An expert panel discussion recorded in May 2020

This educational activity is supported by an educational grant from GlaxoSmithKline

PARP inhibitor maintenance treatment in advanced ovarian

cancer: The who, what and how?

touchPANEL DISCUSSION

PARP, poly(adenosine diphosphate-ribose) polymerase

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Expert panel

Dr Susana Banerjee (Chair)Consultant Medical Oncologist,The Royal Marsden NHS Foundation Trust and Reader in Women’s Cancers, The Institute of Cancer Research,London, UK

Dr Kathleen MooreAssociate Professor,Stephenson Cancer Center, Oklahoma City, OK, USA

Dr Antonio González-MartínCo-director of Medical Oncology,Clínica Universidad de Navarra,Madrid, Spain

Agenda

What do we know about the use of PARP inhibitors in first-line maintenance treatment?Presentation: Susana BanerjeePanel discussion: Kathleen Moore and Antonio González-Martín; moderated by Susana Banerjee

Which factors influence the choice of PARP inhibitor for maintenance treatment?Presentation: Susana BanerjeePanel discussion: Kathleen Moore and Antonio González-Martín; moderated by Susana Banerjee

PARP, poly(adenosine diphosphate-ribose) polymerase

How can we proactively manage PARP-inhibitor related adverse events to improve quality of life for patients?Presentation: Susana BanerjeePanel discussion: Kathleen Moore and Antonio González-Martín; moderated by Susana Banerjee

What do we know about the use of PARP inhibitors in first-line maintenance treatment?

Dr Susana Banerjee (Chair)Consultant Medical Oncologist,The Royal Marsden NHS Foundation Trust and Reader in Women’s Cancers, The Institute of Cancer Research,London, UK

PARP, poly(adenosine diphosphate-ribose) polymerase

Regulatory status of PARP inhibitors for first-line maintenance in ovarian cancer

BRCA, BReast CAncer gene; CR, complete response; EMA, European Medicines Agency; FDA, U.S. Food & Drug Administration; HRD, homologous recombination deficiency; PARP, poly(adenosine diphosphate-ribose) polymerase; PR, partial response; SmPC, Summary of Product Characteristics1. Olaparib prescribing information revised 12/2019: www.accessdata.fda.gov/drugsatfda_docs/label/2019/208558Orig1s010lblrpl.pdf; 2. AstraZeneca press release 11/05/2020: www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/tlynparza-approved-in-the-us-as-1st-line-maintenance-treatment-with-bevacizumab-for-hrd-positive-advanced-ovarian-cancer.html; 3. Niraparib prescribing information revised 04/2020: www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf; 4. Olaparib SmPC updated 11/2019: www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf; 5. GlaxoSmithKline press release 02/2020: www.gsk.com/en-gb/media/press-releases/european-medicines-agency-accepts-submission-of-gsk-s-marketing-authorisation-application-for-zejula-niraparib-in-first-line-maintenance-treatment/ (accessed May 2020)

FDA EMA

Olaparib • Maintenance monotherapy for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer in CR or PR to first-line platinum-based chemotherapy1

• In combination with bevacizumab for the maintenance treatment of patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with HRD positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.2

• Maintenance in adults with advanced BRCA1/2-mutated germline and/or somatic high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer with CR or PR following completion of first-line platinum-based chemotherapy4

Niraparib • Maintenance treatment of patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in CR or PR to first-line platinum-based chemotherapy3

• Submitted to EMA for first-line maintenance indication5

Veliparib • Not licensed • Not licensed

Phase III trials of PARP inhibitors in first-line maintenance for ovarian cancer

BD, twice daily; BICR, blinded independent central review; BRCA, BReast CAncer gene; chemo, platinum-based chemotherapy; CR, complete response; HR, hazard ratio;inv, investigator-assessed; m, mutation; PARP, poly(adenosine diphosphate-ribose) polymerase; PFS, progression-free survival; PR, partial response; QD, once daily1. Moore K, et al. New Engl J Med. 2018;379:2495–505; 2. Harter P, et al. Presented at the 21st International Meeting of the European Society of Gynaecological Oncology (ESGO), Athens, Greece, 2–5 November, 2019. [Abstract No. 2123]; 3. González-Martín A, et al. New Engl J Med. 2019;381:2391–402; 4. Coleman RL, et al. N Engl J Med. 2019;381:2403–15

PRIMA3

NCT02655016

PAOLA-12

NCT02477644

VELIA4

NCT02470585

SOLO-11

NCT01844986PR/CR to chemo

(BRCAm only)

Olaparib 300 mg BD vs placebo Stop at 2 years if CR

HR for PFS (inv) 0.30; p<0.001 vs placebo

PR/CR to chemo + bevacizumab

Bevacizumab ± Olaparib 300 mg BD2 years

HR for PFS (inv) 0.59; p<0.0001 vs bevacizumab

PR/CR to chemo, incl. inoperable and

visible residual disease

Niraparib 200/300 mg QD vs placebo3 years

HR for PFS (BICR) 0.62; p<0.001 vs placebo

Veliparib 150 mg BD+chemo Veliparib 300/400 mg BD

Veliparib 150 mg BD+chemo Placebo maintenance

Chemo Placebo maintenance

HR for PFS (inv) with veliparib+chemo→veliparib0.68; p<0.001 vs chemo only

Untreated advanced

stage III/IV ovarian cancer

Upfront/interval surgery

6 cycles 30 cycles

Which factors influence the choice of PARP inhibitor for maintenance treatment?

Dr Susana Banerjee (Chair)Consultant Medical Oncologist,The Royal Marsden NHS Foundation Trust and Reader in Women’s Cancers, The Institute of Cancer Research,London, UK

PARP, poly(adenosine diphosphate-ribose) polymerase

HRD testing in ovarian cancer

ATM/ATR, ataxia-telangiectasia-mutated/ataxia telangiectasia and Rad3-related; BRCA, BReast CAncer gene; EMSY, BCRA2-interacting transcriptional repressor;HRD, homologous recombination deficiency; PTEN, phosphatase and tensin homolog; RAD51C, RAD51 homolog C; TP53, tumour protein 531. Frey MK and Pothuri B. Gynecol Oncol Res Pract. 2017;4:4; 2. Pennington KP, et al. Clin Cancer Res. 2014;20:764-75; 3. Hodgson DR, et al. Br J Cancer. 2018;119:1401–9

• Important germline HRD genes include BRCA1/2, Fanconi anaemia pathway genes, mismatch repair genes, and TP531

- ~24% of ovarian cancers are associated with HRD gene germline mutations2

• Identified somatic mutations include BRCA1/2, EMSY, PTEN, RAD51C, ATM/ATR and Fanconi anaemia genes1

- ~9% of ovarian cancers have HRD gene somatic mutations2

• The Myriad MyChoice® HRD assay scores DNA instability based on loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions3

• A score of ≥42 is usually used to define HRD3

Biomarkers in PARP inhibitor first-line maintenance

† by Myriad myChoice® HRD Plus assay score; * >99% germline mutationsBRCAm, breast cancer gene mutated; bev, bevacizumab; CI, confidence interval; g, germline; HR, hazard ratio; HRD, homologous recombination deficient; HRprof, homologous recombination proficient; t, tissue-based; PARP, poly(adenosine diphosphate-ribose) polymerase; chemo, platinum-based chemotherapy; PFS, progression-free survival; vel, veliparib; wt, wild type1. Harter P, et al. Presented at the 21st International Meeting of the European Society of Gynaecological Oncology (ESGO), Athens, Greece, 2–5 November, 2019. [Abstract No. 2123]; 2. Moore K, et al. New Engl J Med. 2018;379:2495–505; 3. Monk BJ and González-Martín A. Society of Gynecologic Oncology (SGO) Annual Meeting, 2020. [Abstract No. 31]; 4. Coleman RL, et al. N Engl J Med. 2019;381:2403–2415

OlaparibPAOLA-11 vs bev only

HRD cut-off† ≥42

HRD: 0.33HRD

tBRCAm: 0.31tBRCAwt: 0.43

HRprof 0.92

HR values for PFS vs control

PRIMA3 vs placeboHRD cut-off† ≥42

HRD: 0.43HRD

tBRCAm: 0.40tBRCAwt: 0.50

HRprof 0.68

NiraparibVELIA4 vel+chemo→vel vs chemo only

HRD cut-off† ≥33

Veliparib

HRD: 0.57HRD

BRCAm: 0.44

HRprof 0.81

SOLO-12 vs placebo

gBRCAm*0.30

Values in BOLD: p≤0.05 or 95% CI <1

gBRCAm0.50

tBRCAm0.35

Factors influencing patient preference for maintenance therapy1

GI, gastrointestinal; PFS, progression-free survival1. Sun CC, et al. Society of Gynecologic Oncology (SGO) Annual Meeting, 2020. [Abstract No. 81]

Treatment modality and schedule

Physician recommendation

Efficacy and PFS benefit

Cost

Adverse events and need for routine monitoring and supportive careGI and haematologic events, fatigue

How can we proactively manage PARP inhibitor-related adverse events to improve quality of life for patients?

Dr Susana Banerjee (Chair)Consultant Medical Oncologist,The Royal Marsden NHS Foundation Trust and Reader in Women’s Cancers, The Institute of Cancer Research,London, UK

PARP, poly(adenosine diphosphate-ribose) polymerase

Adverse events with PARP inhibitors1–4

AE, adverse event; AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome; PARP, poly(adenosine diphosphate-ribose) polymerase 1. Moore K, et al. New Engl J Med. 2018;379:2495–505; 2. Ray-Coquard I, et al. New Engl J Med. 2019;381:2416–28; 3. Monk BJ and González-Martín A. Society of Gynecologic Oncology (SGO) Annual Meeting2020. [Abstract No. 31]; 4. Coleman RL, et al. N Engl J Med. 2019;381:2403–15

Anaemia • All grades: 39–64%• Grade ≥3: 17–38%

Neutropenia• All grades: 18–75%• Grade ≥3: 6–58%

Thrombocytopenia• All grades: 8–58%• Grade ≥3: 1–29%

Nausea/vomiting• All grades: 22–80%• Grade ≥3: <1–8%

Asthenia/fatigue• All grades: 35–69%• Grade ≥3: 2–8%

Diarrhoea/constipation• All grades: 10–44%• Grade ≥3: 0–3%

Haematologic AEs Non-haematologic AEs

Rare AEs

AMLMDS

Pneumonitis

Dose modification and quality of life

AEs, adverse events; EORTC-QLQ, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; NFOSI, National Comprehensive Cancer Network (NCCN)/Functional Assessment of Cancer Therapy (FACT) Ovarian Symptom Index; QoL, quality of life1. Moore K, et al. New Engl J Med. 2018;379:2495–505; 2. Harter P, et al. Presented at the 21st International Meeting of the European Society of Gynaecological Oncology (ESGO), Athens, Greece, 2–5 November 2019. [Abstract No. 2123]; 3. González-Martín A, et al. New Engl J Med. 2019;381:2391–402; 4. Monk BJ and González-Martín A. Society of Gynecologic Oncology (SGO) Annual Meeting, 2020. [Abstract No. 31]; 5. Coleman RL, et al. N Engl J Med. 2019;381:2403–15; 6. Pothuri B, et al. Society of Gynecologic Oncology (SGO) Annual Meeting, 2020. [Abstract No. 83]

VELIA maintenance phase:5

• reduction: 24%• interruption: 41%• discontinuation: 19%

SOLO-1:1

• reduction: 28%• interruption: 52%• discontinuation: 12%PAOLA-1 (with bevacizumab):2

• reduction 41%• interruption 54%• discontinuation: 20%

PRIMA:3

• reduction: 71%• interruption: 80%• discontinuation: 12%→200 mg dose for patients <77 kg and/or platelets <150,000/mm3

• Reduction in Grade ≥3 events with dose individualization4

Olaparib Niraparib Veliparib

Dose modification due to AEs

Effect on QoL

PRIMA:6

No difference in QoL between groups on EORTC-QLQ-C30 or EORTC-QLQ-OV28

SOLO-1:1

Stable Trial Outcome Index score over 2 years with no clinically meaningful difference between groups

VELIA maintenance phase:5

NFOSI-18 Disease Related Symptom scores improved over time, with no clinically significant difference between groups

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