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

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

EC Etchebehere et al. Eur J Nucl Med Mol Imaging 2015.

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.

Thank you!