changes in management of ovarian cancer€¦ · 03/12/2019 8 bevacizumab (avastin) 1st line use in...
TRANSCRIPT
03/12/2019
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Changes in Management of Ovarian Cancer
Dr Katie Herbert
Medical Oncology SpR
Oncology Update – Sobell House 22/11/19
Talk outline
• Background to ovarian cancer
• Antiangiogenic treatments
• PARP inhibition
• Other treatments
• Malignant Bowel Obstruction
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Background
• Ovarian cancer is 6th most common cancer and cancer-related death in women in UK
• 7,500 cases in 2016 in UK
• Peak age group 75-79 years old
• Overall survival improving over time 10 year survival 18% to 35% over 40 years…
All stages, all ovarian cancer.
CRUK – cancer stats
Background Ovarian Cancer (C56): 2002-2006 Five-Year Relative Survival (%) by Stage, Adults Aged 15-99, Former Anglia Cancer Network
CRUK – cancer stats
60% diagnosed at advanced stage
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Pathology – Advanced Ovarian Cancer
• 90% are Epithelial Ovarian Cancer
• 80% of these are high-grade serous
• Tubal, peritoneal, ovarian origin
• p53 mutation universal
• 15-20% have BRCA mutation (somatic or germline)
• Express PAX8 and WT1
Diagnosis: Key symptoms
• >12 times per month: high index suspicion • abdominal pain
• bloating
• early fullness after meals
• urinary symptoms
• GP: CA 125 and Ultrasound scan (USS)
• Referral to gynae-oncology- assessment of risk of malignancy
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Risk of Malignancy Index (RMI)
If RMI > 200- referral of patient to Gynae-Oncologist at cancer centre required for further management. Jacobs et al 1990, BJOG, 97 (10)922-929
Treatment Aims
Palliative treatment – advanced ovarian cancer is not curable.
However…
Highly sensitive to chemotherapy:
1st line =60-70% response rate
Improvements in QoL with treatment
Follows a relapsing-remitting course
Multiple lines of treatment available.
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Changing treatment paradigms
Backbone of treatment remains Platinum-based chemotherapy (neoadjuvant vs primary debulking surgery) Aim is to maximise the PFS between lines of chemotherapy. Focus on trials and introduction of other agents as adjunct to chemotherapy Anti-angiogenic PARP inhibition Immunotherapy Novel agents
Antiangiogenic treatment
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Anti-angiogenic therapy
Gale et al. Nature 407(6801):242-248
↑HIF1α
Increased VEGF
Neovascularisation
Suppression of tumour immunogenicity
Anti-angiogenic therapy
VEGF
VEGF- Receptor
Cell-membrane
Bevacizumab
Cedirinib
Signalling cascade leading to Angiogenesis
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Bevacizumab (Avastin) Monoclonal antibody targeting VEGF
GOG-0128 trial: Chemo + Bevacizumab vs Chemo alone for relapse
OS: 42·2 months (95% CI 37·7-46·2) vs 37·3 months (32·6-39·7)
Coleman et al. Lancet Oncol. 2017 Jun;18(6):779-791.
Median PFS = 18 vs 13 months
Bevacizumab (Avastin) Monoclonal antibody targeting VEGF
ICON 7 Chemo + Bevacizumab vs Chemo alone first line
Perren et al. NEJM 2011 365:2484-2496
Median PFS = 10 vs 16.5 months
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Bevacizumab (Avastin)
1st line use in stage IIIc/IV ovarian cancer
Used alongside Neoadjuvant chemotherapy and then maintenance for 1 year.
Standard of Care Chemotherapy = 3 weekly Carboplatin and Paclitaxel
Toxicities – generally very well tolerated:
Hypertension
Proteinuria
Bowel Perforation
Poor wound healing and bleeding
Contraindicated in patients with rectosigmoid disease
Paused around time of surgery
Bevacizumab (Avastin)- ongoing trials
ICON8b trial:
Is weekly Paclitaxel superior to 3 weekly, both in combination with Bevacizumab in first line treatment?
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Cediranib Tyrosine Kinase Inhibitor targeting VEGF-Receptor
ICON 6 trial in relapsed ovarian cancer demonstrated PFS advantage of Cediranib in combination with chemotherapy + maintenance treatment.
Ledermann et al. Lancet.387:10023; P1066-1074. 2016
Toxicities:
Hypertension
Diarrhoea
Fatigue
Myelosuppression
Analysis of ICON 6 QoL outcomes - no detriment in Quality of Life at 1 year
Stark et al. Cancer. 2017 Jul 15;123(14):2752-2761.
PARP inhibition
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PARP inhibition – BRCA mutations
15% germline mutation in BRCA 1/2– all patients tested at diagnosis
Informed consent – implications for patient’s treatment and implications for family – genetic counselling.
Patient’s with BRCA mutation have higher sensitivity to platinum
PARP inhibition – BRCA mutations
Iglehart et al. N Engl J Med 2009; 361:189-191
BRCA mutation causes HR deficiency and therefore sensitivity to PARPi
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PARP inhibitors Olaparib, Niraparib, Rucaparib – all licensed in different settings as maintenance treatment in platinum-sensitive disease
OLAPARIB
1st Line maintenance treatment -BRCA mutation – (SOLO 1 data)
Moore et al. N Engl J Med 2018; 379:2495-2505
PARP inhibitors Olaparib, Niraparib, Rucaparib – all licensed in different settings as maintenance treatment in platinum-sensitive disease
NIRAPARIB
2nd Line maintenance treatment -BRCA mutation OR
2nd/3rd line maintenance treatment - BRCA WT
RUCAPARIB
2nd/3rd line maintenance treatment - BRCA WT and Mutant
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Who benefits from PARPi?
Evidence that patients without germline or somatic mutations have sensitivity to PARP inhibition…
“BRCAness” or Homologous Repair Deficiency (HRD)
Platinum sensitivity is a soft biomarker for BRCAness
Evidence that HRD with or without BRCA mutation sensitises to PARP inhibition
Who benefits from PARPi?
PRIMA study
Niraparib 1st line
following platinum-sensitivity
ARIEL 3 trial of Rucaparib in relapsed platinum-sensitive disease HRD signal
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PARP inhibitors
Toxicities (generally well tolerated):
Myelosuppression
Fatigue
Nausea
Diarrhoea
Analysis of HRQOL and patient-centred outcomes form SOLO2 data:
No deficit in HRQOL
Significant improvement in:
Time Without Significant Symptoms of Toxicity (TWiST)
15·03 [SD 12·79] vs 7·70 [6·42] months
Quality Adjusted Progression Free Survival (QAPFS)
13·96 [SD 10·96] vs 7·28 [5·22] months
Combination treatments
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Cediranib and Olaparib
Hypoxic environment downregulates DNA repair genes therefore enhancing sensitivity to PARP inhibition
Combination of antiangiogenic drugs (Which promote hypoxia) with PARP inhibition (which exploit DNA repair deficiency) increase response rates.
ICON 9 trial ongoing:
Randomisation to Cediranib and Olaparib vs Olaparib alone for platinum-sensitive ovarian cancer.
Bevacizumab (Avastin) vs PARPi
No clear biomarkers as to which patients benefit from antiangiogenesis treatments.
Gathering evidence as to importance of 1st line use of maintenance PARPi in patients with BRCA mutation (SOLO1)
ICON8b study – now allowing switch from Bevacizumab to PARPi
PAOLA1 study examining combination of PARPi and Bevacizumab
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Bevacizumab (Avastin) +/- PARPi: PAOLA 1
Other new treatments
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Immunotherapy
Javelin study of Avelumab (Anti PD1) – no benefit
Combination of Bevacizumab with Nivolumab – concept of antiangiogenic treatment as an immunotherapy sensitiser.
PARP inhibition may increase immunogenicity due to DNA damage repair failure:
ATHENA trial – Rucaparib in combination with Nivolumab for platinum sensitive first line treatment.
PEACOCC study of Pembrolizumab in clear cell carcinoma
Increased VEGF
Neovascularisation
Suppression of tumour immunogenicity
mTOR inhibition – DICE trial
Platinum resistant disease:
Second line chemotherapy usually with weekly taxol.
Aim of study is to determine if addition of mTOR inhibitor improves outcoms vs chemo alone.
mTOR inhibiton may mimic BRCAness by promoting DNA repair deficiency
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TPN in malignant bowel obstruction
Malignant Bowel Obstruction
Usually multi-level due to peritoneal and serosal tumour deposits therefore for conservative management.
Palliative chemotherapy indicated
Controversial role for TPN as palliative treatment for bowel obstruction
Cochrane review (Sowerbutts et al. 2018) of MBO (all cancers):
13 observational studies
Low-quality evidence for survival and quality of life outcomes
Time on TPN 3-1278 days
12% admitted to hospital with complications
Equivocal QoL outcomes
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Ovarian Cancer Workstream Trials Group Meeting – Oct 2019
HPN- cancer accounts for 20% of HPN HPN for cancer patients is routinely considered in countries such as Germany Initial Cochrane review of use of TPN for malignant bowel obstruction (MBO)
performed- only 1 trial that focused solely on OC, majority included multiple
tumour types. Approximate cost is £10,000 per annum Trial question: does the use of HPN in women with MBO secondary to OC improve
QOL and survival N=200-300 patients would be required; Could HPN replace chemotherapy (HM patient representative felt that patients
could potentially be very supportive of this approach) Exploratory endpoints to consider- nutritional status/ skeletal muscle mass
Outcome: NCRI group support for further development of trial proposal-
multidisciplinary approach would be required with involvement of e.g gastro/pall
care teams too/ input from LWBC group
Summary
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Summary
Step-wise improvements in survival and quality of life for advanced ovarian cancer patients.
Identifying appropriate use for:
Antiangiogenic treatments
PARP inhibitors
Trials of combination of chemo/antiangiogenic/PARPi
Finding a role for immunotherapy
Novel agents for platinum-resistant disease
Acknowledgements
• Dr. Shibani Nicum
• Dr. Rene Roux