Post on 20-Feb-2017
Radionuclides in the treatment of advanced prostate cancer
Prof François Jamar Dr Ioana Stoian
Department of Nuclear Medicine Cliniques Universitaires St Luc
Brussels
Transition to Advanced Prostate Cancer: a Major Shift in Tumor Burden
Time
INITIAL DIAGNOSIS & THERAPY ADT
PSA
/Tu
mo
r B
urd
en
DEATH
SREs
METASTASES
CRPC/ APC
ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; SRE, skeletal-related event. Scher H, et al. Urology 2000;55(3):323-327.
The bone as a superior metastatic niche
SITE OF METASTASES1,2
<5%
5%-10%
~90%
Bone ± lymph node/visceral
Lymph node only
Visceral only
Bone metastasis occurs in most prostate cancer patients during the natural course of their disease and typically targets the lumbar spine,
vertebrae, and pelvis3
1. de Bono J, et al. N Engl J Med. 2011;364:1995–2005. 2. Scher H, et al. N Engl J Med. 2012;367:1187–1197. 3. Goh P, et al. Curr Oncol. 2007;14:9–12.
High morbidity and mortality
Bone pain
Skeletal related events (SREs)
Bone marrow insufficiency
HyperCa/ Rarely hypoCa
Spinal cord compression
Use of analgesics/opioids
Decreased QoL
Survival at 5 yrs 30% vs 100% if localized disease
From prostate to bone: Key players in prostate cancer bone metastasis. MN Thobe et al. Cancers 2011 (3): 478-493
The bone as a superior metastatic niche
Migration of metastatic cells
Trabecular metaphysis bone
Permissive environment
Fenestrated capillaries (sinusoids)
Rich and slow blood supply
Adhesion proteins (VCAM-1)
In vitro observation
Metastatic lesions develop at sites of blood supply by sinusoids.
Radium revisited. Targeting of skeletal metastases by the alpha emitter Radium223.Roy H Larsen,Oyvind Bruland. http://www.bruland.info/PDF/195-202.pdf
Bone remodeling and metastatic growth
Highly dynamic tissue. Constant turnover
Osteoblasts
mesenchymal origin bone marrow areas generate collagen matrix Osteoclasts
monocytic lineage bone resorption release of growth factors - osteoblasts
The vicious circle of bone metastatic spread
1. Osteoclastic bone resorption release of growth factors – coopted by tumor cells limits active immune reconnaissance (hypothesis) 2. Tumor cells secrete growth factors: bone resorption 3. Interleukines/growth factors secreted by adipocytes.
Osteomimicry
How to fully benefit the bone metastatic niche? Acquire a bone like phenotype Gene expression of osteoblast and osteoclast activity Metastatic phenotype Gene expression for parathyroid hormone GFs common for other tissues: “homing” possible.
Targeting of osseous sites with radionuclides
β particle emitting therapies significant palliation of painful bone metastases
no overall survival
high risk of myelosuppression low LET (Linear Energy Transfer)
89Sr (Metastron) 153Sm (Quadramet)
Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate cancer with symptomatic bone metastases. Seth Blacksburg et al. Curr Treat Options in Oncol 2015 (16): 11-20
Targeting of osseous sites with radionuclides
α particle emitting therapies
223Ra
high LET
DNA double strands breaks ✓not reparable
high mass short distance in tissues
particle range 100μ
minimize marrow toxicity Integrating bone targeting radiopharmaceuticals into the management of patients with castrate-resistant prostate cancer with symptomatic bone metastases. Seth Blacksburg et al. Curr Treat Options in Oncol 2015 (16): 11-20
Short Range of α-Emitters Reduces Bone Marrow Exposure
Range of β-particle: (long range – 10 to 1000 cell diameters2)
β-emitter
Marrow
Bone
Range of α-particle: (short range – 2 to 10 cell diameters2)
Ra 223
Bone
Marrow
1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.
Radionuclides targeting osteoclasts - Biphosphonates 153Sm 186/188Re Radionuclides targeting osteoblasts – Calcium analogues 223Ra (alpha emitter)
89Sr ( beta emitter)
Short range of alpha emitter
reduces bone marrow exposure
Long range of beta emitters
may increase bone marrow exposure
and associated toxicities
Alpha Emitter (OS benefit + impact on pain)*
Beta Emitters (Pain palliation only)
Marrow
Bone
Radium-223
Marrow
Bone
Strontium-89 and
Samarium-153
1. Henriksen G, et al. Cancer Res. 2002;62:3120-3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-28. 3. Nilsson S, et al. Eur J Cancer 2012;48(5):678-686. 4. Parker C, et al. N Engl J Med. 2013;369(3):213-23.
Mechanism of Action: Alpha vs Beta emitters
223Ra
Independent cell cycle tumor type surface markers
Winning combination
short half life bone seeking high LET short range
Least attractive but most important feature – potent
and irreversible DNA double strand damage. Fighting prostate cancer with Radium-223 – Not your Madame’s Isotope. NEJM 2013 (369): 276-278
Radium is a calcium-mimetic element
17
Ra 88
20
Ca
Radium belongs to
the same group of
elements as Calcium
Radium is a calcium-
mimetic element
Radium (Ra-223) is
quickly taken up in
newly forming bone
Radium-223 preferentially targets areas of increased bone turnover
Radium-223
Phosphate
Calcium
• Hydroxyapatite, an inorganic mineral primarily consisting of calcium and phosphate (Ca10(PO4)6(OH)2), is the principal inorganic component of bone.
• As a bone-seeking agent, Ra223 is incorporated in place of calcium into new hydroxyapatite deposits within the microenvironement of blastic lesions.
• Ra223 rapidly and selectively accumulates in multiple areas of new bone formation, in and around metastases, making it highly localized and targeted.
Histological section of a osteoblastic bone metastasis in a patient with prostate cancer. Note the presence of abundant woven bone distributed as a mesh in between cords of tumour cells.
Radium 223 as a bone-seeking radionuclide
Bruland OS et al. Clin Cancer Res 2006;12:6250s–7s
Target: hydroxyapatite Ca10(PO4)6(OH)2
Phase II studies with Ra223
pain reduction reduction of biomarkers PSA total/bone alkaline phosphatase Suggested improved survival Cancer death is due to bone disease and complications Bone targeting therapies palliation of pain no benefit on survival
Drug indication
Xofigo® is indicated for
the treatment of adults with
castration-resistant prostate cancer (CRPC),
symptomatic bone metastases
and no known visceral metastases.
Xofigo is the first and only alpha particle-emitting radioactive therapeutic agent that has demonstrated improvement in overall survival (OS) and delay in time to first symptomatic skeletal related event (SRE) compared to placebo, as shown in the pivotal Phase III ALSYMPCA trial.
Or lymph nodes < 30mm short axis.
Phase 3 ALSYMPCA trial design
Primary endpoint: OS Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety and QoL
ALP, alkaline phosphatase; mCRPC, metastatic CRPC; QoL, quality of life. Parker C et al. J Clin Oncol 2012;30(suppl.): abstr LBA4512 and accompanying presentation. clinicaltrials.gov NCT00699751
Placebo + best standard of care
FOLLOW-UP PHASE TREATMENT PHASE 6 injections at 4-week intervals
36 16 24 12 0 28 6 20 32 8 10 Month
Stratification factors • Total ALP < 220 U/L vs ≥ 220 U/L • Bisphosphonate use (Yes vs No) • Prior docetaxel (Yes vs No) Key inclusion criteria • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel
Assessments
Randomization 2:1
Radium 223 + best standard of
care
n=921 mCRPC
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Surv
iva
l (%
)
Phase 3 ALSYMPCA: improved overall survival
Radium 223 Placebo
Median OS, months 14.9 11.3
HR 0.695
95% CI 0.581–0.832
p value <0.0001
Radium 223 Placebo
Month
Radium 223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0
Median OS Δ: 3.6 months
Pat
ien
ts (
%)
Parker C et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512 and accompanying presentation. clinicaltrials.gov NCT00699751.
Bottom line 223Ra reduced by 30% the risk of death.
Increase of time to first SRE.
Benefit across all subgroups.
No significant difference with BoC in myelotoxicity.
Liberal definition of best of care, reflecting the day to day clinical practice.
What about SREs?
SRE
Use of radiotherapy to relieve skeletal symptoms
Symptomatic vertebral fracture/spinal compression
Tumor related orthopedic surgery Decrease in QoL Use of analgesics/opioids Neurologic damage
Phase 3 ALSYMPCA: bone pain
50
62
0
10
20
30
40
50
60
70
80
90
Radium 223(n=600)
Placebo(n=301)
Post-hoc analysis
AE, adverse event
Bone pain as an AE (all grades)
Pati
ents
(%
)
Parker C et al. N Engl J Med 2013;369:213–23; Nilsson S et al. ASCO GU 2013 abstract 19
36
50
0
10
20
30
40
50
60
70
80
90
Radium 223(n=600)
Placebo(n=301)
Pat
ien
ts (
%)
Opioid use for bone pain
1st SRE
11.8 months 223Ra 8.4 months placebo
Risk for subsequent SRE
41% 223Ra 46% placebo
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration resistant prostate cancer and bone metastases: results of a phase 3, double blind, randomised trial. O Sartor et al. Lancet Oncol 2014 (15): 738-746
Effects maintained
Across subgroups
Docetaxel use
PSA levels
Bone/Total AF
Effect not maintained when adjusted to superscan status at bone scintigraphy.
Note:
Effect may be overestimated due to concomitant use of biphosphonates.
Biphosphonates correlate strongly with low incidence of bone pathologic fracture.
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration resistant prostate cancer and bone metastases: results of a phase 3, double blind, randomised trial. O Sartor et al. Lancet Oncol 2014 (15): 738-746
• Phase 3 ALSYMPCA study in mCRPC reported no clinically meaningful differences in the frequency of haematological adverse events between Radium 223 and placebo
• Clinically observed bone marrow toxicity with Radium 223 has been inconsistent with that predicted by dosimetric calculations
• New dosimetric models are needed for alpha emitters because they have a much shorter range than the considered anatomical features
Radium 223 bone metastases dosimetry
Parker C et al. N Engl J Med 2013;369:213−23; 2. Hobbs R et al. Phys Med Biol 2012;57:3207–22
Adverse event
Radium 223 (N=600) Placebo (N=301)
All
grades Grade 3 Grade 4 Grade 5
All
grades Grade 3 Grade 4 Grade 5
Number of patients (%)
Haematological
Anaemia 187 (31) 65 (11) 11 (2) 0 92 (31) 37 (12) 2 (1) 1 (<1)
Thrombocytopenia 69 (12) 20 (3) 18 (3) 1 (<1) 17 (6) 5 (2) 1 (<1) 0
Neutropenia 30 (5) 9 (2) 4 (1) 0 3 (1) 2 (1) 0 0
Rare phenomenon
Described only in phase I of ALSYMPCA
Flare of pain usually 1 week after treatment
Can lead to decrease in performance status 1 case report
75yrs old patient with advanced prostate cancer
Androgen deprivation since 2008
Subsequent therapy with 223Ra due to bone PD Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with
radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378
Of flare phenomenon and the evolution of biomarkers
Increase of bone pain at multiples sites
Decrease of performance status lasting for 10 days
After 1st dose
Subsequent doses minimal or no pain flare
Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378
Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with radium-223. A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378
Pain, PSA flare and bone scan response in a patient with metastatic castration resistant prostate cancer treated with radium-223 A case report. MA McNamara et al. BMC Cancer 2015 (15): 371-378
Slight flare phenomenon between 1st and 2nd Ra injection 1. Other authors suggest a steady PSA reduction is rather the exception than the rule. 2
1. EC Etchebehere et al. Eur J Nucl Med Mol Imaging 2015. 2. R Nome et al. Scandinavian Journal of Urology 2015 (49): 211-217
Baseline and FU checkups Before every 223Ra injection:
Hb levels
Kidney and liver function
Alkaline phosphatase levels
PSA
Clinical exam. Remind radioprotection measures.
Before 1st treatment:
check testosterone levels exclude visceral PD if nodal disease : < 30mm short axis
Anemia: day prior / morning of injection: blood transfusion.
Bottom line Remember the pain + PSA flare phenomenon Total/bone AF levels steadily decrease
Demonstrates response
Differentiates flare from true PD
Reassure your patient
PSA reduction is rather the exception than the rule QoL improves. Bone pain will decrease
Exclude true bone or visceral PD Changes in prostate specific antigen,markers of bone metabolism and bone scans after treatment with Radium-223. R Nome et al. Scandinavian Journal of Urology 2015 (49): 211-217
Bottom line !! Small tumor deposits may not lead to osteoblastic response
No 223Ra binding
PD during 223Ra therapy !! Missed at baseline bone scan !! “Mixed” response at FU bone scan Novel FACBC PET/CT Classic NaF PET/CT FACBC Leucine analogue Target:background ratio > 11C-choline PET/CT PET investigates metabolism rather than indirect bone response to insult
Check for PD when AFs increase during 223Ra therapy !
Conclusions
1. Radionuclide therapy with α emitters has the advantage of high potency and specificity owing to a high energy deposition and short range.
2. α particles cause double-stranded DNA breaks that are almost completely unrepairable.
3. Small number of tracks through a cell nucleus can sterilize a cell.
4. The biological effects of α particles are 3−7 times greater than the damage caused by β emitters.
Conclusions
5. Significant survival increase for pts treated with 223Ra.
30% decrease of risk of death vs placebo + BoC. 6. Significantly decreased incidence of SREs, particularly if combined with biphosphonates. 7. Increased quality of life and decrease of analgesics use. 8. Clinically observed bone marrow toxicity with 223Radium has been lower than predicted by dosimetric calculations.