Radium223 for CRPC


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  • I believe investigators didn’t want the myelosuppresion from docetaxel to confound the toxicity and results of Ra223, or perhaps there was some safety concerns
  • Radium223 for CRPC

    1. 1. Radium 223 trial Dr Bala Vellay Registrar, Department of Radiation Oncology National University Cancer Institute, NUH, Singapore
    2. 2. Background >90% of patients with metastatic prostate cancer develop bone mets. Bone mets (and its resultant complications) are a major cause of morbidity and mortality amongst castrate resistant prostate cancer(CRPC) patients Current therapeutic options for bone mets include bisphosphonates, denosumab, samarium-153 or strontium-89. Their effectiveness is mainly limited to pain relief and reduced SRE. TAX327 trial has made docetaxel the mainstay in CRPC, with improvement of survival, QoL and PSA response. But, up to 40% of patients are not eligible to receive docetaxel due to poor PS, comorbities or decline treatment. Radium-223 is an alpha-emitting calcium analogue, with short range <100μm. (about 2-10 cells). Radium-223 induces dsDNA breaks Phase 2 studies: Ra-223 reduces pain and improves disease related biomarkers(ALP,PSA). Suggestion of survival benefit in CRPC patients.
    3. 3. Mechanism and handling
    4. 4. Aim and design of study • To evaluate the effect of radium-223 on survival. comparing the efficacy and safety of radium-223 versus placebo in patients with CRPC and bone metastases • Phase III ✓ • Randomized ✓ • Double-blinded ✓ • Placebo controlled ✓ • Multinational(136 study centres,19 countries!) ✓ • (study was designed, conducted, and analyzed by employees of Algeta and Bayer HealthCare Pharmaceuticals, the sponsors, in collaboration with the investigators)
    5. 5. Inclusion criteria • CRPC, ECOG 0-2, life expectancy 6 months, adequately functioning organs • ≥2 bone mets on scintigraphy, and NO visceral mets • On best standard of care ; and received docetaxel/not healthy enough/declined/not available • Symptomatic disease (regular analgesia, or EBRT within last 12 weeks) • PSA ≥5 ng/ml (progressively rising)
    6. 6. Exclusion criteria • Chemo within the last 4 weeks • Previous hemibody RT • Radioisotope therapy within last 24 weeks • Blood transfusion or EPO withink last 4 weeks • LN > 3cm • Cord compression (or impending)
    7. 7. Study design Best SOC : EBRT, glucocorticoids, antiandrogen, ketoconazole, estrogen derivatives. (abriraterone not listed) Chemo, hemibody RT, other radionuclides were not permitted during study, up until 4 weeks after last injection 06/08 to 02/11
    8. 8. Study endpoints • Primary : OS • Secondary : Efficacy, safety and QoL • Efficacy measured by : - measurements of ALP - time to first symptomatic skeletal event - time to increase in PSA
    9. 9. Stats • Power 90%, predicted HR 0.76(for death), two-sided α 0.05 = sample size 900 • Planned inter-rim analysis at 50% = 320 death • Independent data and safety monitoring committee recommended early stopping and crossover based on inter-rim results (at 314 deaths) showing survival benefit with Ra-223
    10. 10. Cont’d on next pg } balanced
    11. 11. Survival benefit seen with Ra-223 Total of 528 patients died in total. 314/614 (54%) in intervention group, 195/307(64%) in control group.
    12. 12. Across (almost) all subgroups
    13. 13. All secondary endpoints in favour of Ra-223
    14. 14. Ra-223 is safe (at least in the short term)
    15. 15. QoL better in Ra-223 arm • 25% of intervention arm experienced improvement in QoL, compared to 16% in control arm. (P=0.02)
    16. 16. Discussion • Ra-223 prolonged overall survival in selected patients with CRPC and bone only mets • Clinically relevant secondary endpoint – symptomatic skeletal event (as opposed to those detected on radiology) • Alpha particle seems like a good choice -has a short range, therefore lower myelosuppression. - Bragg’s peak - Higher RBE compared to beta/gamma
    17. 17. Discussion -2 • This study allowed background “best standard of care” • Median survival in keeping with other post- docetaxel studies.
    18. 18. Thoughts • Potentially a practice changing trial – but requires a validating study. • Extensive involvement of pharma in trial design, implementation and statistical analysis • Patient : well selected group, representative of everyday practice, 19 countries!! • Included patients who declined, not fit for chemotherapy.. • Strict definition with use of chemotherapy – why?
    19. 19. ≠ • How many of the patients in either arm received other systemic therapy after? (e.g. chemo, mitroxatone) • Were patients not allowed to receive newer agents? ( abiraterone , Sipeleucel-T, carbitaxel, enzalutamide) • Not stated…potential confounder?
    20. 20. Thoughts - 2 • Comparison to Sr-89. Beta emitter, 1.46MeV, T1/2 50days. Range 8 mm • Response rates ~75% • Grade 3,4 hematological toxicities are rare • Why was there no survival benefit seen? RRRR
    21. 21. Thoughts – 3 • Was follow up of 3 years long enough? • Is safety monitoring for 12 weeks enough? • Upcoming trials looking at Ra-223 in combination with docetaxel (since it’s reportedly easy on the marrow) • Next step, pre-docetaxel Ra223? Ra223 for asymptomatic bone mets in CRPC?
    22. 22. Questions • ?
    23. 23. Radium shouldn’t evoke the same emotions as it used to..