Pr Francesco GIAMMARILE

CHLS Lyon

Faculté de Lyon Sud

« Aut tace aut loquere meliora silentio »

TRATAMIENTO DEL DOLOR ÓSEO:

El futuro: tratamiento curativo

Terapéutica con radiofármacos

Palliation of Bone Metastasis:

Beyond beta emitters

Radium-223-chloride acts as a calcium mimic – hence it is

incorporated into the bony matrix and directly targets new

bone formation in and around bone metastases.

Alpha emitters must be

accumulated in tumour to be

effective

Tumour-bound alpha emitters

will not irradiate surrounding

normal tissue

• Alpha particles can kill a

cancer cell by only a few

hits, whilst beta particles

need 100-1,000 hits

targeted cancer therapy with strong cell killing capabilities

and limited side effects

First indication in hormone refractory prostate cancer

Applicable to advanced breast cancer and other cancers with

bone involvement

AlpharadinTM results published in Lancet Oncology (2008)

AlpharadinTM BC1-02 phase II trial:

Ra-223 in metastatic HR-prostate cancer

Skeletal Related Events (SREs)

Maxim

um

tre

atm

en

t

du

rati

on

• Improved overall survival from 46.4 to 65.3 weeks (41% increase)

• At 24 months, 10/33 (30%) patients were alive in Alpharadin arm versus 4/31 (13%) in

placebo arm

• Patients on Alpharadin had 53% reduced risk of death compared with placebo at each

individual time point

• In per protocol population (2 or more injections), the median survival was 71.0 weeks

(53% increase)

Pro

ba

bil

ity o

f s

urv

iva

l

HR 2.103, p= 0.017

Alpharadin™ compares favourably to Taxotere

1) Tannock et al., NEJM 351(15):1502-12, 2004. Patients were treated with 75 mg/m2 docetaxel or 12 mg/m2

mitoxantrone (comparator) 10*q3 week. All patients were given 5 mg prednisone twice daily. Mitoxantrone

has only shown effect on pain vs placebo, and no survival benefit.

2) Data on symptomatic patients: Berthold et al., ASCO Prostate Cancer Symposium, 2007

Even though a comparison between two different studies is difficult, AlpharadinTM

appears to compare favourably with docetaxel on basis of historical data

Study Patients treated Taxotere or

Alpharadin

Comparator Improvement (%)

Median survival

Taxotere study1,2 (TAX

327)

Symptomatic pats.

305 65 weeks 56 weeks 16%

Alpharadin study BC1-

02

64

(ITT population)

65 weeks 46 weeks 41 %

Alpharadin study BC1-

02

58

(PP population)

71 weeks 46 weeks 53%

Alpharadin1 Placebo1 P-value

Bone ALP

(bone formation marker)

-66% +9% <0.0001

Total ALP

(bone formation marker)

-46% +31% <0.0001

PINP

(bone formation marker)

-63% +38% <0.0001

CTX-1

(bone resorption marker)

-31% +32% 0.002

ICPT

(bone resorption marker)

+15% +43% 0.011

PSA

(prostate tumour growth)

-24% +45% 0.003

Relative change from baseline to 4 weeks after last injection

All reductions lasted >6 months <9 months after start of treatment, except PSA that

lasted > 4 months but <6 months 1 Data presented are median values, ITT population

Positive effect on biomarkers (BC1-02)

Slide 11

-100

-50

0

50

100

150

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time (weeks)

Change o

f m

edia

n v

alu

es

(%)

Placebo

Alpharadin

• Pronounced reduction of PSA by Alpharadin

• PSA values return to baseline after 6 months

• Alpharadin treatment beyond 3 months may increase the duration of the PSA reduction

• Patients with the highest PSA values had a tendency of dropping out of the study over time, especially in

the placebo group

Prostate Specific Antigen (PSA) – relative change (%) from baseline

Adverse events reported in association to the treatment period

(up to week 16).

Alpharadin (n=33) Placebo (n=31)

Number of adverse events

155 174

Number of patients with at

least one adverse event

31 30

Number of SAEs1

12 19

Number of patients with at

least one SAE

8 14

1) Serious Adverse Events

Alpharadin

(n=33)

Placebo

(n=31)

Diarrhoea 10 12

Constipation 12 2

Vomiting 8 6

Nausea 9 10

Fatigue 8 7

Bone pain 10 16

Myalgia 5 4

Tumour flare 6 7

Haemoglobin decreased 5 7

Adverse events reported by at least 15% of the patients in the BC1-02

study

Most Frequent Adverse Events by Treatment Group

Hematological toxicity

Confirms benign profile

Changes appear to be transient and fully reversible

Longer term treatment remains to be studied

Adverse event profile

Diarrhea equal in both groups

Constipation needs to be further evaluated

Serious adverse events

More frequent in the placebo group

Convenient, ready to use formulation

Safe and easy to produce, deliver and handle

The randomised, double-blind, placebo controlled Alpharadin Phase II study showed statistically significant effects, including positive survival data

Positive effect on biomarkers (PSA, and bone formation/resorption)

Improved overall survival from 46.4 to 65.3 weeks (41% increase)

Benign haematological profile

Adverse event profile Diarrhea equal in both groups

Constipation to be further evaluated

SAE: more frequent in the placebo group

*Plus best standard of care Assessments www.clinicaltrials.gov. NCT00699751.

Estimated enrollment: 900 patients with symptomatic CRPC and bone metastases

M36 M16 M24 M12 M0

R 2:1

Alpharadin* 50 kBq/kg

Saline* (placebo)

FOLLOW-UP PHASE

TREATMENT PHASE 6 injections at

4-week intervals

M28 M6 M20 M32 M8 M10

Stratification factors •Total ALP < 220 U/L vs ≥ 220 U/L •Bisphosphonate use (Yes vs No) •Prior docetaxel (Yes vs No)

Month

n = 809!

Published:

May 12th 1921

© The New York Times

Radioactivity to Cure Cancer