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
Radium 223 trial
Dr Bala Vellay
Registrar, Department of Radiation Oncology
National University Cancer Institute, NUH, Singapore
>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.
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
• 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)
• CRPC, ECOG 0-2, life expectancy 6 months,
adequately functioning organs
• ≥2 bone mets on scintigraphy, and NO visceral
• On best standard of care ; and received
docetaxel/not healthy enough/declined/not
• Symptomatic disease (regular analgesia, or
EBRT within last 12 weeks)
• PSA ≥5 ng/ml (progressively rising)
• 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)
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
• Primary : OS
• Secondary : Efficacy, safety and QoL
• Efficacy measured by :
- measurements of ALP
- time to first symptomatic skeletal event
- time to increase in PSA
• 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
QoL better in Ra-223 arm
• 25% of intervention arm experienced
improvement in QoL, compared to 16% in
control arm. (P=0.02)
• 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
• This study allowed background “best standard
• Median survival in keeping with other post-
• 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
• Strict definition with use of chemotherapy –
• How many of the patients in either arm
received other systemic therapy after? (e.g.
• Were patients not allowed to receive newer
agents? ( abiraterone , Sipeleucel-T,
• Not stated…potential confounder?
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
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?