NEPTUNE •A trial for women with – ‘Triple negative’ breast cancer (TNBC) – Localised to breast +/- lymph nodes – Recommended standard treatment involves Taxane Chemotherapy Anthracycline Chemotherapy Surgery Goal.
Download ReportTranscript NEPTUNE •A trial for women with – ‘Triple negative’ breast cancer (TNBC) – Localised to breast +/- lymph nodes – Recommended standard treatment involves Taxane Chemotherapy Anthracycline Chemotherapy Surgery Goal.
Slide 1
NEPTUNE
•A trial for women with
– ‘Triple negative’ breast cancer (TNBC)
– Localised to breast +/- lymph nodes
– Recommended standard treatment involves
Taxane
Chemotherapy
Anthracycline
Chemotherapy
Surgery
Goal is cure
+/-
Radio
therapy
Slide 2
• We need to improve
outcomes for women
with Triple Negative
breast cancer
• Currently no targeted
treatment for this type of
breast cancer which is
particularly aggressive.
• We need to find
pathways to target
Slide 3
PARP inhibitors
Some tumours are less able to repair
genetic damage
– This seems to be an ‘Achilles heel’ for these
cancers
– Can be exploited by a group of drugs called
PARP inhibitors.
– PARP inhibitors further impair DNA repair in a
way which is lethal to tumours but not to
normal tissues
Slide 4
Microarray classification
help us understand biological differences between
cancers
ER-ve
ER+ve
HER2+ve
Arrays: Separate breast cancers by gene cluster
‘Basal-like’
subgroup
Adapted from Sorlie PNAS 2001
Slide 5
BRCA1 and Basal-like/TNBC phenotypes overlap
Basal-like Sub-Type
Basal Cancers
BRCA1 mutated
Sorlie PNAS 2003
Slide 6
BRCA 1
• Key role in DNA damage Repair
DNA
repair
DNA
repair
Homologous
recombinatio
n
(HR) repair
Base excision
DNA repair
HR repair
Normal tissue
cells
BRCA1/BRCA2 deficient
Tumor cells
• Implications for targeted agents- PARP
Slide 7
The IKEA principle
Normal tissue cells
DNA
repair
PARP inhibitor
HR
repair
Homologous
recombination
(HR) repair
HR
repair
DNA
repair
Few normal tissue effects
Base excision
DNA repair
Base excision
DNA repair
HR repair
BRCA1/BRCA2 deficient
Tumor cells
Specific tumor cell killing
PARP inhibitor
Base excision
DNA repair
Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
Slide 8
Why PARPi for TNBC
• Many TNBC cancers appear to have a similarly
impaired DNA damage repair to the genetic
breast cancers
→They may benefit from similar approaches
• Current and pending trials
– Test strategies which exploit DNA damage
– Incorporate translational research to define
sensitive subsets
Slide 9
Gemcitabine/ Carboplatin ± Iniparib
in metastatic TNBC
Progression Free Survival
PFS + 2.3 months
HR 0.59; 95% CI 0.39-0.9
Overall Survival-Exploratory
OS + 4.6 months
HR 0.57; 95% CI 0.36-0.90
Safety Summary
•No significant differences in toxicity G3/4 toxicity between GC and GCI arms
•Grade 3 or 4 adverse events (81% vs 86%)—mainly haematologic toxicity
•14% in iniparib group and 27% in chemo-alone group discontinued treatment
because of adverse events
O’Shaughnessy et al. NEJM Jan 2011
Slide 10
NEPTUNE
•Investigates a PARP inhibitor called ‘iniparib’
•We know iniparib works in combination with
chemotherapy in metastatic TNBC
– Stops damage from chemotherapy being repaired in
cancer cells.
– Data especially with platinum in TNBC
– Safety and efficacy testing needed in early breast
cancer
• Iniparib may also work on its own in TNBC
– If this is the case could provide a ‘maintenance’ therapy
Slide 11
Randomise between 4
treatment groups
NEPTUNE
-4 weeks
0
No window
Start chemo
Docetaxel
4 cycles
Iniparib
2wk window
Docetaxel + Iniparib
4 cycles
Iniparib
2wk window
Gem/Carbo
4 cycles
Iniparib
2wk window
Gem/Carbo +
Iniparib 4 cycles
2 weeks
Surgery
14 weeks
Radio
therapy
Adjuvant
chemotherapy
26-30 weeks
2 Tumour biopsies
& surgery specimen
6 Blood samples
•Tests the addition of iniparib to chemotherapy against standard docetaxel
•Iniparib 2 week ‘window’ tests for monotherapy activity
•Primary endpoint is pathological complete response
Slide 12
Randomise between 4
treatment groups
NEPTUNE
-4 weeks
0
No window
Start chemo
Docetaxel
4 cycles
Iniparib
2wk window
Docetaxel + Iniparib
4 cycles
Iniparib
2wk window
Gem/Carbo
4 cycles
Iniparib
2wk window
Gem/Carbo +
Iniparib 4 cycles
2 weeks
Surgery
14 weeks
Optional Functional Imaging Substudies
PET
MRI
Participants would be asked to
have a biopsy after these 3 scans
Adjuvant
chemotherapy
Radio
therapy
26-30 weeks
Slide 13
Why all these extra research assessments?
• Does iniparib work on its own?
– To seek evidence of Iniparib monotherapy activity:
• ?potential maintenance role
– To further understanding of how it works
– Does it only work in certain patients and can we identify them
early on in treatment
• Iniparib with chemotherapy
– To further understanding of how they work together
– Does it only work in certain patients and can we identify them
early on in treatment
•
Why imaging substudies?
- Advantageous to future patients to have non-invasive means of
showing how well treatment is working early on. But we have to
prove it with matching biopsy at this stage.
Slide 14
How you can help us
NEPTUNE trial
• Your initial thoughts?
Our concerns
• Complicated to explain very close to time of diagnosis
• lots of hospital visits
– (up 6 visits every 3 weeks for 14 weeks, some visits will be full
days)
• Number of research biopsies
– not optional… may involve a visit to hospital specifically for a
biopsy…
– PET scans or MRI scans, is this too much to ask of patients? Will
women sign up to an optional substudy which includes 3 or 4 of
these and biopsy?
NEPTUNE
•A trial for women with
– ‘Triple negative’ breast cancer (TNBC)
– Localised to breast +/- lymph nodes
– Recommended standard treatment involves
Taxane
Chemotherapy
Anthracycline
Chemotherapy
Surgery
Goal is cure
+/-
Radio
therapy
Slide 2
• We need to improve
outcomes for women
with Triple Negative
breast cancer
• Currently no targeted
treatment for this type of
breast cancer which is
particularly aggressive.
• We need to find
pathways to target
Slide 3
PARP inhibitors
Some tumours are less able to repair
genetic damage
– This seems to be an ‘Achilles heel’ for these
cancers
– Can be exploited by a group of drugs called
PARP inhibitors.
– PARP inhibitors further impair DNA repair in a
way which is lethal to tumours but not to
normal tissues
Slide 4
Microarray classification
help us understand biological differences between
cancers
ER-ve
ER+ve
HER2+ve
Arrays: Separate breast cancers by gene cluster
‘Basal-like’
subgroup
Adapted from Sorlie PNAS 2001
Slide 5
BRCA1 and Basal-like/TNBC phenotypes overlap
Basal-like Sub-Type
Basal Cancers
BRCA1 mutated
Sorlie PNAS 2003
Slide 6
BRCA 1
• Key role in DNA damage Repair
DNA
repair
DNA
repair
Homologous
recombinatio
n
(HR) repair
Base excision
DNA repair
HR repair
Normal tissue
cells
BRCA1/BRCA2 deficient
Tumor cells
• Implications for targeted agents- PARP
Slide 7
The IKEA principle
Normal tissue cells
DNA
repair
PARP inhibitor
HR
repair
Homologous
recombination
(HR) repair
HR
repair
DNA
repair
Few normal tissue effects
Base excision
DNA repair
Base excision
DNA repair
HR repair
BRCA1/BRCA2 deficient
Tumor cells
Specific tumor cell killing
PARP inhibitor
Base excision
DNA repair
Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
Slide 8
Why PARPi for TNBC
• Many TNBC cancers appear to have a similarly
impaired DNA damage repair to the genetic
breast cancers
→They may benefit from similar approaches
• Current and pending trials
– Test strategies which exploit DNA damage
– Incorporate translational research to define
sensitive subsets
Slide 9
Gemcitabine/ Carboplatin ± Iniparib
in metastatic TNBC
Progression Free Survival
PFS + 2.3 months
HR 0.59; 95% CI 0.39-0.9
Overall Survival-Exploratory
OS + 4.6 months
HR 0.57; 95% CI 0.36-0.90
Safety Summary
•No significant differences in toxicity G3/4 toxicity between GC and GCI arms
•Grade 3 or 4 adverse events (81% vs 86%)—mainly haematologic toxicity
•14% in iniparib group and 27% in chemo-alone group discontinued treatment
because of adverse events
O’Shaughnessy et al. NEJM Jan 2011
Slide 10
NEPTUNE
•Investigates a PARP inhibitor called ‘iniparib’
•We know iniparib works in combination with
chemotherapy in metastatic TNBC
– Stops damage from chemotherapy being repaired in
cancer cells.
– Data especially with platinum in TNBC
– Safety and efficacy testing needed in early breast
cancer
• Iniparib may also work on its own in TNBC
– If this is the case could provide a ‘maintenance’ therapy
Slide 11
Randomise between 4
treatment groups
NEPTUNE
-4 weeks
0
No window
Start chemo
Docetaxel
4 cycles
Iniparib
2wk window
Docetaxel + Iniparib
4 cycles
Iniparib
2wk window
Gem/Carbo
4 cycles
Iniparib
2wk window
Gem/Carbo +
Iniparib 4 cycles
2 weeks
Surgery
14 weeks
Radio
therapy
Adjuvant
chemotherapy
26-30 weeks
2 Tumour biopsies
& surgery specimen
6 Blood samples
•Tests the addition of iniparib to chemotherapy against standard docetaxel
•Iniparib 2 week ‘window’ tests for monotherapy activity
•Primary endpoint is pathological complete response
Slide 12
Randomise between 4
treatment groups
NEPTUNE
-4 weeks
0
No window
Start chemo
Docetaxel
4 cycles
Iniparib
2wk window
Docetaxel + Iniparib
4 cycles
Iniparib
2wk window
Gem/Carbo
4 cycles
Iniparib
2wk window
Gem/Carbo +
Iniparib 4 cycles
2 weeks
Surgery
14 weeks
Optional Functional Imaging Substudies
PET
MRI
Participants would be asked to
have a biopsy after these 3 scans
Adjuvant
chemotherapy
Radio
therapy
26-30 weeks
Slide 13
Why all these extra research assessments?
• Does iniparib work on its own?
– To seek evidence of Iniparib monotherapy activity:
• ?potential maintenance role
– To further understanding of how it works
– Does it only work in certain patients and can we identify them
early on in treatment
• Iniparib with chemotherapy
– To further understanding of how they work together
– Does it only work in certain patients and can we identify them
early on in treatment
•
Why imaging substudies?
- Advantageous to future patients to have non-invasive means of
showing how well treatment is working early on. But we have to
prove it with matching biopsy at this stage.
Slide 14
How you can help us
NEPTUNE trial
• Your initial thoughts?
Our concerns
• Complicated to explain very close to time of diagnosis
• lots of hospital visits
– (up 6 visits every 3 weeks for 14 weeks, some visits will be full
days)
• Number of research biopsies
– not optional… may involve a visit to hospital specifically for a
biopsy…
– PET scans or MRI scans, is this too much to ask of patients? Will
women sign up to an optional substudy which includes 3 or 4 of
these and biopsy?