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