Emerging therapies in prostate cancer Nicholas James @Prof_Nick_James #NJProstatecancer
Nov 08, 2014
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