Kidderminster Prostate Talk April 2013

Emerging therapies in prostate cancer

Nicholas James

@Prof_Nick_James

#NJProstatecancer

Important recent advances

• Use of monitoring for early disease

• Radiotherapy advances

• New hormone therapies

• New bone targeting therapies

• Other new treatments

MRI imaging for diagnosis and monitoring

• MRI can distinguish normal prostate from high grade tumours

MRI imaging for diagnosis and monitoring

• Implications:– May replace need for

biopsy in low grade tumours

– Allows better monitoring in early cases

Important recent advances

• Use of monitoring for early disease

• Radiotherapy advances

• New hormone therapies

• New bone targeting therapies

• Other new treatments

Prostate Cancer Treatment

ClinicallyLocalized

Hormone/castrate

Refractory

Local treatmentDocetaxel, abiraterone,

Cabazitaxeletc

Endocrine

Relapsedand

Newly diagnosed M+

T1/2 T3/4 N+ M+ HRPCLow risk High risk

SPCG-7 trial – hormone therapy vs HT + RT

Locally advancedCaP

PSA up to 70 (n=880)

Randomised

Hormone therapy + RT Hormone therapy alone

SPCG-7 results

Widmark et al The Lancet 2009 373, 301-308

UK/Canadian HT vs HT + RT trial

HR=0.57 (95% C.I. 0.37-0.78) p=0.001

140 Deaths from Prostate Cancer 140 Deaths from Prostate Cancer 89 ADT alone, 51 RT+ADT89 ADT alone, 51 RT+ADT

# at Risk

ADT

ADT+RT

ADT ADT+RT

Pe

rce

nta

ge

0

20

40

60

80

100

0 3 6 9

602

603

509

512

Time (Years)213

232

51

60

7 yr DSS 90%

7 yr DSS 79%

New radiotherapy technologies

• Intensity modulated RT

• Image guided RT

• Cyberknife

Intensity modulated radiotherapy• X –rays delivered from many ports by rotating the linac

around pt• Modification of the shape and intensity of each port

IMRT

IMRT prostate and pelvic nodes

Image Guided Radiotherapy (IGRT)

• Aim: to measure and correct target and critical structure positional errors immediately prior to or during treatment delivery

IGRT

Cyberknife

Radiotherapy conclusions

• Better accuracy

• Fewer side effects

• Better knowledge of who to treat

Important recent advances

• Use of monitoring for early disease

• Radiotherapy advances

• New hormone therapies

• New bone targeting therapies

• Other new treatments

Prostate Cancer Treatment

ClinicallyLocalized

Hormone/castrate

Refractory

Local treatmentDocetaxel, abiraterone,

Cabazitaxeletc

Endocrine

Relapsedand

Newly diagnosed M+

T1/2 T3/4 N+ M+ HRPCLow risk High risk

Hormone therapy

20

Anterior Pituitary

LH

TestisLeydig

cells

Testosterone

Prostate

Androgen pathways in human prostate

LHRH Agonists

Antiandrogens

X

X

ACTH

Adrenal

cortex

Non-testicular androgens

Prostate

Effect of castration on androgen levels

Labrie F. Nature Reviews Urology 2011

Development of CRPC

0

50

100

150

200

250

300

1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months

PS

A

LHRH Agonist Chemotherapy

Castrate Resistant phase

Te

stos

tero

ne

30

25

20

10

15

5

Normal signalling and resistant disease

Cytoplasm Nucleus

1AR binding

2Nuclear translocation

3DNA binding and activation

Androgenreceptor

AndrogenTumourgrowth

• Cells manufacture their own Androgen• The androgen receptor becomes “super-sensitive”

Abiraterone mode of action

• Blocks synthesis of androgen both inside and outside prostate cancer cells

Cytoplasm Nucleus

1AR binding

2Nuclear translocation

3DNA binding and activation

Androgenreceptor

AndrogenTumourgrowth

AbirateroneAbiraterone

Abiraterone

Abiraterone post chemotherapy trial results

• A 35% improvement in survival times compared to prednisolone alone

• Improvement was unaffected by the amount of prior chemotherapy

• Patients with cancer related pain frequently experienced rapid reductions in symptoms

• Side effects were minimal

Abiraterone pre-chemotherapy trial results

• A 45% improvement in time to worsening of disease

• Side effects were minimal

• Trend towards improved overall survival

Enzalutamide mode of action

Cytoplasm Nucleus

1AR binding

2Nuclear translocation

3DNA binding and activation

Androgenreceptor

AndrogenTumourgrowth

MDV3100MDV3100

• Blocks binding of androgen inside cells as well as downstream effects

AFFIRM phase 3 trial of Enzalutamide (MDV3100) post-chemotherapy

N = 1199mCRPC1–2 prior

chemotherapy regimens*

N = 1199mCRPC1–2 prior

chemotherapy regimens*

R2:1

R2:1

MDV3100 160 mg qdMDV3100 160 mg qd

Placebo qdPlacebo qd

• Phase 3 randomized, double-blind, placebo-controlled trial

http://clinicaltrials.gov/ct2/show/NCT00974311http://www.astellas.com/en/corporate/news/pdf/111104_Eg.pdf

• Primary endpoint: Overall survival• Secondary endpoints: radiographic PFS, time to first SRE, • time to PSA progression

* ≥ 1 docetaxel

AFFIRM trial: Summary of adverse events

*Includes terms hyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increasedThe adverse event reporting period was on average more than twice as long for MDV3100 compared with placeboData are percent of patients

Total events Grade ≥ 3 events

MDV3100(n = 800)

Placebo(n = 399)

MDV3100(n = 800)

Placebo(n = 399)

Adverse events 98.1% 97.7% 45.3% 53.1%

Serious adverse events 33.5% 38.6% 28.4% 33.6%

Discontinuations due to adverse events

7.6% 9.8% 4.6% 7.0%

Adverse events leading to death 2.9% 3.5% 2.9% 3.5%

Adverse events of interest

Cardiac disorders 6.1% 7.5% 0.9% 2.0%

Myocardial infarction 0.3% 0.5% 0.3% 0.5%

LFT abnormalities* 1.0% 1.5% 0.4% 0.8%

Seizure 0.6% 0.0% 0.6% 0.0%

Scher HI et al. J Clin Oncol 2012;30 (suppl 5; abstr LBA1).

MDV3100 trial results

• 37% improvement in survival times• More side effects reported in placebo arm

– Minimal drug related side effects

• Control arm patients had longer survival times than in the abiraterone trial due to exposure abiraterone and cabazitaxel– Suggests different drugs can be added to each other for

further benefit

Hormone therapy conclusions

• New ways of targeting failure of traditional hormone therapies emerging

• Abiraterone now available pre- and post-chemotherapy

• Enzalutamide set for EU licence shortly

Bone secondaries

Orthopaedic Surgery

Radiation to Bone

Pathological Fracture

Spinal Cord compression

Skeletal related events are clinically important

Normal bone remodeling

Resting

Resorption

Formation

Reversal

Treating bone disease

• Multiple targets– The tumour

cells

– The bone cells

– The signalling mechanisms

Tumor cell

Osteoclast Osteoblast3

Tumour cells

Targeting the bone cells - bisphosphonate therapy

33%

44%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

All patients

P=.021

Zoledronic acid 4 mgPlacebo

% with SRE at 15 monthsSaad F, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer JNCI 2004 96 879-882.

Targeting the bone cells – denosumab

Rate Ratio = 0.82 (95% CI: 0.71, 0.94)

Study Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

Cum

ulat

ive

Mea

n N

umbe

r of

S

RE

s pe

r P

atie

nt

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

Denosumab Zoledronic acid

Radium-223• Alpharadin is Ra-223 salt in solution

• Behaves like calcium:

– a natural bone-seeker

– incorporated into bony matrix

• Emits radioactive particles that kill adjacent tumour cells

Targets new bone in metastases Irradiates adjacent tumour cells

Bone marrowTumorcells

Osteoclast

Osteoblast

Newlyformed

bone

Radium-223deposition

Alphaparticleradiation

Baseline Day 2 Day 6

99mTc -MDP 223 Rabased on

Alpharadin uptake and elimination

• Cleared rapidly, directly into gut

• Spares kidney – radiation dose low

Alsympca trial

Alsympca trial SRE outcomes

Parker et al ESMO 2011.

Effects of Ra223 on PSA

Nilson et al Lancet Oncology 2007. 8 587-94

Alsympca overall survival

• 31% improvement in survival times

• Again, more side effects reported in placebo arm

Parker et al ESMO 2011.

Bone therapies – summary

• Bone disease is important cause of clinical problems

• New ways of reducing or preventing damage emerging

Other new drugs

• Cabozantinib

• Ipilumimab

• Immunotherapies – GVAX, Provenge

Cabozantinib

• Inhibits proteins involved in tumour invasion and growth of new blood supply

• Given as daily tablets

• Impressive responses seen in early trials

• Some issues with side effects

• Currently in phase 3 studies

Cabozantinib

Smith et al, JCO 2013 31:412

Conclusions

• Important new treatments coming on stream across whole disease spectrum

• DNA sequencing technology will give us better understanding of biology in next few years, leading to further advances