Journal reading

Ra-223 treatment for metastatic prostate cancer

Ra-223 treatment for metastatic prostate cancer

Kaohsiung Veterans General Hospital
Department of Nuclear Medicine
Sin-di Lee

NCCN, Version 1.2014


  1. Sartor O, Hoskin P, Bruland OS. Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev. 2013;39(1):18-26.
  2. Pinto A, Cruz P. Radium-223 chloride: a new treatment option for metastatic castration-resistant prostate carcinoma. Drugs R D. 2012;12(4):227–233.
  3. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2013;369(3):213–223.

Bony metastases in prostate cancer

More than 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of bone metastases.

Unlike other cancers, deaths from prostate cancer are often due to bone disease and its complication.

Mechanism of bony metastasis

Seed and soil

Stephen Paget, Lancet 1889

Both tumor cells and a variety of stromal cells interact with a number of secreted paracrine factors in a “vicious cycle” that promotes the survival and proliferation of tumor cells.


In bone, cells such as the osteoblasts, osteoclasts, and hematopoietic cells (and their precursors) also represent components of the tumor micro-environment.

Variable bony metastases

It is the tumor associated upregulated osteoblastic activity that promotes new bone formation and incorporation of the ‘bone seeking radioisotopes’ (BSRs) used therapeutically.

Combination of other drugs

The uptake of BSRs is proportional to the osteoblastic nature of the bone metastatic disease.

Flare up

Another approach to increase BSR uptake is through exploiting the ‘flare’ seen after LHRH agonists or abiraterone used in prostate cancer or after hormonal therapies in breast cancer.

Timing BSR therapy administration to take advantage of this flare is an unexplored but attractive concept.

Mechanism of Denosumab and Biphosphates

Bone scans in a breast-cancer patient before/after chronic bisphosphonate therapy

Alteration of Tc-99 MDP bone scan uptake in myeloma after bortezomib treatment

Selected BSRs

Isotope Half-life Targeting agents Particle Max energy (MeV) Mean energy Penetration
Ra-223 11.4 d - Alpha 27.78 6.94 <0.1 mm
Sr-89 50.5 d - Beta 1.46 0.58 2.4 mm
Sm-153 1.9 d EDTMP Beta 0.81 0.22 0.5 mm
P-32 14.3 d - Beta 1.71 0.69 3.0 mm
Y-90 2.7 d Citrate Beta 2.27 0.93 4.0 mm
Lu-177 6.7 d EDTMP Beta 0.49 0.14 0.3 mm
I-131 8.0 d HDBP Beta 0.61 0.19 0.8 mm
Re-186 3.8 d HEDP/etidronate Beta 1.07 0.33 1.0
Re-188 0.7 d HEDP Beta 2.12 0.64 3.8
Ho-166 1.1 d DOTMP/EDTMP Beta 1.84 0.67 3.3 mm
Sn-117m 13.6 d DTPA Conversion electron 0.15 0.14 0.2

Decay chain of Ra-223

  • 4n+3 Decay chain, 4 alpha and 2 beta
  • Less penetrant in tissue.
  • Cellular repair after alpha particle
    induced damage is much less efficient.

Clinical trial

Phase I trial of Ra-223

Published in 2005, 25 p'ts with bone mets from breast or prostate cancer received single injection of Ra-223 with different dose:
46, 93, 163, 213 or 250 kBq/kg and follow 8 weeks.

Phase II trial of Ra-223

Published in 2007, only enrolled CRPC p'ts (2004-02 ~ 2005-05). Randomized to received:

Phase II trial of Ra-223 - cont.

Phase II trial of Ra-223 - cont.

Outcome Ra-223 Placebo P value
Median relative change in bone ALP level -65.6% 9.3% <0.0001
Other tumor markers
(total ALP, PINP, CTX-1, ICTP)
Median time to SREs 14 wks 11 wks 0.065
Hazard ratio: 1.75
Median relative change PSA level
(baseline and 4 wks after last injection)
-23.8% 44.9% 0.003
Median time to PSA progression 26 wks 8 wks 0.048
Median overall survival 65.3 wks 46.4 wks 0.066
Harzard ratio: 2.12
Myelotoxicity and other side effect not different

Second phase II trial

Published in 2012. Randomized, double-blind.

Aimed to investigate the dose-response relationship and pain-relieving effect in CRPC with bone metastases.

100 p'ts were randomized to received different doses of a single injection (5, 25, 50 or 100 kBq/kg).

Second phase II trial - cont.

Dose 5 25 50 100
W2 Significant difference, p = 0.035
W8, pain responders 40% 63% 56% 71%
Complete response in responders 30% 42% 44% 52%
Overall survival 50 wk. No diff.

Second phase II trial - Side effect

About 97% of patients reported at least one side effect.

Hematologic events were generally not severe, with slightly greater rates in the two highest-dose groups. Most frequent: anemia (11%) and Hb decrease (15%).

Most freq. non-hematologic AEs: nausea, vomiting, diarrhea, constipation, peripheral edema and bone pain. No difference across dose groups.

Second phase II trial - cont.

These two trials suggested efficacy of Ra-223 in p'ts with mCRPC, in both symptomatic improvement and prolongation of survival, and with a favorable safety profile.

Phase III trial - ALSYMPCA trial

Alpharadin in Symptomatic Prostate Cancer Patients study.

Double-blind, RCT, placebo-controlled study.

Primary end point: OS
Secondary end points: time to the first SRE, time to total ALP progression and normalization, total ALP response, time to PSA progression, safety and QoL.

Phase III trial - Patients

A total of 921 p'ts were randomized on a 2:1 basis to receive Ra-223 (2008-06~2011-02).

Phase III trial - Exclusion criteria

Phase III trial - Protocol

50 kBq/kg/dose, 6 injection every 4 wks.

P'ts with CRPC during maintenance treatments were required to continue the treatment throughout the study.

Analgesic medication or EBRT for symptom control.

Phase III trial - Flowchart

Phase III trial - Result

The interim results were analyzed after 314 events and in light of these results the Independent Data monitoring Committee (IDMC) recommened stopping the trial early, because there was evidence of a significant OS benifit favoring Ra-223.

Baseline clinical characteristics was balanced between the study group.

Phase III trial - Result 2

The safety population included 901 pt's (600 in Ra-223 group).

The planned interim analysis was based on data from 809 p'ts (541 in Ra-223 group).

Group Completed 6 injection Median number of injection
Ra-223 387, 63% 6
Placebo 145, 47% 5

Phase III trial - Efficacy

Phase III trial - Efficacy cont.


Phase III study - Safety

Adverse events rate was onsistently lower in the Ra-223 group than in the placebo group.

Group All AEs Grade 3 or 4 AEs Seriour AEs Withdraw study-drug
Ra-223 n=600 558, 93% 339, 56% 281, 47% 99, 16%
Placebo n=301 290, 96% 188, 62% 181, 60% 62, 21%

Phase III study - Safety - cont.

Group Ra-223 Placebo
Disease progression 11% 12%
Bone pain 10% 16%
Anemia 8% 9%
Spinal cord compression 4% 5%

Phase III trial - Quality of Life

More rate of patient in Ra-223 group had improvement of quality of life according to FACT-P score.

Increasing >=10 points on a scale of 0 to 156: 25% vs 16%, P=0.02

Mean change in FACT-P score from baseline to 16th wk: -2.7 vs -6.8, P=0.006

Phase III trial - Discussion

Phase III trial - Discussion - conts.

Phase III trial - Limitation

The treatment of prostate cancer has evolved

Further studies

New data on use of cabazitaxel, abiraterone and enzalutamide is published as well.

A phase 1-2 trial of Ra-223 combined with docetaxel in patients with CRPC and bone metastases is currently ongoing.

Thank You