combination with Abiraterone Primary outcome: symptomatic skeletal event free survival (SSE-FS) EORTC-1333 / Phase III Radium 223 mcrpc-peace III (n = 560) 2 Asymptomatic or mildly symptomatic CRPC with bone metastases Enzalutamide vs Enzalutamide + Radium-223 Primary outcome: radiologic progression free survival (rpfs) Randomized Phase IIa Ra-223 vs Ra-223 plus Enza or Abi (n = 66) 3 patients with CRPC and bone metastases Radium-223 vs Radium-223 plus Enzalutamide or Abiraterone/Prednisone Primary outcome: Bone scan response Phase II eradicate (n = 40) 4 patients with symptomatic CRPC and bone metastases Radium-223 plus Abiraterone Acetate Primary outcome: Bone pain assessments and quality of life Phase II Radium-223 plus Enzalutamide (n = 35) 5 patients with CRPC and bone metastases Radium-223 plus Enzalutamide Primary outcome: levels of bone formation markers CRPC=castration-resistant prostate cancer. q6w, = every six weeks. Ph = phase. 1. NCT02043678 on www.clinicaltrials.gov, accessed 26 September 2014. 2. NCT02194842 on www.clinicaltrials.gov, accessed 26 September 2014. 3. NCT02034552 on www.clinicaltrials.gov, acessed 26 September 2014. 4. NCT02097303 on www.clinicaltrials.gov, accessed 26 September 2014. 5. NCT02199197 on www.clinicaltrials.gov, accessed 26 September 2014 34

Combination studies with radium-223 in CRPC Phase I/IIa Radium-223 and Docetaxel combination (n=63) 1 patients with CRPC and bone metastases Ra-223 q6w and docetaxel q3w, dose escalation in ph I, established dosing in ph II Primary outcome: safety CRPC=castration-resistant prostate cancer. q6w, = every six weeks. 1. NCT01106352 on www.clinicaltrials.gov, accessed 26 September 2014. 35

Conclusions Efficacité du traitement en fin de course? Administration plus précoce dans le stade de la maladie? Avant chimiothérapie? En combinaison? Administration à d autres tumeurs (sein)?

Futures indications? Cancer du sein A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride Versus Placebo When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases Treated With Hormonal Treatment Background Therapy