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New strategies and new drugs
Gerhardt Attard MD MRCP PhD
Cancer Research UK Clinician Scientist and Honorary Consultant
The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust
Some key questions
Tumour Volume and Activity
Who should receive docetaxel at start of ADT?
Who should receive docetaxel
before enza/abi?
Is there any benefit in using abi/enza
after the previous one has been used?
Enzalutamide/
Abiraterone and
Prednisolone
LHRH
analogue with addition
of anti-androgen
Local
therapy
Castrate Sensitive
Abiraterone and
prednisolone/
Enzalutamide
Docetaxel
chemotherapy
Castrate Resistant Disease
Time
How can we treat abi/enza/taxa
ne resistant disease?
Trials and/or
cabazitaxel
second line
chemotherapy
• The results of the COU‐302 and PREVAIL trials can be extrapolated to symptomatic chemotherapy‐naïve patients
• Yes
• No
• Enzalutamide or abiraterone should now be initiated prior to bicalutamide or other vintage anti‐androgens for the majority of patients
1. Yes
2. No
• Hypothesis: Delay to initiation of most effective treatments in progressing patients is detrimental
• TERRAIN trial
• 375 patients enza vs bicalutamide
• Significant increase in PFS (HR = 0.44; 95% Cl, 0.34‐0.57; p < 0.0001). • Median PFS was 15.7 months for enza vs 5.8 months for bicalutamide
EAU 2015
 Bulky, rapidly progressing metastases
• GIVEN THE POOR METHODS FOR PREDICTING RESONSE, THE MORE EFFECTIVE TREATMENT SHOULD BE INITIATED IMMEDIATELY TO DELAY SYMPTOMS AND ALLOW SUBSEQUENT USE OF ALL LIFE‐PROLONGING TREATMENTS BEFORE FITNESS LEVELS DETERIORATE
 Asymptomatic with rising PSA but low volume metastases • Bicalutamide is at least as well tolerated but significantly cheaper – why not try bicalutamide
1st?
Castration‐resistant state – hypothetical scenarios
b
3
a
2
AA
1
3
2
SCENARIO 1
c
1
3
SCENARIO 2
1
b
FACT: b > a
??: c >> a+b
2
TIME
Castration‐resistant state – hypothetical scenarios
b
3
a
2
AA
1
3
2
SCENARIO 1
OMIT VINTAGE AA
c
1
SCENARIO 2
USE VINTAGE AA
1
3
b
FACT: b > a
??: c >> a+b
2
TIME
• Abiraterone or enzalutamide is the treatment of choice for a symptomatic patient who has progressed on the alternative novel AR targeting agent
• Yes
• No Sequencing of enzalutamide followed by abiraterone
enzalutamide
abiraterone
Loriot Y et al. Ann Oncol 2013
Noonan K L et al. Ann Oncol 2013
Sequencing of abiraterone followed by enzalutamide
< 50% PSA decline on prior abiraterone
> 50% PSA decline on prior abiraterone
Treatment
duration
(months)
Median (95% CI)
Range
2.9 (1.7–4.0)
0.6‐7.2
> 3 months
17 (43%)
> 6 months
4 (10.3%)
CRPC samples (Tumor biopsies or plasma containing genomic
Pre-Castration
samples
material from multiple metastases)
1
(TRBP or cores from
prostatectomy samples)
2
1
Tumour Volume and Activity
1
Enzalutamide/
Abiraterone and
Prednisolone
LHRH
analogue with addition
of anti-androgen
Local
therapy
Castrate Sensitive
Abiraterone and
prednisolone/
Enzalutamide
Docetaxel
chemotherapy
Castrate Resistant Disease
Time
Trials and/or
cabazitaxel
second line
chemotherapy
Circulating tumour cell enumeration Veridex CellSearch®
• Analytically Valid and FDA Cleared (Breast, Colorectal,
and Prostate)
• Sample must be analysed within 96 hours
• Immunomagnetic selection by anti-EpCAM MAB bound
to ferrofluids
• Immunofluorescence for CTC identification
Tibbe AG et al, Nature Biotechnology, 1999
Identification of CTC
Morphology
CTC
Unassigned
Event
CTC
Unassigned
Event
CTC
CTC
CD45 APC
Cytokeratin PE
DAPI (DNA)
CTC counts by strict CellSearch definition are prognostic & identify response to treatment in chemotherapy‐treated patients
Colorectal
%Probability of Survival
Breast
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
n=83 (47%)
n=38 (21%)
n=39 (22%)
0
5
10
n=17 (10%)
15
20
25
30
35
40
45
50
Prostate
100
90
80
70
n=303 (70%)
n=88 (38%)
n=45 (20%)
60
50
n=74 (17%)
n=24 (6%)
n=29 (7%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
40
30
20
10
0
n=26 (11%)
n=71 (31%)
0
2 4
Time from Baseline (Months)
Remain Favorable
Convert to Unfavorable
Remain Unfavorable
Convert to Favorable
6
8 10 12 14 16 18 20 22 24 26 28 30
AR splice variants lacking a ligand binding domain
Dehm SM, Tindall DJ, Endocr Relat Cancer 2011;18:R183-R196
AR‐V7 associates with resistance
Abiraterone
Enzalutamide
• Identifies >75% of resistant patients with a negligible error rate Antonarakis E, NEJM 2014
Several questions remain
• Positive enrichment of CTC (not visualised):
– differences in CTC count?
– heterogeneous expression in CTC?
– earlier stage patients with fewer CTC?
• Define threshold for detection/achieve a quantitative assay?
• Is detection of AR‐V7 a marker of a different underlying process that causes resistance?
– Increasing full length AR?
– AR amplification?
– Stress reaction?
Leveraging circulating free tumor DNA
1. Early detection and monitoring
2. Risk stratification of early patients 3. Genomic characterisation
•
treatment selection
•
dissecting resistance
4. Monitoring response
Bidard FC et al. Sci Transl Med 2014
Spatial and temporal heterogeneity of AR genomic aberrations
Clonal and PM differences in matched tumor biopsies and plasma samples
Emergence of AR L702H on treatment
NKX3.1‐
PSA
AR L702H
PTEN‐
21q‐
CTC
AR‐L702H causes resistance to abi/enza when given with pred
Richards et al, Cancer Res 2012
Multiplex circulating biomarker assays
• Next‐generation sequencing of circulating tumor DNA detects genomic aberrations in the AR that associate with resistance
Carreira et al. Sci Transl Med 2014; 6(254):254ra125
Somatic aberrations in DNA repair machinery
Grasso et al, Nature 2013
Responses to PARP inhibition
Mateo et al, ESMO 2014
AR‐independent disease progression
• 75 year old previously progressed on castration, bicalutamide, dexamethasone – Started abiraterone and prednisone in Jan 2010
– Baseline PSA 50ng/dl – Good PSA response (nadir: 6.7, July 2010)
March 2011
10
June
11
1 Sep
18
15 Nov
18
Biopsied
x2
8 Dec
11
AR IHC
ERG IHC
ERG FISH
Pre‐treatment biopsy
Tumor biopsy
whilst responding to treatment
New liver
metastasis
Circulating
tumor cells
N=36
Pezaro et al, Eur Urol 2014
Conclusions
• Abiraterone and enzalutamide are effective and well tolerated
• Probably preferred treatment for chemotherapy‐
naïve CRPC
• Limited activity when used sequentially
• Drugs inducing DNA damage could exploit DNA repair defects in ~30% of cancers • Biomarkers could improve current management paradigm of sequential abi/enza‐taxanes +/‐
Rad223