TESARO Pioneers Summit

TESARO Pioneers Summit
November 9–10, 2018 Hilton Rome Airport, Italy This meeting is organized and funded by TESARO Bio GmbH November 2018 | NP-ZEJ-INT-0004

Welcome and introductions
Patrik Zintl TESARO Bio GmbH, Zug, Switzerland

Housekeeping In the event of a fire, please follow the signposted fire exits Please switch your mobile phones and other devices to silent The toilets are located in the lobby

TESARO mission TESARO is a biopharmaceutical company devoted to providing transformative therapies to people bravely facing cancer. We see new possibilities to responsibly develop and commercialize innovative treatments where others may not. Relationships are vital to the success of our business, and we are committed to being a trusted partner to the cancer community.

A balanced portfolio of product candidates
Compound Therapeutic area Discovery Preclinical Phase I Phase II Phase III Registration Niraparib (PARP inhibitor) First-line ovarian cancer maintenance (PRIMA) Recurrent ovarian cancer treatment (QUADRA) + anti-PD-1 mAb and niraparib monotherapy Advanced NSCLC, squamous cell carcinoma of the lung (JASPER) + bevacizumab First-line ovarian cancer maintenance (OVARIO) Ovarian cancer (AVANOVA)* + pembrolizumab Ovarian cancer / triple-negative breast cancer (TOPACIO) TSR-042 (anti-PD-1 mAb) MSI-H tumors, including metastatic endometrial cancer (GARNET) TSR-042 ± bevacizumab + niraparib or carboplatin-paclitaxel Advanced or metastatic cancer TSR-022 (anti-TIM-3 mAb) ± TSR-042 Various tumor types (AMBER) TSR-033 (anti-LAG-3 mAb) Various tumor types (CITRINO) TSR-075 (PD-1/LAG-3 bispecific mAb) Various tumor types Undisclosed biologics and small molecule I-O candidates Registrational trial Confidential – for business discussion purposes. *In collaboration with ENGOT. ENGOT, European Network for Gynaecological Oncological Trial groups; I‑O, immuno-oncology; LAG-3, lymphocyte activation gene-3; mAb, monoclonal antibody; MSI-H, microsatellite instability – high; NSCLC, non–small cell lung cancer; PARP, poly(ADP-ribose) polymerase; PD-1, programmed cell death protein-1; TIM-3, T-cell immunoglobulin and mucin domain-containing protein 3.

Building a leading oncology franchise
Robust oncology portfolio led by ZEJULA ZEJULA PARP inhibitor Development programs ongoing with monotherapy and combinations in ovarian, lung, and breast cancers TSR-042 Anti-PD-1 Enables strategic development and commercial flexibility in combination with ZEJULA, TSR-022, and TSR-033 TSR-022 Anti-TIM-3 NSCLC, melanoma, and CRC TSR-033 Anti-LAG-3 Multiple tumor types TSR-075 Anti-PD-1/LAG-3 bispecific Approved in the USA and Europe Registration trial ongoing in MSI-H tumors TSR-042 combination trial ongoing IND-enabling studies  Immuno-oncology Niraparib Click here for more information on TESARO products and pipeline CRC, colorectal cancer; IND, investigational new drug; LAG-3, lymphocyte activation gene-3; MSI-H, microsatellite instability – high; NSCLC, non–small cell lung cancer; PARP, poly(ADP-ribose) polymerase; PD-1, programmed cell death protein-1; TIM-3, T-cell immunoglobulin and mucin domain-containing protein 3.

Welcome to the TESARO Pioneers Summit
At this meeting, we hope that you will: Develop and practice skills for presenting scientific data Learn about the key niraparib clinical trial data and how to apply these in the real‑world setting Broaden your knowledge of clinical trial design and the use of statistics to interpret study data Share experiences of the real‑world use of niraparib since its launch in Europe Connect with colleagues from across Europe and enjoy the opportunity to engage and participate in discussions with fellow experts in the field

Domenica Lorusso, MD, PhD Claudia Marchetti, MD, PhD
Our faculty Domenica Lorusso, MD, PhD Fondazione IRCCS National Cancer Institute, Italy Joachim Gerß, PhD Institute of Biostatistics and Clinical Research, Germany Claudia Marchetti, MD, PhD Sapienza University of Rome, Italy Kenrick Ng, MD UCL Cancer Institute, UK Vanda Salutari, MD Policlinico Universitario Agostino Gemelli, Italy IRCCS, Istituto di Ricovero e Cura a Carattere Scientifico; UCL, University College London.

Agenda – Day 1 Time Session Speaker/moderator 13:30–13:35
Welcome and introductions Patrik Zintl 13:35–13:45 Look back on the January Pioneers Summit Kenrick Ng 13:45–13:55 PARP inhibitors: Addressing unmet needs in recurrent ovarian cancer Vanda Salutari 13:55–14:30 Introduction to PARP inhibition and niraparib Claudia Marchetti 14:30–15:00 Maintenance therapy with PARP inhibitors Part 1: Clinical efficacy and safety of niraparib in the Phase III NOVA trial Domenica Lorusso 15:00–15:15 Maintenance therapy with PARP inhibitors Part 2: Changing clinical practice for recurrent ovarian cancer 15:15–15:30 Coffee break PARP, poly(ADP-ribose) polymerase.

Agenda – Day 1 (continued)
Time Session Speaker/moderator 15:30–15:50 Understanding statistics in oncology trials – Presentation Joachim Gerß 15:50–16:20 Understanding statistics in oncology trials – Workshop 16:20–16:45 Maintaining outcomes with dose adjustment and individualization Domenica Lorusso 16:45–17:30 Panel discussion: Practical experiences with niraparib Panel 17:30–17:50 Niraparib: Looking forward Patrik Zintl 17:50–18:00 Summary and close 19:00 Dinner

Look back on the January Pioneers Summit
Kenrick Ng, MD UCL Cancer Institute, UK This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Disclosures The content and interpretation of this presentation are the view and comment of the speaker and not of TESARO

The January Pioneers Summit
Two-day program held on January 18–19, 2018, at the Catalonia Barcelona Plaza Hotel, Spain Attended by 26 delegates from 6 countries

Overview of Day 1 Interactive presentations and workshops delivered by an international panel of experts. Topics included: Recurrent ovarian cancer: Treatment landscape Introduction to PARP inhibition Clinical safety and efficacy of niraparib in Phase I Niraparib: A durable, selective PARP inhibitor Clinical efficacy of niraparib in the Phase III NOVA trial Maintaining efficacy with dose adjustment Niraparib: Looking forward Putting niraparib data into context (workshop) PARP, poly(ADP-ribose) polymerase.

Overview of Day 2 Delegate presentations Country Number of delegates
AUSTRIA 5 FINLAND 1 GERMANY 7 SPAIN SWITZERLAND UNITED KINGDOM

Presentation skills Purpose: To empower delegates to deliver impactful, informative, and memorable presentations Format: Delegates were split into small groups (based on language) and guided by an enthusiastic facilitator from Excel Communications

Personalized coaching
Developed skills for delivering presentations directed at medical professionals Practiced presenting scientific and clinical data Individual group sessions were conducted in participants’ native language Clinical expert/advisor on niraparib was available to support with individual discussion and help delegates understand niraparib data

Group presentation Very well received (definitely my favorite part of the two days!) Each group was given a different patient case scenario and asked how they would manage the patient Option of presenting in native language (one of the most passionate deliveries was in German!) Facilitated by experts in the field, with emphasis on Q&A focusing on: When maintenance therapy is not suitable (e.g. burden of disease) Anecdotal experience of starting dose of niraparib vs. licensed doses Regularity of monitoring for thrombocytopenia

Impact on individual and institution
Continued relationship with TESARO TESARO representatives maintain contact (if desired) and sponsor study days for consultants and specialist trainees within my institution and the rest of London Keep abreast of exciting R&D developments within TESARO Networking with clinicians within the UK and other countries Practical experience of using niraparib and extending this knowledge to the use of other PARP inhibitors and, to a broader sense, gynecologic cancers PARP, poly(ADP-ribose) polymerase.

PARP inhibitors: Addressing unmet needs in recurrent ovarian cancer
Vanda Salutari, MD Policlinico Universitario Agostino Gemelli, Italy PARP, poly(ADP-ribose) polymerase. This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Disclosures Grants: TBC Honoraria: TBC Consulting fees: TBC
To be provided by speaker. Grants: TBC Honoraria: TBC Consulting fees: TBC Investments: TBC Other: TBC Presentation materials: TESARO Bio GmbH

Ovarian carcinoma is a common cancer that is often lethal
most common female cancer after breast, cervical, and corpus uteri carcinoma*,1 3.4% of an estimated 8.6 million new cases of cancer in women worldwide in 2018*,1 8th most common cause of cancer-related mortality in women worldwide*,1 1st most lethal gynecologic cancer in women in the USA2 Ovarian cancer is the most lethal gynecologic malignancy3 *Based on GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. 1. Bray F et al. CA Cancer J Clin 2018; Epub ahead of print (DOI: /casc.21492). 2. Karakashev S et al. Cell Rep ; 21 (12): 3398– Chan JK et al. Clin Exp Metastasis 2018; Epub ahead of print (DOI: /s10585–018–9889). 22

Advanced ovarian cancer is a disease with multiple relapses
Despite a high initial response rate, around 70% of patients with ovarian cancer will experience disease recurrence1,2 After the first recurrence, definitive cure is almost impossible2 Disease-free survival in patients with ovarian cancer1 First-line chemotherapy Platinum‑sensitive relapse Platinum‑resistant relapses Surgery * Occlusion Symptoms 4 months CA-125 (mU/mL) 8 months PFI: 12 months Months CA-125, cancer antigen-125; PFI, platinum-free interval or duration of disease control without chemotherapy. 1. Giornelli GH. Springerplus 2016; 5 (1): About ovarian cancer: Recurrence. Available at: Accessed October 2018. 23

Next line of chemotherapy
Treatment of advanced ovarian cancer aims to extend the treatment‑free (watch and wait) interval Debulking surgery Next line of chemotherapy Chemotherapy Watch and wait Treatment-free interval Tumor volume Recurrence Symptoms Time PARP, poly(ADP-ribose) polymerase. Adapted from DiSilvestro P et al. Cancer Treat Rev 2018; 69: 53–65.

‘Watch and wait’ was the prior standard of care for recurrent ovarian cancer
Many women who recur and are treated with chemotherapy then undergo ‘watch and wait’ or a ‘drug holiday’1 However: Platinum-based chemotherapy is less effective over time PFS and PFI become shorter after every treatment regimen Cumulative toxicities increase with each cycle2 Ending active treatment generates anxiety, referred to as fear of relapse/recurrence (FCR) Several studies have demonstrated that around half of women living with ovarian cancer experience FCR3 In a cross‑sectional survey of women with ovarian cancer (N=50), 78% listed FCR as their top unmet need3 PFI, progression-free interval; PFS, progression-free survival. 1. Giornelli GH. Springerplus 2016; 5. (1): Cumulative toxicity increase: Dunton CJ, Management of treatment-related toxicity in advanced ovarian cancer. Oncologist 2002; 7 (Suppl 5): Ozga M et al. Palliat Support Care 2015; 13 (6): 1771–1780.

Fear of disease recurrence is a psychological burden
Psychological assessments of survivors of early-stage ovarian cancer (N=58)1 Survivors (%) Score below normal on the MHI‑17 survey Report anxiety when CA‑125 levels tested Fear cancer recurrence Score suggestive of PTSD CA‑125, cancer antigen‑125; MHI‑17, Mental Health Inventory‑17; PTSD, post-traumatic stress disorder. 1. Matulonis UA et al. Int J Gynecol Cancer 2008; 18 (6): 1183–1193.

The watch-and-wait approach is burdensome to patients and healthcare systems
Harrow et al. (2017) performed a retrospective database analysis of 1,312 patients with recurrent ovarian cancer in the USA, who had received ≥2 lines of platinum-based therapy The median duration of watch-and-wait period was 162 days During watch-and-wait period: Inpatient admissions: ER visits: Median time to first inpatient admission: 56 days Median time to the first ER visit: 68 days 395 patients (30.1%) had inpatient admission The mean length of stay was 10 days 359 patients (27.4%) had an ER visit Most common reasons for inpatient admission: Malignant neoplasm of the ovary, n=59 (9.1%); intestinal obstruction, n=41 (6.3%) Most common reasons for ER visit: Abdominal pain, n=112 (15.4%); malignant neoplasm of the ovary, n=42 (5.8%) Effective maintenance therapies may reduce the burden on patients with ovarian cancer and healthcare systems ER, emergency room. Harrow B et al. Poster 962P presented at ESMO 2017; Madrid, Spain, September 8–12, 2017.

The goal of maintenance therapy is to slow the rate of disease progression and lengthen life
Considerations for maintenance therapy for patients with recurrent ovarian cancer include: The watch-and-wait approach is burdensome for patients and healthcare systems1 Effective treatment is now available2,3 Why treat? Maintenance therapy should: Be effective Be convenient Have low impact on QoL Have low cumulative toxicity Which treatment? All patients with recurrent disease who have responded to chemotherapy treatment Who should be treated? QoL, quality of life. 1. Harrow B et al. Poster 962P presented at ESMO 2017; Madrid, Spain, September 8–12, Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274– Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Next line of chemotherapy
The introduction of PARP inhibitors for maintenance therapy resulted in a paradigm shift in ovarian cancer care Debulking surgery Next line of chemotherapy Chemotherapy Watch and wait Treatment-free interval Tumor volume Recurrence Symptoms Time PARP, poly(ADP-ribose) polymerase. Adapted from DiSilvestro P et al. Cancer Treat Rev 2018; 69: 53–65.

PARP inhibitor maintenance therapy
The introduction of PARP inhibitors for maintenance therapy resulted in a paradigm shift in ovarian cancer care Debulking surgery Chemotherapy PARP inhibitor maintenance therapy Tumor volume Treatment-free interval Symptoms Point of decision Maintenance Time PARP, poly(ADP-ribose) polymerase. Adapted from DiSilvestro P et al. Cancer Treat Rev 2018; 69: 53–65.

Despite positive data from several clinical studies, utilization of PARP inhibitors for maintenance therapy is low Patients (%) BRCAmut BRCAwt BRCA status unknown BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; Chemo, chemotherapy; PARP, poly(ADP-ribose) polymerase; Waiting, watch and wait. 1. Maintenance of patients who had platinum-chemo treatment for 4-8 cycles. Analysis report; June 27, Data source: US Flatiron (April 2018 data).

Summary Ovarian carcinoma is a common cancer that is often lethal1,2
Advanced ovarian cancer is a disease with multiple relapses; response to treatment declines with each recurrence3 The prior standard of care for advanced recurrent ovarian cancer was ‘watch and wait’, which is burdensome for patients and healthcare systems4 An alternative option is to provide maintenance therapy, which aims to slow the rate of disease progression and lengthen life3–5 PARP inhibitors have proven to be effective in the second‑line treatment setting in patients with ovarian cancer and resulted in a paradigm shift in ovarian cancer care6,7 Despite this, utilization of PARP inhibitors for maintenance therapy is low8 PARP, poly(ADP-ribose) polymerase. 1. Bray F et al. CA Cancer J Clin 2018; Epub ahead of print (DOI: /casc.21492). 2. Chan JK et al. Clin Exp Metastasis 2018; Epub ahead of print (DOI: /s10585–018–9889). 3. Giornelli GH. Springerplus 2016; 5 (1): Harrow B et al. Poster 962P presented at ESMO 2017; Madrid, Spain, September 8–12, DiSilvestro P et al. Cancer Treat Rev 2018; 69: 53–65. 6. Pujade-Lauraine E et al. Lancet Oncol 2017; 18: 1274– Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Maintenance of patients who had platinum-chemo treatment for 4-8 cycles. Analysis report; June 27, 2018.

Introduction to PARP inhibition and niraparib
Claudia Marchetti, MD, PhD Sapienza University of Rome, Italy PARP, poly(ADP-ribose) polymerase. This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

PARP inhibitors: Mechanisms of action
PARP, poly(ADP-ribose) polymerase.

DNA repair protects the genome from deleterious mutation
DNA damage Unrepaired SSBs in dividing cells Single-strand breaks (SSBs) Double-strand breaks (DSBs) Mismatch repair Nucleotide excision repair Base excision repair Homologous recombination Highly accurate Non-homologous end joining Error prone Adapted from Jones P et al. 2015 Homologous recombination is mediated by several proteins, including BRCA1 and BRCA2 BRCA, breast cancer susceptibility gene protein. Jones P et al. J Med Chem 2015; 58 (8): 3302–3314. 35

Impaired homologous recombination can lead to tumor development
Homologous recombination is an essential process that accurately repairs DSBs Proteins such as BRCA1 and BRCA2 are key mediators of homologous recombination; mutated versions of these proteins can lead to tumor development Impaired homologous recombination in cells leads to: Genomic instability due to use of impaired low-fidelity repair mechanisms Tumor development due to uncontrolled growth and survival Acquisition of deleterious mutations during cell division or after DNA damage BRCA, breast cancer susceptibility gene protein; DSB, double-strand break. Jones P et al. J Med Chem 2015; 58 (8): 3302–3314.

Germline BRCA mutations are present in a small proportion of patients with ovarian cancer
Germline BRCA mutations are hereditary1 Approximately 17% of patients with high-grade serous ovarian cancer have a germline BRCA mutation2 ~17% gBRCA BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation. 1. Jones P et al. J Med Chem 2015; 58 (8): 3302– Cancer Genome Atlas Research Network. Nature 2011; 474 (7353): 609–615.

~25% non‑BRCA HR‑deficient
DNA repair defects other than BRCA mutations are present in a high proportion of patients About one quarter of women with high-grade serous ovarian cancer have other HR deficiencies ~49% HR‑proficient ~25% non‑BRCA HR‑deficient ~17% gBRCA ~3% sBRCA ~5% other BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; HR, homologous recombination; sBRCA, somatic BRCA mutation. Cancer Genome Atlas Research Network. Nature 2011; 474 (7353): 609–615.

Loss of heterozygosity (LOH)
In addition to HRD, genomic instability may indicate deficiencies in DNA repair Genomic instability1 Loss of heterozygosity (LOH) Chromosomal alterations, nucleotide substitutions, insertions, and deletions that accumulate in the absence of DNA repair because of mutations to DNA repair genes These genomic changes can alter cell behavior, drive development of malignancy, and influence response to therapy Loss of a wild-type allele in the presence of a mutated gene allele produces an abnormal or non‑functional locus2 LOH is common in individuals with an inherited cancer predisposition syndrome (e.g. BRCA1 or BRCA2)3 BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency. 1. Lord CJ et al. Nature 2012; 481 (7381): 287– Merajver SD et al. Clin Can Res 1995; 1 (5): 539– Ryland GL et al. BMC Med Genomics 2015; 8: 45.

Testing for LOH alone may not give a complete picture of HRD
The NOVA trial used a DNA-based assay designed to detect multiple biomarkers of HRD, rather than LOH alone1,2 DNA Repair BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; LOH, loss of heterozygosity. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Myriad. Data on file.

Tumor BRCA1/2 sequence analysis Genomic instability score
In the NOVA trial, genomic instability was tested: Score is the sum of LOH, LST, and TAI Tumor BRCA1/2 sequence analysis HRD result Genomic instability score (LOH, LST, TAI) Loss of heterozygosity (LOH) The combined genomic instability score is the unweighted sum of LOH + LST + TAI Each biomarker is a type of genomic error resulting from HRD Score range is 0–100 Score of ≥42 = HRD positive Score of <42 = HRD negative Large-scale state transitions (LST) Telomeric allelic imbalance (TAI) BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency. Myriad. Data on file.

Inhibition of PARP can lead to accumulation of double-strand breaks
Single-strand breaks Double-strand breaks PARP inhibitor Base excision repair (BER) Homologous recombination (HR) Non-homologous end joining (NHEJ) Microhomology-mediated end joining (MMEJ) High-fidelity DNA repair High-fidelity DNA repair Error-prone DNA repair Error-prone DNA repair BER is inhibited Accurate repair of double-strand breaks is largely reliant upon homologous recombination Limited effect in normal cells PARP, poly(ADP-ribose) polymerase. Figure adapted from Konecny GE et al. Br J Cancer 2016; 115 (10): 1157–1173.

Inhibiting PARP in cells that are HR deficient increases genomic stability
Single-strand breaks Double-strand breaks PARP inhibitor HR deficiency Base excision repair (BER) Homologous recombination (HR) Non-homologous end joining (NHEJ) Microhomology-mediated end joining (MMEJ) High-fidelity DNA repair High-fidelity DNA repair Error-prone DNA repair Error-prone DNA repair BER is inhibited HR-deficient cells are highly reliant on PARP to maintain genomic stability1 PARP, poly(ADP-ribose) polymerase. Figure adapted from Konecny GE et al. Br J Cancer 2016; 115 (10): 1157–1173. 1. Ohmoto A et al. Onco Targets Ther 2017; 10: 5195–5208.

Accumulation of DNA damage in these cells can lead to cell death
Single-strand breaks Double-strand breaks PARP inhibitor HR deficiency Base excision repair (BER) Homologous recombination (HR) Non-homologous end joining (NHEJ) Microhomology-mediated end joining (MMEJ) High-fidelity DNA repair High-fidelity DNA repair Error-prone DNA repair Error-prone DNA repair BER is inhibited Lack of high-fidelity repair mechanism Error-prone repair of DSBs and accumulation of DNA damage Cell death PARP, poly(ADP-ribose) polymerase. Figure adapted from Konecny GE et al. Br J Cancer 2016; 115 (10): 1157–1173.

PARP inhibitors may cause cell death in HR‑deficient cells via several mechanisms
Inhibition of PARP-mediated SSB repair: Leads to collapse of replication forks Obstructing replication forks by trapping PARP: Leads to blocked DNA repair Preventing restart of stalled replication forks: Leads to blocked DNA repair Collapsed fork Stalled fork Inhibited PARP Trapped PARP Inhibited PARP PARP inhibitor PARP inhibitor PARP inhibitor Different PARP inhibitors have shown different potencies for inhibiting PARP via these mechanisms: Olaparib Rucaparib Niraparib Talazoparib Veliparib Iniparib ? ? This slide is adapted from a presentation by Thomas Helleday available on the PRIME oncology website Not yet investigated ? ? ? ? HR, homologous recombination; PARP, poly(ADP-ribose) polymerase; SSB, single-strand break. Figure adapted from PARP inhibition and ovarian cancer: Leading the field in exploiting DNA repair as a therapeutic target. Available at: Accessed October 2018. Helleday T. Mol Oncol 2011; 5 (4): 387–393.

Niraparib selectively inhibits PARP1 and PARP2
Niraparib is highly selective for PARP1 and PARP2 in vitro1 Talazoparib and rucaparib are less selective and inhibit tankyrase 1 and 2 (PARP5a/b) in vitro1 Tankyrase inhibition has been linked with severe gastrointestinal toxicity in mice2 IC50 of PARP inhibitors determined by in vitro assays1 PARP1 PARP2 PARP3 TNKS1 TNKS2 PARP6 PARP7 PARP8 PARP10 Niraparib 2.8 nM 0.6 nM >1 µM Olaparib 1.4 nM 0.8 nM 33 nM NA 722 nM Rucaparib 0.3 nM 39 nM 201 nM 135 nM 787 nM Talazoparib 1.0 nM 0.4 nM 29 nM 15 nM 6.7 nM 988 nM 588 nM <10 nM 10 nM – 100 nM 100 nM – 1 µM >1 µM IC50, half maximal inhibitory concentration; PARP, poly(ADP-ribose) polymerase; NA, not available; TNKS, tankyrase. 1. Wang S et al. Presentation at the 28th EORTC-NCI-AACR Symposium; Munich, Germany, November 29 – December 2, Zhong Y et al. Toxicol Pathol 2016; 44 (2): 267–278.

Niraparib ‘traps’ PARP on DNA
PARP trapping occurs when the dissociation of PARP from DNA is inhibited Trapped PARP–DNA complexes are more cytotoxic than unrepaired single‑strand breaks caused by PARP inactivation Drug concentration (µmol/L) 0.10 0.01 1.00 10.0 100 120 140 160 Fluorescence anisotropy (mA) Biochemical trapping of PARP by PARP inhibitors Olaparib Niraparib Veliparib PARP, poly(ADP-ribose) polymerase. Murai J et al. Cancer Res 2012; 72 (21): 5588–5599.

Evidence from preclinical studies with niraparib

Change in tumor volume during treatment
Niraparib antitumor activity was sustained and not limited by platinum resistance Mice with resistance to carboplatin were shown to have tumor regression when treated with niraparib After being dosed with carboplatin, which they did not respond to, mice received 50 mg/kg/day niraparib Tumors of 2 out of 3 models evaluated regressed completely, and regression was maintained after cessation of treatment 50 1,000 200 150 100 500 1,500 2,000 Change in tumor volume during treatment Tumor volume (mm³) Study day Niraparib dosing stopped Carboplatin > niraparib Carboplatin Mikule K et al. Abstract #716 presented at ECCO 2017; Amsterdam, Netherlands, January 27–30, 2017.

The concentration of niraparib in tumor tissue was higher than that of olaparib
In mice bearing ovarian cancer patient–derived tumor xenografts, the concentration of niraparib in tumor tissue was 3- to 5-fold higher than in plasma At steady state, the concentration of niraparib in tumor tissue was approximately 30-fold higher than that of olaparib Plasma concentration (ng/mL) Tumor concentration (ng/g) Tumor/plasma ratio 6 h after final dose ± SD (steady state) 24 h after final dose ± SD (steady state) 6 h and 24 h Niraparib (50 mg/kg) 1,219 ± 343 62 ± 8 3,837 ± 1,987 345 ± 146 3.1–5.5 Olaparib (75 mg/kg) 168 ± 87 ND 123 ± 32 0.7–ND ND, not determined; SD, standard deviation. Mikule K et al. Abstract #716 presented at ECCO 2017; Amsterdam, Netherlands, January 27–30, 2017.

Individual tumor volume on Day 9
Niraparib demonstrated superior inhibition of tumor growth compared with olaparib in HRD-negative xenograft tumor models Mice bearing BRCAwt, HRD-negative ovarian tumor xenografts that were treated with niraparib exhibited greater reductions in tumor growth than those treated with olaparib Tumor growth Individual tumor volume on Day 9 1,000 500 1,500 2,000 2,500 3,000 2 4 6 8 10 Time (days) P=0.005 Tumor volume (mm³) 2,000 1,000 3,000 4,000 5,000 6,000 Vehicle Olaparib Niraparib Tumor volume (mm³) Vehicle Olaparib Niraparib TGI percentage (Day 9) P-value* Niraparib (62.5 mg/kg QD) 56.4 0.003 Olaparib (100 mg/kg QD) 15.6 0.267 *Compared with vehicle. BRCA, breast cancer susceptibility gene; BRCAwt, BRCA wild-type; HRD, homologous recombination deficiency; QD, once a day; TGI, tumor growth inhibition. Sun K et al. Oncotarget; In press. Sun K et al. Poster presented at AACR-NCI-EORTC 2017; Philadelphia, PA, USA, October 26–30, 2017.

Switching from olaparib to niraparib led to tumor regression
When a mouse bearing a BRCA2mut, platinum-sensitive tumor xenograft (OV5311) was switched from olaparib to niraparib*, tumor regression was observed Change in tumor volume in a single mouse 1,000 500 1,500 20 60 40 Study day 80 100 Tumor volume (mm³) Day 44: Switch to niraparib Control Olaparib Olaparib > niraparib *Olaparib was dosed at 75 mg/kg/day; niraparib was dosed at 50 mg/kg/day. BRCA, breast cancer susceptibility gene; BRCA2mut, BRCA2 mutation. Mikule K et al. Abstract #716 presented at ECCO 2017; Amsterdam, Netherlands, January 27–30, 2017.

Niraparib 300 mg orally once daily, 28‑day cycles
The concentration of niraparib in tumor tissue observed in preclinical studies* may offer a clinically meaningful benefit Niraparib was the first PARP inhibitor to demonstrate antitumor activity in a real‑world, late‑line treatment setting1 The QUADRA study is a Phase II study designed to evaluate the safety and efficacy of niraparib in patients with recurrent ovarian cancer who have received 3 or 4 previous chemotherapy regimens1,2 Study design1,2 Patients (N=463) with histologically diagnosed advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 3 or 4 previous chemotherapy regimens Niraparib 300 mg orally once daily, 28‑day cycles Endpoint assessment Primary endpoint ORR in HRD‑positive, platinum‑sensitive, PARP inhibitor–naive patients who have received 4 or 5 lines of chemotherapy (n=45) *In mice bearing ovarian cancer patient–derived tumor xenografts, the concentration of niraparib in tumor tissue was 3- to 5-fold higher than in plasma. At steady state, the concentration of niraparib in tumor tissue was approximately 30-fold higher than that of olaparib.3 HRD, homologous recombination deficiency; ORR, objective response rate; PARP, poly(ADP-ribose) polymerase. 1. Moore KN et al. Abstract #5514 presented at ASCO 2018; Chicago, IL, USA, June 1–5, ClinicalTrials.gov QUADRA. Available at: Accessed October 2018.

QUADRA: Clinical benefit rate (CBR16)1
The clinical benefit observed in QUADRA extends beyond the primary endpoint population QUADRA: Clinical benefit rate (CBR16)1 Patients (%) Platinum-sensitive or ‑ineligible* Platinum-resistant or -refractory† BRCAmut HRDpos BRCAwt/ HRDpos HRDneg/ unknown *Platinum‑sensitive is defined as time from last platinum‑based treatment until next progression ≥6 months, including platinum-ineligible. †Platinum‑resistant is defined as time from last platinum‑based treatment until next progression between 28 days and 6 months; platinum‑refractory is defined as progression on or within 28 days from last platinum‑based treatment. BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; CBR16, clinical benefit rate (complete response + partial response + stable disease for at least 16 weeks); HRD, homologous recombination deficiency; HRDpos, HRD positive; HRDneg, HRD negative. 1. Moore KN et al. Abstract #5514 presented at ASCO 2018; Chicago, IL, USA, June 1–5, 2018.

Niraparib: Clinical safety and efficacy in Phase I

Niraparib Phase I study: Design
(N=100) Phase I dose-escalation study in patients with advanced solid tumors who were not suitable for established therapies*,1 Part A: Accelerated dose escalation (N=60) enrolled in cohorts of three to six1 30 mg (n=6) 40 mg (n=3) 60 mg (n=7) 80 mg 110 mg (n=5) 150 mg 210 mg 290 mg 300 mg (n=10) 400 mg Part B: Dose expansion at a recommended Phase II dose of 300 mg (n=40)1 Platinum-resistant high-grade serous ovarian cancer (n=22)1 Castration-resistant prostate cancer (CRPC; n=18)1 *Eligible patients were aged ≥18 years, had a life expectancy of ≥12 weeks, had an ECOG Performance Status of ≤2, had assessable disease, were not suitable to receive any established treatments, had adequate organ function, and had discontinued any previous anticancer treatments ≥4 weeks previously. ECOG, Eastern Cooperative Oncology Group. 1. Sandhu SK et al. Lancet Oncol 2013; 14 (9): 882–892.

Niraparib demonstrated antitumor activity* in BRCAwt patients
Of 49 patients with ovarian cancer, 42 could be assessed; 22 were not carriers of BRCA1 or BRCA2 mutations (BRCAwt) Five of these BRCAwt patients achieved RECIST and/or CA-125 GCIG partial response 67% (2/3 patients) were deemed platinum sensitive and 16% (3/19 patients) were deemed platinum resistant Non-BRCA related Best change in size of target lesions from baseline 100 50 −50 −100 400 mg 300 mg 290 mg 210 mg 150 mg 110 mg 80 mg 60 mg 30 mg 40 mg Prostate Breast Ovarian Colorectal Hemangiopericytoma Renal Melanoma Rectal Adenoid cystic carcinoma NSCLC †Platinum-resistant disease ‡Platinum-sensitive disease *Defined as RECIST and/or CA-125 GCIC partial response. BRCA, breast cancer susceptibility gene; BRCAwt, no BRCA mutations; CA-125, cancer antigen-125; GCIG, Gynecologic Cancer Intergroup; NSCLC, non–small cell lung carcinoma; RECIST, Response Evaluation Criteria in Solid Tumours. Sandhu SK et al. Lancet Oncol 2013; 14 (9): 882–892.

Niraparib: A durable and selective PARP inhibitor

Niraparib has a favorable PK profile
Absorption Distribution Metabolism Elimination F (%) Papp (10−6 cm/s) Vd/F (L) Major enzyme t½ (h) Niraparib 731 12–182 1,0741 CE1 48–511 Absorption Distribution Metabolism Elimination F (%) Papp (10−6 cm/s) Vd/F (L) Major enzyme t½ (h) Olaparib ND3 4–84 1675 CYP3A45 11.95 Absorption Distribution Metabolism Elimination F (%) Papp (10−6 cm/s) Vd/F (L) Major enzyme t½ (h) Rucaparib 366 6–87 113–2626 CYP2D66 17–196 Niraparib is characterized by: High tumor penetration – largest volume of distribution No relevant drug–drug interaction Once-daily dosing with or without food1 F, bioavailability; ND, not determined; Papp, apparent permeability; PK, pharmacokinetic; t½, half-life; Vd, volume of distribution. 1. TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018. 2. TESARO, Inc. Data on file. 3. CHMP Assessment Report: Lynparza (EMA/CHMP/789139/2014). Available at: Accessed October 2018. 4. Clinical pharmacology and biopharmaceutics review: Lynparza. Available at: Accessed October 2018. 5. AstraZeneca AB. LYNPARZA – summary of product characteristics; May Clovis Oncology UK Ltd. RUBRACA – summary of product characteristics; May Durmus S et al. Pharm Res 2015; 32 (1): 37–46

Concentration (ng/mL)
Niraparib demonstrated favorable exposure over olaparib in tumor, plasma, and brain* Mice bearing BRCA1mut tumor xenografts treated with niraparib exhibited greater AUCs in samples from tumor, plasma, and brain than those treated with olaparib 10 100 10,000 1,000 100,000 Concentration (ng/mL) 6 4 2 8 12 14 16 18 20 22 24 Time (hours) Tumor concentration Plasma concentration Brain concentration LLOQ Niraparib 75 mg/kg QD ×5 Olaparib 100 mg/kg QD ×5 Tumor PK Plasma PK Brain PK Cmax (ng/g) AUC0–24h (ng×h/g) Cmax (ng/g) Niraparib 19,100 213,959 7,620 65,077 1,783 18,721 Olaparib 600 7,586 1,773 11,283 89 336 *All mice were treated for 5 days, and samples were collected on the last day of treatment at pre‑dose, 1, 2, 4, 8, 12, and 24 hours post-dose for niraparib and at pre‑dose, 0.5, 1, 2, 6, 12, and 24 hours post-dose for olaparib. AUC0–24h, area under the plasma concentration–time curve from 0 to 24 hours; BRCA, breast cancer susceptibility gene; BRCA1mut, BRCA1 mutation; Cmax, maximum concentration; LLOQ, lower limit of quantification; PK, pharmacokinetics; QD, once a day. Sun K et al. Oncotarget; In press. Sun K et al. Poster presented at AACR-NCI-EORTC 2017; Philadelphia, PA, USA, October 26–30,

The concentration of niraparib in the brain tissue observed in preclinical studies may offer a clinically meaningful benefit Brain metastasis is a rare complication of ovarian cancer; however, incidence has been increasing over time1–3 Patients with ovarian cancer with BRCA mutations have a greater risk of developing brain metastasis within 5 years of primary diagnosis than BRCAwt patients*,4 Therapeutic agents that prolong survival may lead to an increase in the incidence of brain metastasis in patients with ovarian cancer4 Time from ovarian cancer diagnosis to diagnosis of brain metastasis by BRCA status† 1.00 BRCAwt 0.95 Probability of survival BRCAmut 0.90 0.85 0.80 0.75 0.70 0.00 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Duration (months) Probability of developing MBC at 5th year: BRCAmut: 0.057 BRCAwt: 0.014 HR: 4.44 (1.97, 10.00); P<0.0001 *Based on retrospective analysis of 4,515 patients with ovarian cancer. †Kaplan–Meier estimates for the probability of developing brain metastasis based on time-to-event analysis.4 BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; MBC, metastatic brain cancer. 1. Pakneshan SD et al. J Neurooncol 2014; 119: 1–6. 2. Kolomainen DF et al. J Clin Oncol 2002; 20: 982– Piura E et al. ISRN Oncology 2011: Ratner E et al. Abstract presented at ESMO 2018; Munich, Germany, October 19–23, 2018.

Niraparib is a durable and selective PARP inhibitor
Durable suppression of PARP in BRCAmut cell lines1 48 hours Long half-life2 Mean half-life of 48–51 hours, allowing once-daily dosing >90% PARP inhibition up to hours after a single dose1 High bioavailability2 High concentration in tissues relative to plasma2 Absolute bioavailability of approximately 73%, indicating minimal first-pass effect Extensive tissue distribution, with an apparent volume of distribution of 1,074 L2 High selectivity1 Selectively inhibits PARP1 and PARP2, with minimal off-target activity BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; PARP, poly(ADP-ribose) polymerase. 1. Jones P et al. J Med Chem 2015; 58 (8): 3302– TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

Summary In cells with impaired homologous recombination such as cancer cells, inhibiting PARP can lead to accumulation of DNA damage and, ultimately, cell death1 Niraparib is a durable, highly selective PARP inhibitor with a favorable PK profile2–4 Preclinical studies in mouse models support greater antitumor activity of niraparib compared with olaparib: Favorable exposure of niraparib over olaparib in tumor, plasma, and brain5 Superior inhibition of tumor growth by niraparib compared with olaparib in both HRD‑positive and HRD-negative tumor xenograft modules5 Switching from olaparib to niraparib led to tumor regression6 Niraparib also demonstrated clinical antitumor activity in Phase I, irrespective of BRCA status or platinum sensitivity7 The mean terminal half-life of niraparib was 36 hours; RP2D was established at 300 mg once daily, orally Niraparib can be taken once daily, with or without food4 AE, adverse event; BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; PARP, poly(ADP-ribose) polymerase; RP2D, recommended Phase II dose. 1. Konecny GE et al. Br J Cancer 2016; 115 (10): 1157– Jones P et al. J Med Chem 2015; 58 (8): 3302– Wang S et al. Presented at the 28th EORTC-NCI-AACR Symposium; Munich, Germany, November 29 – December 2, TESARO UK Ltd. ZEJULA – summary of product characteristics; February Sun K et al. Oncotarget; In press. 6. Mikule K et al. Abstract #716 presented at ECCO 2017; Amsterdam, Netherlands, January 27–30, Durmus S et al. Pharm Res 2015; 32 (1): 37–46 7. Sandhu SK et al. Lancet Oncol 2013; 14 (9): 882–892.

Maintenance therapy with PARP inhibitors Part 1: Clinical efficacy and safety of niraparib in the Phase III NOVA trial Domenica Lorusso, MD, PhD Fondazione IRCCS National Cancer Institute, Italy PARP, poly(ADP-ribose) polymerase. This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Repeating 28-day cycle (no treatment breaks)‡
NOVA assessed the efficacy of niraparib in both gBRCA and non-gBRCA patients NOVA (N=553) Randomized, double-blind Phase III trial in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer after ≥2 lines of platinum‑based therapy who had a CR or PR to their penultimate platinum-based therapy that lasted ≥6 months gBRCA mutation status assessed using BRACAnalysis® (Myriad Genetics, USA) gBRCA (n=203) Non-gBRCA (n=350)* Randomization 2:1† Randomization 2:1† Niraparib 300 mg once daily (n=138) Placebo once daily (n=65) Niraparib 300 mg once daily (n=234) Placebo once daily (n=116) Endpoint assessment Endpoint assessment Repeating 28-day cycle (no treatment breaks)‡ *In the non-gBRCA cohort, tumors were retrospectively defined as HRD by the myChoice® HRD test (Myriad Genetics). †Randomization occurred no later than 8 weeks after completing the last dose of platinum-based therapy and was stratified according to time to progression after the penultimate platinum regimen (6 to <12 months vs. ≥12 months), use of bevacizumab in conjunction with the penultimate or last platinum regimen (yes vs. no), and best response during the last platinum regimen (complete response vs. partial response). ‡Patients continued study treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, or loss to follow-up (whichever came first). BRCA, breast cancer susceptibility gene; CR, complete response; gBRCA, germline BRCA mutation; HRD, homologous recombination deficiency; non‑gBRCA, no germline BRCA mutation; PR, partial response. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Exploratory patient subgroups
An exploratory analysis of PFS was performed for patients in several biomarker populations Stored tissue samples of tumors from patients in the non-gBRCA cohort were retrospectively tested for HRD using the myChoice® HRD test (Myriad Genetics) 553 patients enrolled Predefined primary efficacy groups Exploratory efficacy subgroups Not analyzed gBRCA (n=203) Non-gBRCA (n=350) HRD-positive (n=162) HRD-negative (n=134) HRD status not determined (n=54) sBRCA (n=47) BRCAwt (n=115) Missing specimen (n=14) Inconclusive result (n=26) Inadequate specimen (n=14) BRCA, breast cancer susceptibility gene; BRCAwt, BRCA wild-type; gBRCA, germline BRCA mutation; HRD, homologous recombination deficiency; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival; sBRCA, somatic BRCA mutation. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

Efficacy was analyzed in the ITT population (all randomized patients)
NOVA study endpoints Primary endpoint Duration of PFS: The time from treatment randomization to the earliest date of disease progression or death from any cause Efficacy was analyzed in the ITT population (all randomized patients) Secondary endpoints Changes from baseline in patient-reported outcomes PFS2* Time to second subsequent therapy Chemotherapy-free interval Overall survival Time to first subsequent therapy Safety Safety was analyzed for the safety population (all patients who received at least one dose of niraparib or placebo) *The time from randomization until assessment of progression during receipt of the next anticancer therapy after the study treatment or until death. ITT, intention-to-treat; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Assessment of primary endpoint (PFS)
PFS was defined as the time from treatment randomization to the date of assessment of progression or death by any cause in the absence of progression, whichever is earlier Computed tomography or magnetic resonance imaging were performed: At baseline Every 8 weeks through cycle 14 Every 12 weeks until treatment discontinuation Progression was assessed by RECIST v.1.1 criteria and clinical criteria using blinded central review by two independent radiologists and an arbiter if necessary, as well as by blinded central clinician review Progressive disease will not be diagnosed in case of CA-125 progression in the absence of at least one of the criteria defined above CA‑125, cancer antigen‑125; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Patient demographics and baseline characteristics
Most patients (>80%) had ovarian cancer; and the majority (>80%) had Stage III or IV disease1,2 gBRCA Non-gBRCA Niraparib (n=138) Placebo (n=65) Niraparib (n=234) (n=116) Median age (range), years1 57 (36–83) 58 (38–73) 63 (33–84) 61 (34–82) Primary tumor site, n (%)2 Ovarian 122 (88.4) 53 (81.5) 192 (82.1) 96 (82.8) Primary peritoneal 7 (5.1) 6 (9.2) 24 (10.3) 8 (6.9) Fallopian tube 9 (6.5) 18 (7.7) 11 (9.5) Cancer stage, n (%)*,1 I–II 23 (16.7) 10 (15.4) 22 (9.4) 5 (4.3) III 95 (68.8) 46 (70.8) 173 (73.9) 86 (74.1) IV 20 (14.5) 9 (13.8) 38 (16.2) 24 (20.7) *Staging was performed with the use of the International Federation of Gynecology and Obstetrics system.1 Data with respect to staging were not available for one patient in the placebo arm in the non-gBRCA cohort.1 One patient in the niraparib arm in the non-gBRCA cohort was Stage 0 at time of diagnosis.1 BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

In both cohorts, stratification factors were well balanced between treatment arms
Almost half of patients had achieved a PR after their most recent platinum regimen1,2 Approximately one-quarter of patients had received prior bevacizumab in conjunction with the penultimate or last platinum therapy1 gBRCA Non-gBRCA Niraparib (n=138) Placebo (n=65) Niraparib (n=234) (n=116) Time to progression after penultimate platinum therapy, n (%)1 6 to <12 months 54 (39.1) 26 (40.0) 90 (38.5) 44 (37.9) ≥12 months 84 (60.9) 39 (60.0) 144 (61.5) 72 (62.1) Best response to most recent platinum therapy, n (%)1 CR 71 (51.4) 33 (50.8) 117 (50.0) 60 (51.7) PR* 67 (48.6) 32 (49.2) 56 (48.3) Prior bevacizumab use, n (%)1 Yes 33 (23.9) 17 (26.2) 62 (26.5) 30 (25.9) No 105 (76.1) 48 (73.8) 172 (73.5) 86 (74.1) *42 patients had at least one tumor lesion >2 cm at baseline per IRC radiological review.2 BRCA, breast cancer susceptibility gene; CR, complete response; gBRCA, germline BRCA mutation; IRC, independent review committee; non‑gBRCA, no germline BRCA mutation; PR, partial response. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. Mahner S et al. Oral presentation at SGO 2017; National Harbor, MD, USA, March 12–15, 2017.

More than one-third of patients had received ≥3 prior lines of platinum-based chemotherapy
Prior treatment gBRCA Non-gBRCA Niraparib (n=138) Placebo (n=65) Niraparib (n=234) (n=116) Prior lines of chemotherapy, n (%)* 1 1 (0.7) 2 70 (50.7) 30 (46.2) 155 (66.2) 77 (66.4) ≥3 67 (48.6) 35 (53.8) 79 (33.8) 38 (32.8) Prior platinum therapies, n (%) <2 79 (57.2) 37 (56.9) 174 (74.4) 87 (75.0) >2 58 (42.0) 28 (43.1) 60 (25.6) 28 (24.1) Unknown 1 (0.9) *Previous chemotherapy data for one non-gBRCA/placebo patient was missing. BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

The NOVA trial Primary efficacy endpoints

Median PFS in the gBRCA cohort Time since randomization (months)
Median PFS was almost four times longer with niraparib than with placebo Niraparib demonstrated a 73% reduction in the risk of disease progression or death Median PFS in the gBRCA cohort Niraparib (n=138) vs. placebo (n=65): HR: 0.27 (95% CI: 0.17–0.41; P<0.001) 100 80 60 PFS (%) 40 20 Median PFS 5.5 months Median PFS months 4 8 12 16 20 24 Time since randomization (months) Niraparib Placebo BRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCA, germline BRCA mutation; HR, hazard ratio; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Median PFS was significantly longer in the niraparib group than in the placebo group
Niraparib demonstrated a 62% reduction in the risk of disease progression or death Median PFS in the non-gBRCA, HRD-positive cohort Niraparib (n=106) vs. placebo (n=56): HR: 0.38 (95% CI: 0.24–0.59; P<0.001) 100 80 60 PFS (%) 40 Median PFS months 20 Median PFS 3.8 months 4 8 12 16 20 24 Time since randomization (months) Niraparib Placebo BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Median PFS in the non-gBRCA cohort Time since randomization (months)
Median PFS was significantly longer in the niraparib group than in the placebo group Niraparib demonstrated a 55% reduction in the risk of disease progression or death Median PFS in the non-gBRCA cohort Niraparib (n=234) vs. placebo (n=116): HR: 0.45 (95% CI: 0.34–0.61; P<0.001) 100 80 60 PFS (%) 40 20 Median PFS 3.9 months Median PFS 9.3 months 4 8 12 16 20 24 Time since randomization (months) Niraparib Placebo BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Primary endpoint: Niraparib improved the probability of PFS compared with placebo
Kaplan–Meier estimates of PFS show that niraparib was associated with long-term efficacy across cohorts with and without gBRCA mutations Kaplan–Meier estimated probability of PFS: gBRCA cohort Kaplan–Meier estimated probability of PFS: Non-gBRCA cohort Estimated probability of PFS (%) Estimated probability of PFS (%) Time since randomization (months) Time since randomization (months) BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival. Matulonis UA et al. Poster presented at ASCO 2017; Chicago, IL, USA, June 2–6, 2017.

Almost a fifth of patients treated with niraparib in the NOVA trial demonstrated a long‑term response* Number of patients receiving treatment in the NOVA trial Treatment arm Number of patients on treatment, n (%) 0–3 months 3 months – 1 year 1–2 years 2–4 years Niraparib 367 (100.0) 298 (81.2) 143 (39.0) 69 (18.8) Placebo 179 (100.0) 145 (81.0) 31 (17.3) 10 (5.6) *Up to 4 years on treatment. Mirza MR et al. Oral presentation at the 17th Biennial Meeting of the IGCS; Kyoto, Japan, September 14–16, 2018.

Niraparib demonstrated significant benefit in PFS over placebo, regardless of HRD status
HRD-positive HRD-negative sBRCA1 BRCAwt1 Non-gBRCA1 100 100 100 75 75 75 PFS (%) 50 50 50 25 25 25 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Months since randomization Months since randomization Months since randomization Niraparib Placebo Median PFS (months): Niraparib 20.9 Placebo 11.0 HR: 0.27 (95% CI: 0.08–0.90) P=0.022 Median PFS (months): Niraparib 9.3 Placebo 3.7 HR: 0.38 (95% CI: 0.23–0.63) P=0.0012 Median PFS (months): Niraparib 6.9 Placebo 3.8 HR: 0.58 (95% CI: 0.36–0.92) P=0.022 At 18 months, 52% of patients treated with niraparib were progression free At 18 months, 27% of patients treated with niraparib were progression free At 18 months, 19% of patients treated with niraparib were progression free BRCA, breast cancer susceptibility gene; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival; sBRCA, somatic BRCA mutation. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

The NOVA trial Secondary efficacy endpoints

Niraparib significantly improved the chemotherapy-free interval in each cohort
gBRCA Non-gBRCA Overall HRD-positive 100 100 100 75 75 75 PFS (%) 50 50 50 25 25 25 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Months since randomization Months since randomization Months since randomization Niraparib Placebo Median CFI (months) Niraparib 22.8 Placebo 9.4 HR: 0.26; P<0.0001 Median CFI (months) Niraparib 12.7 Placebo 8.6 HR: 0.50; P<0.0001 Median CFI (months) Niraparib 18.2 Placebo 7.7 HR: 0.31; P<0.0001 BRCA, breast cancer susceptibility gene; CFI, chemotherapy-free interval; gBRCA, germline BRCA mutation; HR, hazard ratio; HRD, homologous recombination deficiency; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mahner S et al. Oral presentation at SGO 2017; National Harbor, MD, USA, March 12–15, 2017.

Niraparib significantly improved time to first subsequent treatment in both cohorts
gBRCA Non-gBRCA Overall HRD-positive 100 100 100 75 75 75 PFS (%) 50 50 50 25 25 25 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Months since randomization Months since randomization Months since randomization Niraparib Placebo Median TFST (months) Niraparib 21.0 Placebo 8.4 HR: 0.31; P<0.0001 Median TFST (months) Niraparib 11.8 Placebo 7.2 HR: 0.55; P<0.0001 Median TFST (months) Niraparib 15.9 Placebo 6.0 HR: 0.36; P<0.0001 BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; HR, hazard ratio; HRD, homologous recombination deficiency; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival; TFST, time to first subsequent treatment. Mahner S et al. Oral presentation at SGO 2017; National Harbor, MD, USA, March 12–15, 2017.

Niraparib had no impact on the efficacy of next-line therapy vs
Niraparib had no impact on the efficacy of next-line therapy vs. placebo The impact of a treatment on the efficacy of the next-line therapy can be estimated by measuring the time difference between first and second progressions after study treatment PFS1 is the time to the first disease progression after randomization to study treatment (niraparib or placebo)1 PFS2 is the time to the next disease progression after subsequent treatment1 Platinum Niraparib or Placebo Chemotherapy Progression 2 Progression 1 Randomization PFS1−PFS2 gives a measure of the impact of study treatment on the efficacy of the next-line therapy PFS1 PFS2−PFS1 PFS2 PFS1−PFS2 did not differ significantly between niraparib and placebo (HR: 1.02; 95% CI: 0.765–1.349)2 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Mahner S et al. Oral presentation at SGO 2017; National Harbor, MD, USA, March 12–15, 2017.

The NOVA trial Subgroup analysis of patients with a partial response to their last platinum-based therapy

Patient demographics and baseline characteristics
gBRCA (n=203) Non-gBRCA (n=350) PR to last platinum (n=99) CR to last platinum (n=104) PR to last platinum (n=173) CR to last platinum (n=177) Median age (range), years 60 (39–83) 52 (36–76) 63 (33–83) 63 (40–84) Screening ECOG status, n (%) 62 (62.6) 77 (74.0) 106 (61.3) 132 (74.6) 1 37 (37.4) 27 (26.0) 67 (38.7) 45 (25.4) Mean (SD) duration of last platinum-based chemotherapy, months 4.7 (1.95) 4.8 (2.01) 4.7 (1.76) 4.7 (2.09) Best response to penultimate platinum chemotherapy, n (%)* PR 40 (40.4) 17 (16.3) 73 (42.2) 23 (13.0) CR 58 (58.6) 87 (83.7) 99 (57.2) 152 (85.9) *Data were missing for one patient with PR to last platinum-based therapy in the gBRCA cohort, one patient with PR to last platinum-based chemotherapy in the non‑gBRCA cohort, and two patients with CR to last platinum-based chemotherapy in the non-gBRCA cohort. BRCA, breast cancer susceptibility gene; CR, complete response; ECOG, Eastern Cooperative Oncology Group; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation; PR, partial response; SD, standard deviation. Mirza MR et al. Poster 5517 presented at ASCO 2017; Chicago, IL, USA, June 2–6, 2017.

Improvement in PFS vs. placebo in patients with PR to their last platinum-based therapy was similar to that in the overall cohort gBRCA cohort Non-gBRCA cohort 1.0 1.0 Niraparib/all Niraparib/PR Placebo/all Placebo/PR 0.8 0.8 0.6 0.6 Probability of PFS Probability of PFS 0.4 0.4 0.2 0.2 0.0 0.0 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Time since randomization (months) Time since randomization (months) 107 50 34 14 98 45 21 9 89 41 12 3 79 37 8 3 63 27 6 1 44 19 2 28 10 2 26 9 2 16 5 1 3 1 1 234 117 116 56 188 90 88 40 145 66 52 13 113 54 33 5 88 39 23 2 75 31 19 2 57 26 10 2 41 16 8 1 23 8 4 1 21 7 4 1 16 6 3 1 7 2 1 3 1 gBRCA (n=203) non-gBRCA (n=350) PR to last platinum (n=99) Overall (n=203) PR to last platinum (n=173) Overall (n=350) PFS, HR (95% CI)* 0.24 (0.131–0.441) 0.27 (0.173–0.410) 0.35 (0.230–0.532) 0.45 (0.338–0.607) *Niraparib compared with placebo. BRCA, breast cancer susceptibility gene; CI, confidence interval; CR, complete response; gBRCA, germline BRCA mutation; HR, hazard ratio; non-gBRCA, no germline BRCA mutation; PFS, progression-free survival; PR, partial response. Mirza MR et al. Poster 5517 presented at ASCO 2017; Chicago, IL, USA, June 2–6, 2017.

Safety outcomes with niraparib in the NOVA trial

The most common non‑hematological AEs were nausea and fatigue
Non‑hematological AEs (all grades) occurring in ≥10% of patients treated with niraparib (n=367) or placebo (n=179)* Niraparib Placebo Fatigue† Fatigue† Incidence (%) Incidence (%) *Along with corresponding incidence of Grade 3/4 events. Frequencies above 1% were rounded to whole numbers. †The category of fatigue includes reports of fatigue, asthenia, malaise, and lethargy. AE, adverse event. Figure adapted from Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Incidence of AEs (percentage of patients)
Incidence of some of the most common non‑hematological AEs decreased over time 61.9 32.4 19.6 10.4 5.3 8.8 3.8 1.8 2.7 7.3 3.4 1.2 1.6 4.9 2.0 0.7 1.1 2.1 Month 1 Month 2 Month 3 Month 4 Month 5 Incidence of AEs (percentage of patients) 20 40 60 Nausea Fatigue Vomiting Diarrhea AE, adverse event. Figure adapted from Oza AM et al. Oral presentation at ESMO 2017; Madrid, Spain, September 8–12, 2017, and TESARO, Inc. Data on file.

The most common hematological AEs were thrombocytopenia, neutropenia, and anemia
Hematological AEs occurring in ≥10% of patients treated with niraparib (n=367) or placebo (n=179)* Niraparib Placebo Thrombocytopenia† Neutropenia‡ Anemia§ Thrombocytopenia† Neutropenia‡ Anemia§ Incidence (%) Incidence (%) Grade 3/4 All grades Grade 3/4 All grades *Along with corresponding incidence of Grade 3/4 events. Frequencies above 1% were rounded to whole numbers. †The category of thrombocytopenia includes reports of thrombocytopenia and decreased platelet count. ‡The category of neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia. §The category of anemia includes reports of anemia and decreased hemoglobin count. AE, adverse event. Figure adapted from Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Thrombocytopenia was transient and typically manifested in the first month of treatment
Mean change in platelet levels from baseline over time: Safety population (n=546)1 150 120 89 59 28 Mean change from baseline (10⁹/L, ± SE) −2 −32 −63 −93 Niraparib (n=367) −124 Placebo (n=179) Month 1 −154 Cycle 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Day 21 New incidence of thrombocytopenia of any grade was ≤1.2% after Month 22 SE, standard error. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018. 90

Treatment discontinuation due to hematological AEs of any grade1
Less than 4% of patients discontinued treatment because of any one hematological abnormality Treatment discontinuation due to hematological AEs of any grade1 AE (any grade), % Niraparib (n=367) Placebo (n=179) Thrombocytopenia* 3.3 0.6 Neutropenia† 1.9 Leukopenia‡ Anemia§ 1.4 Pancytopenia 0.8 *Thrombocytopenia includes reports of thrombocytopenia and decreased platelet count.1 No Grade 3 or 4 bleeding events were associated with thrombocytopenia.2 †Neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia.1 ‡Leukopenia includes reports of neutropenia, decreased neutrophil count, decreased white blood cell count, leukopenia, decreased lymphocyte count, lymphopenia, febrile neutropenia, and decreased monocyte count.1 §Anemia includes reports of anemia and decreased hemoglobin counts.1 AE, adverse event. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164. 91

Incidence of most Grade 3/4 TEAEs with niraparib was infrequent after cycle 3
Grade 3/4 TEAEs during the NOVA study for patients receiving niraparib1,2 n=124 n=1 n=93 n=19 n=72 n=4 n=30 n=5 n=30 NR Thrombocytopenia* Anemia† Neutropenia‡ Fatigue§ Hypertension *Thrombocytopenia includes reports of thrombocytopenia and decreased platelet count.1 No Grade 3 or 4 bleeding events were associated with thrombocytopenia.1 †Anemia includes reports of anemia and decreased hemoglobin counts.1 ‡Neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia.1 §Fatigue includes reports of fatigue, asthenia, malaise, and lethargy.1 AE, adverse event; NR, not reported. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

Less than 15% of patients discontinued niraparib because of TEAEs
TEAE,1 n (%) Niraparib (n=367) Placebo (n=179) Any TEAE 367 (100.0) 171 (95.5) Any related TEAE 358 (97.5) 127 (70.9) Any CTCAE Grade ≥3 TEAE 272 (74.1) 41 (22.9) Any related CTCAE Grade ≥3 TEAE 237 (64.6) 8 (4.5) Any serious TEAE 110 (30.0) 27 (15.1) Any related serious TEAE 62 (16.9) 2 (1.1) Any TEAE leading to treatment interruption 253 (68.9) 9 (5.0) Any TEAE leading to dose reduction 244 (66.5) 26 (14.5) Any TEAE leading to treatment discontinuation 54 (14.7) 4 (2.2) The median number of cycles started in NOVA was higher in the niraparib arm (9 cycles) than in the placebo arm (6 cycles); consistent with these results, median overall treatment exposure from first to last dose was longer in the niraparib arm (250 days) than the placebo arm (163 days). No deaths resulted from a TEAE during study treatment.2 CTCAE, Common Terminology Criteria for Adverse Events; TEAE, treatment-emergent adverse event. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. TESARO, Inc. Data on file.

Summary The Phase III NOVA trial assessed the efficacy and safety of niraparib as maintenance treatment in patients with platinum-sensitive, recurrent ovarian cancer1 In NOVA, niraparib significantly improved PFS in patients with platinum‐sensitive recurrent ovarian cancer, regardless of prior response, HRD, or BRCA mutation status1 Almost a fifth of patients treated with niraparib in the NOVA trial demonstrated a long‑term response*,2 When compared with placebo, niraparib did not have a significant impact on the efficacy of next‑line chemotherapy2 In a subgroup analysis, niraparib treatment also provided significant benefit in patients with a partial response3 Hematological AEs, fatigue, and hypertension were some of the most common reported Grade 3/4 TEAEs in NOVA1 Incidence of most Grade 3/4 AEs with niraparib was infrequent beyond cycle 31,4 *Up to 4 years on treatment. AE, adverse event; BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; PFS, progression-free survival; TEAE, treatment‑emergent adverse event. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Mirza MR et al. Oral presentation at the 17th Biennial Meeting of the IGCS; Kyoto, Japan, September 14–16, Mirza MR et al. Poster 5517 presented at ASCO 2017; Chicago, IL, USA, June 2–6, Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

Maintenance therapy with PARP inhibitors Part 2: Changing clinical practice for recurrent ovarian cancer Domenica Lorusso, MD, PhD Fondazione IRCCS National Cancer Institute, Italy PARP, poly(ADP-ribose) polymerase. This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Not indicated as maintenance therapy yet7
PARP inhibitor maintenance therapy is changing clinical practice in ovarian cancer In clinical studies, several PARP inhibitors have demonstrated improved PFS compared with placebo1–3 Key trials and current approval status of PARP inhibitors as maintenance therapy for recurrent ovarian cancer: Niraparib NOVA trial, 20161 Olaparib Study 19, 20142 SOLO2, 20173 Rucaparib ARIEL3 study, 20174 Indicated as maintenance therapy for adult patients with high‑grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer, regardless of BRCA status, who are in CR or PR to platinum‑based therapy5 Indicated as monotherapy for the maintenance treatment of adult patients with platinum‑sensitive relapsed high‑grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or PR to platinum‑based therapy6 Not indicated as maintenance therapy yet7 Europe BRCA, breast cancer susceptibility gene; CR, complete response; PARP, poly(ADP) ribose polymerase; PR, partial response; PFS, progression-free survival. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Ledermann J et al. Lancet Oncol 2014; 15 (8): 852– Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274– Coleman RL et al. Lancet 2017; 390: 1949– TESARO UK Ltd. ZEJULA – summary of product characteristics; February AstraZeneca AB. LYNPARZA – summary of product characteristics; October Clovis Oncology UK Ltd. RUBRACA – summary of product characteristics; May 2018.

Study 19 investigated the efficacy of olaparib maintenance therapy in recurrent ovarian cancer
Study 19 (N=265) Randomized, double-blind, placebo-controlled, Phase II trial Patients with recurrent, platinum-sensitive, high-grade serous ovarian cancer after ≥2 lines of platinum‑based therapy, who had a CR or PR to their most recent platinum‑based therapy Patients randomized 1:1 Olaparib 400 mg BID (n=136) Placebo BID (n=129) Primary endpoint Investigator-assessed PFS Key secondary endpoints: OS HRQoL Safety and tolerability BID, twice a day; CR, complete response; HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival; PR, partial response. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852–861.

BRCA biomarker testing
Pre-planned, retrospective biomarker testing was performed on all patients Blood samples taken before randomization were retrospectively analyzed for BRCA mutations PFS was assessed for the overall population and by BRCA mutation status Placebo (n=62) BRCA biomarker testing Olaparib (n=74) BRCAmut* (n=136) BRCAwt† (n=118) Placebo (n=61) Olaparib (n=57) *Patients were included in the BRCAmut group if they harbored a deleterious or suspected deleterious germline or tumor BRCA mutation. †Patients with no known or reported BRCA mutation and patients with BRCA variants of unknown significance were included in the wild-type BRCA group. BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; PFS, progression-free survival. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852–861.

Olaparib improved PFS compared with placebo
Overall BRCAmut BRCAwt 100 100 100 90 90 90 80 80 80 70 70 70 60 60 60 PFS (%) 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 3 6 9 12 15 3 6 9 12 15 3 6 9 12 15 Months since randomization Months since randomization Months since randomization Olaparib Placebo Olaparib (n=136) Placebo (n=129) Olaparib (n=74) Placebo (n=62) Olaparib (n=57) Placebo (n=61) Median (95% CI) PFS, months 8.4 (7.4–11.5) 4.8 (4.0–5.5) 11.2 (8.3–NR) 4.3 (3.0–5.4) 7.4 (5.5–10.3) 5.5 (3.7–5.6) HR: 0.35 95% CI: 0.25–0.49 P<0.0001 HR: 0.18 95% CI: 0.10–0.31 HR: 0.54 95% CI: 0.34–0.85 P=0.0075 BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; NR, not reached; PFS, progression-free survival. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852–861.

Olaparib failed to demonstrate statistical significance in OS in either the BRCAmut or BRCAwt cohort
Treatment BRCAmut BRCAwt Total population Olaparib Placebo 1°: PFS (months) 11.2* (HR: 0.18) 4.3 7.4* (HR: 0.54) 5.5 8.4* (HR: 0.35) 4.8 2°: OS 34.9 (HR: 0.62) 31.9 24.5 (HR: 0.83) 26.2 29.8 (HR: 0.73) 27.8 2°: TFST 15.6* (HR: 0.32) 6.2 12.9* (HR: 0.45) 6.9 13.4* (HR: 0.39) 6.7 2°: TSST 23.8* (HR: 0.41) 15.2 17.1* (HR: 0.63) 14.7 19.1* (HR: 0.52) 14.8 Secondary endpoints for TFST and TSST were statistically significant for the BRCAmut group, with a 68% risk reduction and a 59% risk reduction, respectively *Denotes a statistically significant increase over comparator where P<0.05. BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild‑type; OS, overall survival; PFS, progression-free survival; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy. 1. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852–861.

SOLO2 investigated the efficacy of olaparib maintenance therapy in recurrent ovarian cancer
SOLO2 (N=295) Randomized, double-blind, placebo-controlled, Phase III trial Patients with BRCA1/2 mutation and: Platinum-sensitive relapsed ovarian cancer after ≥2 lines of platinum‑based therapy, who had a CR or PR to their most recent platinum‑based therapy Patients randomized 2:1 Olaparib 300 mg BID (n=196) Placebo BID (n=99) Primary endpoint Investigator-assessed PFS Key secondary endpoints: Time to first subsequent therapy or death, time to second progression, time to second subsequent therapy or death, OS Safety, patient‑reported HRQoL* *Patient‑reported HRQoL was assessed with the TOI score, derived from the FACT-O questionnaire. BID, twice a day; BRCA, breast cancer susceptibility gene; CR, complete response; FACT‑O, Functional Assessment of Cancer Therapy – Ovarian; HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival; PR, partial response; TOI, Trial Outcome Index. Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274–1284.

Time since randomization (months)
In patients with BRCA1/2 mutations, olaparib improved PFS compared with placebo Olaparib (n=196) Placebo (n=99) Events, n (%) 107 (55) 80 (81) Median (95% CI) PFS, months 19.1 (16.3–25.7) 5.5 (5.2–5.8) HR: 0.30 95% CI: 0.22–0.41 P<0.0001 100 80 60 PFS (%) 40 20 5.5 19.1 3 6 9 12 15 18 21 24 27 30 33 36 Time since randomization (months) Olaparib Placebo No. at risk Olaparib Placebo 196 99 182 70 156 37 134 22 118 18 104 17 89 14 82 12 32 7 29 6 3 2 Median (IQR) follow-up in censored patients was 22.1 (21.9–27.4) months in the olaparib group and 22.2 (8.3–27.5) months for placebo. BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; PFS, progression-free survival. Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274–1284.

ARIEL3 investigated the efficacy of rucaparib in recurrent ovarian cancer
ARIEL3 (N=564) Randomized, double-blind, placebo-controlled, Phase III trial Patients with high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma after ≥2 lines of platinum‑based therapy, who had a CR or PR to their most recent platinum‑based therapy Patients randomized 2:1 Rucaparib 600 mg BID (n=375) Placebo BID (n=189) Primary endpoint Investigator-assessed PFS in three cohorts: BRCAmut; HRD-positive (LOH only),* including BRCAmut; all patients It is important to note that the HRD-positive population in ARIEL3 consisted only of patients with loss of heterozygosity. In other studies, such as NOVA, several measurements are used to determine the presence of HRD in tumors. Key secondary endpoints: PFS according to BICR, patient-reported outcomes, OS; Safety and population PK modeling *HRD was defined as high genomic LOH. BICR, blinded independent central review; BID, twice a day; BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; CR, complete response; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; PR, partial response. Coleman RL et al. Lancet 2017; 390 (10106): 1949–1961. 103

Rucaparib improved PFS compared with placebo
BRCAmut HRD-positive (LOH only)* ITT population 100 100 100 80 80 80 60 60 60 PFS (%) 40 40 40 20 20 20 6 12 18 24 30 36 6 12 18 24 30 36 6 12 18 24 30 36 Months since randomization Months since randomization Months since randomization Rucaparib Placebo Rucaparib (n=130) Placebo (n=66) Rucaparib (n=236) Placebo (n=118) Rucaparib (n=375) Placebo (n=189) Median (95% CI) PFS, months 16.6 (13.4–22.9) 5.4 (3.4–6.7) 13.6 (10.9–16.2) (5.1–5.6) 10.8 (8.3–11.4) (5.3–5.5) HR: 0.23 95% CI: 0.16–0.34 P<0.0001 HR: 0.32 95% CI: 0.24–0.42 P<0.0001 HR: 0.36 95% CI: 0.30–0.45 P<0.0001 It is important to note that the HRD-positive population in ARIEL3 consisted only of patients with loss of heterozygosity. In other studies, such as NOVA, several measurements are used to determine the presence of HRD in tumors. *HRD was defined as high genomic LOH. BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; ITT, intention-to-treat; LOH, loss of heterozygosity; PFS, progression-free survival. Coleman RL et al. Lancet 2017; 390 (10106): 1949–1961.

ARIEL3: Investigator-assessed PFS in tumors with high and low LOH
High LOH Low LOH 100 100 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 6 12 18 24 30 36 6 12 18 24 30 36 Months Months Rucaparib Placebo Rucaparib (n=106) Placebo (n=52) Rucaparib (n=107) Placebo (n=54) Median (95% CI) PFS, months 9.7 (7.9–13.1) 5.4 (4.1–5.7) 6.7 (5.4–9.1) (5.3–7.4) HR: 0.44 95% CI: 0.29–0.66 P<0.0001 HR: 0.58 95% CI: 0.40–0.85 P=0.0049 CI, confidence interval; HR, hazard ratio; LOH, loss of heterozygosity; PFS, progression-free survival. Coleman RL et al. Lancet 2017; 390 (10106): 1949–1961.

PARP inhibitors have proven to be effective in the second‑line treatment setting in patients with ovarian cancer PARP inhibition: gBRCA patients PARP inhibition: Non-gBRCA patients Chemotherapy 6 months Phase III SOLO23 NOVA1 ARIEL34 N=116 N=234 Phase II Study 192 5 10 15 20 N=57 N=61 Δ15.5 Δ6.9 Δ13.6 Δ11.2 Δ5.4 Δ1.9 25 Not studied Not studied as a cohort HR: 0.45 HR: 0.54 9.3 months‘ PFS 21.0 months‘ 5.5 N=99 19.1 N=196 21.0 N=138 N=65 11.2 N=74 4.3 N=62 16.6 N=130 5.4 N=66 7.4 9.3 3.9 HR: 0.27 HR: 0.18 HR: 0.30 HR: 0.23 Treatment Placebo BRCA, breast cancer susceptibility gene; gBRCAmut, germline BRCA mutation; PARP, poly(ADP) ribose polymerase; PFS, progression-free survival. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– Ledermann J et al. Lancet Oncol 2014; 15: 852– Pujade-Lauraine E et al. Lancet Oncol 2017; 18: 1274– Coleman RL et al. Lancet 2017; 390: 1949–1961.

Niraparib was the first licensed maintenance treatment for recurrent ovarian cancer regardless of biomarker status Approximately 75% of patients do not have a germline BRCA mutation, meaning that prior to the licensing of niraparib in Europe, they were not eligible for PARP inhibitor treatments1 Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or PR to platinum‑based chemotherapy2 BRCA, breast cancer susceptibility gene; CR, complete response; non-gBRCA, no germline BRCA mutation; PARP, poly(ADP-ribose) polymerase; PR, partial response. 1. Pennington KP et al. Clin Cancer Res 2014; 20 (3): 764– TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

PARP inhibitor maintenance therapy: Broadening the therapeutic indication

PARP inhibitor maintenance therapy has proven to be effective in the first‑line setting in the SOLO‑1 trial Newly diagnosed Stage III–IV ovarian, primary peritoneal, or fallopian tube cancer High-grade serous or endometrioid history Only patients with documented deleterious BRCA mutation Stage III: One optimal debulking attempt Stage IV: Biopsy and/or one upfront or interval debulking In CR or PR at the end of front-line platinum-based chemotherapy R 2:1 Olaparib 300 mg PO BID up to 2 years* or to progression Placebo BID up to 2 years* or to progression N=391 n=131 n=260 Primary endpoint: Investigator-assessed PFS by RECIST v1.1 Secondary endpoints: OS, PFS2, best ORR, HRQoL by TOI of the FACT-O, TFST, TSST, and safety and tolerability *At investigator’s discretion. BID, twice a day; BRCAmut, BRCA mutation; CR, complete response; FACT‑O, Functional Assessment of Cancer Therapy – Ovarian; HR, hazard ratio; HRQoL, health-related quality of life; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, time to second disease progression or death; PO, by mouth; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; TFST, time to first subsequent therapy; TOI, Trial Outcome Index; TSST, time to second subsequent therapy. Moore K et al. N Engl J Med 2018; Epub ahead of print (DOI: /NEJMmo18/0858).

Olaparib met the primary endpoint of PFS in women with BRCAmut advanced ovarian cancer
(95% CI, 0.23–0.41) BRCAmut, BRCA mutation; PFS, progression-free survival. Moore K et al. N Engl J Med 2018; Epub ahead of print (DOI: /NEJMmo18/0858).

Key secondary endpoints
Niraparib is being assessed for maintenance therapy in the first‑line setting in the PRIMA study High-grade Stage III or IV ovarian cancer (all comers) and achieved a CR or PR after front-line platinum-based chemotherapy Stratification factors Neoadjuvant chemotherapy administered: Yes or no Best response to first platinum therapy: CR or PR HRD status: positive or negative / not determined 2:1 Niraparib 300 mg daily Placebo daily Enrollment completed June 2018 (N=733) Results expected end 2019 Endpoint assessment Primary endpoint Hierarchical testing for PFS (radiological, central review) PFS in HRD-positive population (HR: 0.5) PFS in ITT population (HR: 0.65) Key secondary endpoints OS | Patient-reported outcomes (FOSI, EQ-5D-5L, EORTC QLQ-30, EORTC QLQ-OV28) | Safety and tolerability | Time to CA-125 progression Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Please consult the summary of product characteristics. CR, complete response; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-OV28, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Ovarian Cancer Module; EQ-5D-5L, EuroQol 5-dimension 5-level questionnaire; FOSI, Functional Assessment of Cancer Therapy – Ovarian Symptom Index; HR, hazard ratio; HRD, homologous recombination deficiency; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; PR, partial response; QoL, quality of life. ClinicalTrials.gov PRIMA. Available at: Accessed October 2018.

Summary Various clinical studies have demonstrated that PARP inhibitors are effective for maintenance therapy for patients who: Have received ≥2 lines of platinum‑based therapy Had a CR or PR to their most recent platinum‑based therapy1–3 Niraparib was the first licensed maintenance treatment for recurrent ovarian cancer regardless of biomarker status Latest data have shown that PARP inhibitor maintenance therapy has proven to be effective in the first‑line setting in gBRCA patients4 The PRIMA study will investigate PARP inhibitor maintenance therapy in the first-line setting in non-gBRCA patients5 BRCA, Breast cancer susceptibility gene; CR, complete response; gBRCA, germline BRCA mutation; non-gBRCA, no germline BRCA mutation; PARP, poly(ADP-ribose) polymerase; PR, partial response; QoL, quality of life. 1. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852– Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274– Coleman RL et al. Lancet 2017; 390 (10106): 1949– Moore K et al. N Engl J Med 2018; Epub ahead of print (DOI: /NEJMmo18/0858) Accessed October 2018

Understanding statistics in oncology trials
Dr. rer. nat. Joachim Gerß, Dipl.-Stat. Institute of Biostatistics and Clinical Research, Germany This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Introduction: The NOVA trial – Study design (1)
(Mirza et al. N Engl J Med 2016) BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non‑gBRCA, no germline BRCA mutation; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Introduction: The NOVA trial – Study design (2)
(Mirza et al. N Engl J Med 2016) BRCA, breast cancer susceptibility gene; gBRCAmut, germline BRCA mutation; HRD, homologus recombination deficiency; non‑gBRCAmut, no germline BRCA mutation. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Introduction: The NOVA trial – Results
(Mirza et al. N Engl J Med 2016) PFS (%) Time since randomization (months) Non-gBRCA, HRD-positive cohort HR: 0.38 (95% CI: 0.24–0.59; P<0.001) 80 24 100 60 40 20 16 12 8 4 gBRCA cohort PFS (%) HR: 0.27 (95% CI: 0.17–0.41; P<0.001) Time since randomization (months) 80 24 100 60 40 20 16 12 8 4 Niraparib Placebo Non-gBRCA cohort 100 HR: 0.45 (95% CI: 0.34–0.61; P<0.001) 80 PFS (%) 60 40 20 4 8 12 16 20 24 Time since randomization (months) BRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCA, germline BRCA mutation; HR, hazard ratio; HRD, homologus recombination deficiency; non‑gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Introduction: The NOVA trial – Summary
(Mirza et al. N Engl J Med 2016) Patients with platinum-sensitive, recurrent ovarian cancer Randomization: Niraparib (300 mg) or placebo Primary endpoint: PFS, assessed by BICR Significance level: α=0.025 (one‑sided) Hierarchical-testing procedure Kaplan–Meier method Median duration of PFS HR with two-sided 95% CI BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Understanding statistics in oncology trials: Contents
Statistical significance testing P‑value Multiple testing Confirmatory and exploratory statistical evidence Survival function The Kaplan–Meier method Median duration of PFS HR CI CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

1. Statistical significance testing (I) Research question and decision rule
Randomized clinical trial: Active treatment (A) vs. placebo (P) Primary endpoint: PFS Sample of n patients in each treatment group Statistical inference from the sample (observed PFS data) to the total population Research question Is PFS in Group A different to Group P? Decision rule Compute the P‑value If P≤0.05: Declare that PFS in Group A is significantly different to Group P If P>0.05: No significant difference in PFS PFS, progression-free survival.

Randomized clinical trial: Active treatment (A) vs. placebo (P) Primary endpoint: PFS The NOVA trial Two‑sided significance test One‑sided significance test Sample of n patients in each treatment group Statistical inference from the sample (observed PFS data) to the total population Research question Is PFS in Group A different to Group P? Decision rule Compute the two‑sided P‑value If P≤0.05: Declare that PFS in Group A is significantly different to Group P If P>0.05: No significant difference in PFS BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non‑gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Randomized clinical trial: Active treatment (A) vs. placebo (P) Primary endpoint: PFS Two‑sided significance test One‑sided significance test Sample of n patients in each treatment group Statistical inference from the sample (observed PFS data) to the total population Research question Is PFS in Group A different to Group P? Is PFS in Group A longer than in Group P? Decision rule Compute the two‑sided P‑value If P≤0.05: Declare that PFS in Group A is significantly different to Group P If P>0.05: No significant difference in PFS Compute the one‑sided P‑value If P≤0.025: Declare significant superiority of Group A PFS, progression-free survival.

Randomized clinical trial: Active treatment (A) vs. placebo (P) Primary endpoint: PFS Two‑sided significance test One‑sided significance test Sample of n patients in each treatment group Statistical inference from the sample (observed PFS data) to the total population Research question Is PFS in Group A different to Group P? Is PFS in Group A longer than in Group P? Decision rule Compute the two‑sided P‑value If P≤0.05: Declare that PFS in Group A is significantly different to Group P If P>0.05: No significant difference in PFS Compute the one‑sided P‑value If P≤0.025: Declare significant superiority of Group A Significance level: α=0.05 (two‑sided) Significance level: α=0.025 (one‑sided) PFS, progression-free survival.

The NOVA trial One‑sided significance test Sample of n patients in each treatment group Statistical inference from the sample (observed PFS data) to the total population Research question Is PFS in Group A longer than in Group P? Decision rule Compute the one‑sided P‑value If P≤0.025: Declare significant superiority of Group A If P>0.05: No significant difference in PFS Significance level: α=0.025 (one‑sided) BRCA, breast cancer susceptibility gene; gBRCA, germline BRCA mutation; non‑gBRCA, no germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

1. Statistical significance testing (II) Significance level α
Decision rule: Prevent a false positive decision!

Decision rule: Prevent a false positive decision! Example Randomized clinical trial: Black chocolate vs. white chocolate Primary endpoint: PFS Is black chocolate superior to white chocolate? PFS, progression-free survival.

Decision rule: Prevent a false positive decision! Example Randomized clinical trial: Black chocolate vs. white chocolate Primary endpoint: PFS Is black chocolate superior to white chocolate? Decision If p>α=0.025: No significant difference in PFS If p≤α=0.025: Declare significant superiority of black chocolate – Negative decision + Positive decision PFS, progression-free survival.

Decision rule: Prevent a false positive decision! Example Randomized clinical trial: Black chocolate vs. white chocolate Primary endpoint: PFS Is black chocolate superior to white chocolate? Decision If p>α=0.025: No significant difference in PFS If p≤α=0.025: Declare significant superiority of black chocolate – Negative decision + Positive decision true negative decision false positive decision PFS, progression-free survival.

Decision rule: Prevent a false positive decision! Example Randomized clinical trial: Black chocolate vs. white chocolate Primary endpoint: PFS Is black chocolate superior to white chocolate? Decision If p>α=0.025: No significant difference in PFS If p≤α=0.025: Declare significant superiority of black chocolate – Negative decision + Positive decision true negative decision false positive decision Significance level α=0.025: Maximal probability of a false positive decision = 2.5% PFS, progression-free survival.

1. Statistical significance testing (III) Scientific evidence
High scientific evidence Lower scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis

1. Statistical significance testing (III) Multiple testing
Example: High scientific evidence Lower scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis

High scientific evidence Lower scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis Unique primary endpoint: E.g. PFS, assessed by BICR Multiple endpoints, e.g.: PFS, investigator-assessed PFS, assessed by BICR OS, investigator-assessed OS, assessed by BICR BICR, blinded independent central review; OS, overall survival; PFS, progression-free survival.

High scientific evidence Controlled probability of a false positive decision (‘type I error’) Confirmatory statistical analysis Unique primary endpoint: E.g. PFS, assessed by BICR Multiple endpoints, e.g.: PFS, investigator-assessed PFS, assessed by BICR OS, investigator-assessed OS, assessed by BICR ? BICR, blinded independent central review; OS, overall survival; PFS, progression-free survival.

High scientific evidence Lower scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis Unique primary endpoint: E.g. PFS, assessed by BICR Multiple endpoints, e.g.: PFS, investigator-assessed PFS, assessed by BICR OS, investigator-assessed OS, assessed by BICR If p≤α  significant Multiple testing without adjustment p1≤α or p2≤α or p3≤α or p4≤α BICR, blinded independent central review; OS, overall survival; PFS, progression-free survival.

High scientific evidence Lower scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis Unique primary endpoint: E.g. PFS, assessed by BICR Multiple endpoints, e.g.: PFS, investigator-assessed PFS, assessed by BICR OS, investigator-assessed OS, assessed by BICR If p≤α  significant Adjustment for multiple testing e.g. Bonferroni: If p1≤α/4 or p2≤α/4 or p3≤α/4 or p4≤α/  significant Multiple testing without adjustment p1≤α or p2≤α or p3≤α or p4≤α ? BICR, blinded independent central review; OS, overall survival; PFS, progression-free survival.

The NOVA trial High scientific evidence Controlled probability of a false positive decision (‘type I error’) Uncontrolled probability of a false positive decision (‘type I error’ inflation) Confirmatory statistical analysis Exploratory statistical analysis Unique primary endpoint: E.g. PFS, assessed by BICR Multiple endpoints, e.g.: PFS, investigator-assessed PFS, assessed by BICR OS, investigator-assessed OS, assessed by BICR If p≤α  significant Adjustment for Multiple testing e.g. Bonferroni: If p1≤α/4 or p2≤α/4 or p3≤α/4 or p4≤α/  significant BICR, blinded independent central review; BRCA, breast cancer susceptibility gene; HRD, homologus recombination deficiency; non‑gBRCA, no germline BRCA mutation; OS, overall survival; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

The NOVA trial 1. Statistical significance testing Confirmatory and exploratory statistical analysis BRCA, breast cancer susceptibility gene; gBRCAmut, germline BRCA mutation; HRD, homologous recombination deficiency; non‑gBRCAmut, no germline BRCA mutation. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

2. Survival function – the NOVA trial
(Mirza et al. N Engl J Med 2016) Median PFS in the gBRCA cohort Niraparib (n=138) vs. placebo (n=65): HR: 0.27 (95% CI: 0.17–0.41; P<0.001) 100 80 Niraparib Placebo 60 PFS (%) 40 20 Median PFS 5.5 months Median PFS months 4 8 12 16 20 24 Time since randomization (months) No. at risk Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1 Placebo 65 52 34 21 12 8 6 2 BRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCA, germline BRCA mutation; HR, hazard ratio; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

2. Survival function Pat-ID PFS 1 5 months 2 9 months 3 10 months 4
−20% −20% −20% −20% −20% Cum, cumulative; Pat‑ID, patient identification; PFS, progression-free survival.

2. Survival function Censored cases
The patient was under observation for up to 10 months At this time point the patient did not yet have a progression Pat-ID PFS Status 1 5 months 2 9 months 3 10 months 4 16 months 5 20 months Pat‑ID, patient identification; PFS, progression-free survival.

2. Survival function Censored cases
The patient was under observation for up to 10 months At this time point the patient did not yet have a progression Pat-ID PFS Status 1 5 months 2 9 months 3 10 months 4 16 months 5 20 months −20% −20% −(20%+10%) −(20%+10%) Number of patients at risk: Number of events: Cum, cumulative; Pat‑ID, patient identification; PFS, progression-free survival.

2. Survival function Median PFS
Pat-ID PFS Status 1 5 months 2 9 months 3 10 months 4 16 months 5 20 months Median PFS: 16 months Number of patients at risk: Number of events: Cum, cumulative; Pat‑ID, patient identification; PFS, progression-free survival.

2. Survival function – NOVA trial
(Mirza et al. N Engl J Med 2016) Median PFS Niraparib: 21.0 months Placebo: 5.5 months Median PFS in the gBRCA cohort HR: 0.27 (95% CI: 0.17–0.41; P<0.001) 80 24 100 PFS (%) 60 40 20 16 12 8 4 Median PFS 5.5 months Median PFS months Time since randomization (months) Niraparib Placebo No. at risk Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1 Placebo 65 52 34 21 12 8 6 2 BRCA, breast cancer susceptibility gene; CI, confidence interval; HR, hazard ratio; gBRCA, germline BRCA mutation; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

2. Survival function – SOLO2 trial
(Pujade‑Lauraine et al. Lancet Oncol 2017) Median PFS (BICR) Olaparib: 30.2 months Placebo: 5.5 months 5.5 30.2 BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. Pujade-Lauraine E et al. Lancet Oncol 2017; 18 (9): 1274–1284.

2. Survival function – Study 19
(Ledermann et al. Lancet Oncol 2014/2016) Median PFS in the BRCAwt cohort Olaparib (n=57) Placebo (n=61) Median (95% CI) PFS, months 7.4 (5.5–10.3) 5.5 (3.7–5.6) HR: 0.54 (95% CI: 0.34–0.85) P=0.0075 6 3 9 12 15 10 20 30 40 50 90 70 80 60 100 Median PFS 5.5 months Median PFS 7.4 months Olaparib Placebo PFS (%) Time since randomization (months) No. at risk Olaparib 57 45 18 9 2 Placebo 61 35 10 4 1 BRCA, breast cancer susceptibility gene; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio, PFS, progression-free survival. Ledermann J et al. Lancet Oncol 2014; 15 (8): 852–861.

3. Hazard ratio – NOVA trial
(Mirza et al. N Engl J Med 2016) Median PFS Niraparib: 21.0 months Placebo: 5.5 months HR: 0.27 95% CI: 0.17–0.41 Median PFS in the gBRCA cohort HR: 0.27 (95% CI: 0.17–0.41; P<0.001) 80 24 100 60 40 20 16 12 8 4 Median PFS 5.5 months Median PFS months Niraparib Placebo PFS (%) Time since randomization (months) No. at risk Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1 Placebo 65 52 34 21 12 8 6 2 BRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCA, germline BRCA mutation; HR, hazard ratio; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

3. Hazard ratio Example: Randomized clinical trial
Active treatment (A) vs. placebo (P) Primary endpoint: PFS Hazard ratio HRA versus P = 0.5 The odds that a patient in Group A reaches the endpoint before a patient in Group P is equal to 1.2 HR, hazard ratio; PFS, progression-free survival.

3. Hazard ratio Example: Randomized clinical trial
Active treatment (A) vs. placebo (P) Primary endpoint: PFS Hazard ratio HRA versus P = 0.5 The odds that a patient in Group A reaches the endpoint before a patient in Group P is equal to 1.2 Comparison of survival functions in the whole course of time Illustration (exponential survival) Ratio of areas (A vs. P) = 2 HR (A vs. P) = 1/2 = 0.5 HR, hazard ratio; PFS, progression-free survival.

3. Hazard ratio – NOVA trial
The NOVA trial 3. Hazard ratio – NOVA trial (Mirza et al. N Engl J Med 2016) Median PFS Niraparib: 21.0 months Placebo: 5.5 months HR: 0.27 95% CI: 0.17–0.41 Median PFS in the gBRCA cohort HR: 0.27 (95% CI: 0.17–0.41; P<0.001) 80 24 100 60 40 20 16 12 8 4 Median PFS 5.5 months Median PFS months Niraparib Placebo PFS (%) Uncertainty in the estimation of the HR: We are 95% sure that the true HR is between 0.17 and 0.41 Time since randomization (months) No. at risk Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1 Placebo 65 52 34 21 12 8 6 2 BRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCA, germline BRCA mutation; HR, hazard ratio; PFS, progression-free survival. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Statistical significance testing P‑value Multiple testing Confirmatory and exploratory statistical evidence Survival function The Kaplan–Meier method Median duration of PFS HR CI Randomized clinical trial Treatments A vs. P PFS in the total population: Is Group A significantly different to Group P: Yes or no? How large is the difference in PFS between Groups A and P? CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

Maintaining outcomes with dose adjustment and individualization
Domenica Lorusso, MD, PhD Fondazione IRCCS National Cancer Institute, Italy This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

PARP inhibitors are associated with toxicities in rapidly dividing cell populations
Gastrointestinal and hematological toxicities, and fatigue are common to all PARP inhibitors Hematological toxicities, resulting from the death of myeloid cells, can be dose limiting and make combining PARP inhibitors with other myelosuppressive agents challenging Fatigue Hematological toxicity Anemia Neutropenia Thrombocytopenia Gastrointestinal toxicity Nausea Vomiting Anorexia PARP, poly(ADP-ribose) polymerase. Evans T et al. Ther Adv Med Oncol 2017; 9 (4): 253–267.

In NOVA, hematological AEs occurred early in niraparib treatment and incidence decreased over time1
Incidence and time to onset of hematological AEs in patients receiving niraparib (n=367) in the NOVA trial1,2 Anemia* Neutropenia† Thrombocytopenia‡ Incidence of AE, % Any grade Grade 3/4 50 25 30 20 60 34 Median time to onset, days 42 85 27 29 22 23 Cumulative Grade 3/4 hematological AEs that occurred after cycle 3 through to end of treatment in patients receiving niraparib at 300 mg (n=82) in the NOVA trial2 Anemia* Neutropenia† Thrombocytopenia‡ Incidence of AE, n (%) 19 (23.2) 4 (4.9) 1 (1.2) *Anemia includes reports of anemia and decreased hemoglobin counts. †Neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia. ‡Thrombocytopenia includes reports of thrombocytopenia and reduced platelet count. AE, adverse event. 1. TESARO UK Ltd. ZEJULA – summary of product characteristics; February Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

Hematological AEs have been reported for other PARP inhibitors used to treat recurrent ovarian cancer1 Incidence of hematological AEs in patients receiving olaparib (n=136) in Study 191 Anemia Neutropenia Thrombocytopenia Incidence of AE, n (%) Any grade Grade 3/4 29 (21) 7 (5)* 7 (5) 5 (4)† NA *Includes one patient with a Grade 4 AE. †Includes three patients with a Grade 4 AE. Incidence of hematological AEs in patients receiving rucaparib (n=372) in ARIEL32 Anemia Neutropenia Thrombocytopenia Incidence of AE, n (%) Any grade Grade 3/4 139 (37) 70 (19)* 67 (18) 25 (7)† 104 (28) 19 (5)‡ *Includes three patients with a Grade 4 AE. †Includes six patients with a Grade 4 AE. ‡Includes six patients with a Grade 4 AE. Management of hematological AEs due to PARP inhibitor treatment involves dose interruptions and/or dose reductions3–5 AE, adverse event; NA, not available; PARP, poly(ADP-ribose) polymerase. 1. Ledermann J et al. Lancet Oncol 2014; 15: 852– Coleman RL et al. Lancet 2017; 390: 1949– TESARO UK Ltd. ZEJULA® 100 mg hard capsules – summary of product characteristics. TESARO UK Ltd., London, UK, February AstraZeneca AB. LYNPARZA® 50 mg hard capsules – summary of product characteristics. AstraZeneca AB, Södertälje, Sweden, May Clovis Oncology UK Ltd. RUBRACA® 200mg/250/mg/300mg film‑coated tablets – summary of product characteristics. Clovis Oncology UK Ltd., Cambridge, UK, May 2018.

In NOVA, incidence of commonly reported Grade 3/4 TEAEs was highest at 300 mg and lower at the 200 mg and 100 mg dose* Grade 3/4 TEAEs reported in ≥5% of patients in the niraparib arm overall by dose at onset of event1,2 100 90 80 70 60 50 40 30 20 10 Patients (%) Thrombocytopenia† Anemia‡ Neutropenia§ Hypertension Fatigue Grade 3/4 TEAE *The incidence of anemia (overall and Grade 3/4) was similar at the 300 mg and 200 mg doses and lower at 100 mg.1 †Thrombocytopenia includes reports of thrombocytopenia and decreased platelet count.1 ‡Anemia includes reports of anemia and decreased hemoglobin counts.1 §Neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia.1 TEAE, treatment‑emergent adverse event. 1. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255). 2. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255) – supplementary material.

The NOVA protocol mandated dose interruptions and dose reductions for Grade 3/4 AEs
Treatment was withheld for 28 days for patients experiencing Grade 3/4 AEs1 Patients could then be restarted on niraparib at a reduced dose2 Niraparib treatment was discontinued if: A Grade 3/4 AE had not resolved within the 28-day dose interruption period, and/or The patient had undergone two dose reductions to the minimum dose of 100 mg per day1 AE, adverse event. 1. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material. 2. Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164.

Platelet count <75,000/µL
Hematological AEs were managed with dose interruption and dose modification Thrombocytopenia Neutropenia Anemia Grade 1 Platelet count 75,000–99,999/µL Grade ≥2 Platelet count <75,000/µL Grade 3/4 Neutrophils <1,000/µL Grade 3/4 Hemoglobin <8 g/dL Dose interruptions and dose modifications were required when hematological parameters fell within these prespecified ranges AE, adverse event. Adapted from Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

The NOVA dose-reduction algorithm for managing AEs
If the value has not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose modification to 100 mg once daily, discontinue treatment with niraparib Thrombocytopenia Interrupt treatment for ≤28 days if values drop below the above cut-off values Monitor CBCs weekly, resume treatment when the following values are reached* Grade 1 Platelet count 75,000–99,999/µL Grade ≥2 Platelet count <75,000/µL Neutropenia Grade 3/4 Neutrophils <1,000/µL Anemia Hemoglobin <8 g/dL ≥100,000/µL ≥1,500/µL ≥9 g/dL Continue monitoring CBCs weekly during the first month after dose modification and modify dose/discontinue treatment if needed First occurrence: Resume treatment at the same or a reduced dose Second occurrence: Resume treatment at a reduced dose *If the AE has not resolved within 28 days or the dose has already been reduced to 100 mg once daily, treatment should be discontinued. AE, adverse event; CBC, complete blood count; QD, once a day. Adapted from Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

The NOVA dose-reduction algorithm for managing AEs
If the value has not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose modification to 100 mg once daily, discontinue treatment with niraparib Thrombocytopenia Interrupt treatment for ≤28 days if values drop below the above cut-off values Monitor CBCs weekly, resume treatment when the following values are reached* Grade 1 Platelet count 75,000–99,999/µL Grade ≥2 Platelet count <75,000/µL Neutropenia Grade 3/4 Neutrophils <1,000/µL Anemia Hemoglobin <8 g/dL ≥100,000/µL ≥1,500/µL ≥9 g/dL Continue monitoring CBCs weekly during the first month after dose modification and modify dose/discontinue treatment if needed First occurrence: Resume treatment at the same or reduced dose Second occurrence: Resume treatment at a reduced dose Discontinue niraparib if the AE has not resolved within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg QD Withhold niraparib for ≤28 days or until resolution of AE Non-hematological AEs Resume treatment at a reduced dose *If the AE has not resolved within 28 days or the dose has already been reduced to 100 mg once daily, treatment should be discontinued. AE, adverse event; CBC, complete blood count; QD, once a day. Adapted from Mirza MR et al. N Engl J Med 2016; 375 (22): 2154–2164 – supplementary material.

Most dose reductions occurred in the first few months of treatment
Niraparib dose level by month among patients remaining on treatment in NOVA1 100 90 80 70 60 50 40 30 20 10 Patients (%) Month Of the 163 patients on niraparib at Month 12, 37 (23%) remained on a daily dose of 300 mg and did not require a dose reduction 1. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255). 164

Dose reductions did not compromise efficacy
PFS after cycle 3 was comparable for patients receiving 100 mg, 200 mg, and 300 mg niraparib Kaplan–Meier estimated probability of PFS by dose beyond cycle 3 Dose optimization period First 3 cycles: Niraparib 300 mg Niraparib 200 mg Niraparib 100 mg BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; PFS, progression-free survival. Figure adapted from Lord L et al. Presentation at SGO 2018; New Orleans, LA, USA, March 24–27, 2018. 165

Predictive value of baseline characteristics for individualized dosing

Body weight at baseline may be a predictive factor for early dose modification
In NOVA, approximately 25% of patients had low body weight (<58 kg) and 25% had high body weight (≥77 kg)1 The incidence of Grade 3/4 thrombocytopenia was higher in patients with low body weight than in patients with high body weight1 Patients (%) <58 kg ≥58 to <77 kg ≥77 kg Weight at baseline Grade 3/4 thrombocytopenia within 30 days of first dose by baseline weight2 Only 13% of patients with low body weight remained on a dose of 300 mg per day beyond cycle 31 For patients weighing less than 58 kg, a starting dose of 200 mg may be considered1 1. TESARO UK Ltd. ZEJULA – summary of product characteristics; February Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255).

Thrombocyte count at baseline
Thrombocyte count at baseline may be a predictive factor for early dose modification Grade 3/4 thrombocytopenia within 30 days of first dose by baseline platelet count1 In NOVA, thrombocytopenia occurred most commonly in patients whose baseline thrombocyte count was lower than 180,000/µL2 Patients (%) Approximately 45% of patients with baseline platelets <180,000/µL experienced Grade 3/4 thrombocytopenia2 ≤180,000/µL 180,000– 215,000/µL 215,000– 273,000/µL ≥273,000/µL Thrombocyte count at baseline 1. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255). 2. TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

Rapid Adjustment of Dose to reduce Adverse Reactions: RADAR analysis
RADAR was an exploratory analysis of data from the NOVA trial that examined predictive factors for the development of Grade 3/4 thrombocytopenia Patients (%) Grade 3/4 thrombocytopenia within 30 days of first dose (integrated analysis of baseline weight and platelet count)1 Body weight <77 kg and/or thrombocyte count <150,000/µL Body weight ≥77 kg and thrombocyte count ≥150,000/µL The patients deemed to be most likely to develop thrombocytopenia had: Baseline body weight lower than 77 kg and/or Baseline thrombocyte count lower than 150,000/µL1,2 1. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255). 2. Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255) – supplementary material.

Dosing amendment based on PRIMA: A Phase III study of niraparib maintenance treatment in patients with advanced ovarian cancer after response on front-line platinum-based chemotherapy

PRIMA dosing amendment
Starting dose in the PRIMA study was determined by initial patient weight and platelet levels In the event of a >Grade 3 AE, dose reductions were mandatory* For a patient with an initial dose of 300 mg, a reduction to 200 mg was allowed For a patient with an initial dose of 200 mg, a reduction to 100 mg was allowed Baseline criteria Niraparib/placebo starting dose ≥77 kg and ≥150,000 platelets/µL 300 mg daily <77 kg or <150,000 platelets/µL 200 mg daily Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib is NOT licensed for the treatment of advanced ovarian cancer after front-line platinum-based therapy. Please consult the summary of product characteristics. *Dose interruption or reduction was also at the investigator’s discretion for an AE of any grade that was deemed intolerable by the patient. AE, adverse event. Gonzalez-Martin A et al. Poster 941PD presented at ESMO 2018; Munich, Germany, October 19–23, 2018.

In the PRIMA study, incidence of hematological AEs was reduced when the starting dose was individualized instead of fixed Hematological toxicities Grade Pre-amendment, fixed starting dose 300 mg QD (pooled niraparib and placebo) N=480 Post-amendment, individualized starting dose mg QD (pooled niraparib and placebo) N=247 Thrombocytopenia Any grade, n (%) 164 (34.2) 50 (20.2) ≥Grade 3, n (%) 110 (22.9) 22 (8.9) Grade 4, n (%) 76 (16.5) 8 (3.2) Anemia* 229 (47.7) 77 (31.2) 101 (21.0) 27 (10.9) Neutropenia† 148 (30.8) 57 (23.1) 75 (15.6) 23 (9.3) Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib is NOT licensed for the treatment of advanced ovarian cancer after front-line platinum-based therapy. Please consult the summary of product characteristics. *Anemia includes reports of anemia and decreased hemoglobin counts. †Neutropenia includes reports of neutropenia, decreased neutrophil count, and febrile neutropenia. QD, once a day. Gonzalez-Martin A et al. Poster 941PD presented at ESMO 2018; Munich, Germany, October 19–23, 2018.

Recommendations for monitoring patients during treatment with niraparib

Complete blood counts are needed regularly at the beginning of therapy
Regardless of starting dose, it is recommended that complete blood counts are taken weekly during the first month of treatment Based on individual laboratory values, weekly monitoring for the second month may be warranted Recommended monitoring schedule: Complete blood counts TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

Blood pressure should be monitored regularly
Regardless of starting dose, it is recommended that blood pressure is monitored monthly during the first year of treatment with niraparib Recommended monitoring schedule: Blood pressure TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

Summary PARP inhibitors are associated with hematological toxicities, including thrombocytopenia1 Grade 3/4 AEs in NOVA were managed with dose interruption and dose reduction2,3 The 200 mg and 100 mg doses were associated with a lower incidence of Grade 3/4 AEs compared with the 300 mg dose, with no reduction in efficacy4 Baseline body weight and thrombocyte count may be predictive of early dose modifications4 Individualized dosing based on body weight and/or thrombocyte count may reduce the need for subsequent dose interruptions In the PRIMA study, incidence of hematological AEs was reduced when the starting dose was individualized instead of fixed at 300 mg QD5 Complete blood counts and blood pressure should be monitored regularly for the first month and first year of treatment, respectively3 AE, adverse event; PARP, poly(ADP-ribose) polymerase; QD, once a day. 1. Evans T et al. Ther Adv Med Oncol 2017; 9 (4): 253– Mirza MR et al. N Engl J Med 2016; 375 (22): 2154– TESARO UK Ltd. ZEJULA – summary of product characteristics; February Berek JS et al. Ann Oncol 2018; Epub ahead of print (DOI: /annonc/mdy255). 5. Gonzalez-Martin A et al. Poster 941PD presented at ESMO 2018; Munich, Germany, October 19–23, 2018. 176

Panel discussion: Practical experiences with niraparib Q&A
Moderated by Patrik Zintl TESARO Bio GmbH, Zug, Switzerland This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Niraparib prescribing information
Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

TESARO is committed to advancing the treatment of ovarian cancer
Guiding principle: Establish monotherapy with niraparib then advance doublet and triplet combinations with bevacizumab, PD‑(L)1s, and novel agents 1 2 3 Establish broad leadership position in first‑line treatment Strengthen leadership position in recurrent platinum‑responsive ovarian cancer Advance standard of care in platinum‑resistant ovarian cancer 1. Monotherapy PRIMA (PhIII): Broaden the nirap label to include maintenance indication in first line 1. Monotherapy NOVA (PhIII): Establish nirap QUADRA (PhII): Broaden nirap indication to include treatment of 4L+ 1. Monotherapy QUADRA (PhII): Secondary endpoints in platinum‑resistant patients treated with nirap 2. Doublet (+bev) OVARIO (PhII): Generate rapid proof‑of‑concept for nirap+bev 2. Doublets (+bev or +PD‑L1) AVANOVA* (PhII): Nirap; nirap+bev ANITA* (PhII/III): Nirap+atezo 2. Doublets (+PD‑1) TOPACIO (PhI/II): Build on signal for nirap+pembro PhIII study: Nirap+TSR‑042 3. Triplet (+PD‑1&±bev) FIRST (PhIII): Expand 1L indication for nirap+TSR‑042±bev 3. Triplet (+bev&+PD‑1) AVANOVA‑IMMUNE* (PhII): Nirap+bev+TSR‑042 3. Triplet (+PD‑1&bev or novel agent) OPAL (PhI/II): Identify breakthrough combinations; prioritize triple combination (nirap+bev+TSR‑042) Click here for more information on TESARO products and pipeline Ongoing trial New studies in progress 1L, first-line; 4L, fourth-line; Atezo, atezolizumab; Bev, bevacizumab; Nirap, niraparib; PD‑1, programmed cell death protein‑1; PD‑L1, programmed death ligand‑1; Pembro, pembrolizumb; Ph, phase.

PRIMA: A Phase III study of niraparib maintenance treatment in patients with advanced ovarian cancer after response on front-line platinum-based chemotherapy NCT Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib is NOT licensed for the treatment of advanced ovarian cancer after front-line platinum-based therapy. Please consult the summary of product characteristics.

The PRIMA study design reflects real‑world clinical practice
SOLO1 (olaparib)1 PRIMA (niraparib)2 Patient population N=391 (randomized to olaparib [n=260] or placebo arm [n=131]) High-grade (Stage III–IV) ovarian, fallopian tube, or primary peritoneal cancer Stage III patients must have had one debulking surgery One attempt at optimal debulking, upfront or IDS Stage IV patients must have had either biopsy and/or debulking surgery Biopsy and/or upfront or interval debulking Completed 1L platinum-based chemo 6-9 cycles of front-line chemotherapy, per protocol CR/PR or NED to 1L platinum regimen Some patients had residual macrospcopic disease BRCAmut (mostly germline; 2 patients had somatic) Randomized within 8 weeks of last dose of chemo N=733 (LPI June 2018; increase from 468) Stage III patients required to have visible residual disease after primary surgery Stage IV patients are eligible, irrespective of residual disease, after primary or interval debulking Patients with inoperable Stage III or IV disease are eligible CR/PR to 1L platinum regimen All comers Randomized within 12 weeks of last dose of chemo Dosing 300 mg BID Dose reduction to 250 mg and 200 mg permitted 200 mg QD starting dose for low body weight (<170 lb) or low baseline platelet count (<150,000 μL) 300 mg QD for all other patients Primary endpoint PFS; investigator-assessed RECIST (scans every 12 weeks up to 3 years; every 24 weeks thereafter until radiological disease progression) PFS; central review RECIST (scans every 12 weeks until progression) Hierarchical testing: HRD+; ITT Key secondary endpoints OS; HRQoL; time to earliest progression by RECIST or CA‑125; PFS2; TFST; TSST; TDT; safety OS; PRO (HRQoL); PFS2; time to CA-125 progression; safety and tolerability 1L, first-line; BID, twice a day; BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; CA-125, cancer antigen-125; CR, complete response; HRD, homologous recombination deficiency; HRQoL, health-related quality of life; IDS, interval debulking surgery; ITT, intention-to-treat; OS, overall survival; LPI, last patient in; PFS, progression-free survival; PFS2, time to second disease progression or death; PR, partial response; PRO, patient-reported outcomes; QD, once a day; RECIST, Response Evaluation Criteria in Solid Tumours; TDT, tumor doubling time; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy. 1. Moore K et al. N Engl J Med 2018; Epub ahead of print (DOI: /NEJMmo18/0858). 2. González A et al. Poster presented at ESGO 2017; Vienna, Austria, November 4–7, 2017.

TOPACIO: A Phase I/II study of niraparib in combination with pembrolizumab in patients with triple‑negative breast cancer or ovarian cancer NCT Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib + pembrolizumab combination therapy is NOT licensed for the treatment of ovarian cancer or triple‑negative breast cancer. Please consult the summary of product characteristics.

Blocking interaction of PD-1 with its ligands may restore anticancer immune function
PD-1 ligands are upregulated in many tumors, including in ovarian cancer1 High expression of PD-L1 in ovarian cancer cells is associated with poor clinical outcome1 Pembrolizumab is a monoclonal antibody that blocks ligand binding of PD-11,2 Pembrolizumab is approved in several cancers, but it is not yet approved for use in ovarian or breast cancer2 PD-1, programmed cell death protein-1; PD-L, programmed death-ligand. 1. Gaillard SL et al. Gynecol Oncol Res Pract 2016; 3: Merck Sharp & Dohme B.V. Keytruda – summary of product characteristics; October 2018.

TOPACIO: Study design Phase I Phase II
TOPACIO Phase I: Dose escalation1 Patients with ovarian or triple-negative breast cancer Phase I Dose 11 Niraparib 200 mg + pembrolizumab 200 mg Dose 21 Niraparib 300 mg + pembrolizumab 200 mg Niraparib dose will be decreased if needed Primary endpoint1 Establish dose-limiting toxicities and establish RP2D Phase II TOPACIO Phase II1 Patients with ovarian cancer or triple-negative breast cancer; Treatment at the RP2D Primary endpoint1 ORR Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.1 Niraparib + pembrolizumab combination therapy is NOT licensed for the treatment of ovarian cancer or triple‑negative breast cancer. Please consult the summary of product characteristics. ORR, objective response rate; RP2D, recommended Phase II dose. 1. Konstantinopoulos PA et al. Poster presented at ESMO 2017; Madrid, Spain, September 8–12, TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

TOPACIO results: Primary endpoint
ORR by RECIST v1.1 RP2D Niraparib 200 mg/day + pembrolizumab 200 mg/21 days Evaluable patients* Integrated efficacy analysis (combined Phase I+II) PROC (N=60) n (%) Still on treatment, n Complete response (CR) 2 (3) 1 Partial response (PR) 13 (22) 8 Stable disease (SD) 26 (43) 9 Progressive disease (PD) 19 (32) 2 ORR (CR + PR) 15 (25) Disease control rate (CR + PR + SD) 41 (68) *Two patients were not evaluable for efficacy; data are immature, responses include both confirmed and unconfirmed; evaluable patients had at least 1 on-treatment scan: data as of January 22, 2018. ORR, objective response rate; PFI, platinum-free interval; RECIST, Response Evaluation Criteria in Solid Tumours. Konstantinopoulos PA et al. Presented at SGO 2018; New Orleans, LA, USA, March 24–27, 2018.

TOPACIO results: Approximately 25% of patients achieved an ORR and 64% achieved a DCR regardless of biomarker presence Response All,* n (%) BRCAmut, n (%) BRCAwt, HRDpos,† HRDneg, ORR 11/46 (24) 2/7 (29) 9/35 (26) 4/15 (27) 7/24 (29) DCR 31/46 (67) 4/7 (57) 23/34 (68) 10/15 (67) 15/24 (63) HRD status does not correlate with response to this combination in platinum‑resistant/platinum‑refractory population The addition of pembrolizumab to niraparib in BRCAwt and HRDneg led to ORR similar to PARP inhibitor efficacy in the BRCAmut population This did not raise new safety concerns during this trial *Patients with inconclusive biomarker results were not included in the biomarker subpopulations. †HRDpos includes BRCA mutation or HRD score ≥42 per Myriad assay. BRCA, breast cancer susceptibility gene; BRCAmut, mutated germline or somatic BRCA gene; BRCAwt, BRCA wild-type; DCR, disease control rate; HRD, homologous recombination deficiency; HRDpos, HRD positive; HRDneg, HRD negative; ORR, objective response rate; PARP, poly(ADP-ribose) polymerase. Konstantinopoulos PA et al. Presented at SGO 2018; New Orleans, LA, USA, March 24–27, 2018.

GARNET: A phase 1 dose escalation and cohort expansion study of TSR-042, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors NCT PD-1, programmed cell death protein-1.

GARNET: Study design Phase I Phase II GARNET Primary endpoint 2B1,2
Part 1: DLT-based dose escalation 1–10 mg/k Q2W (N=21) Phase II Part 2A: Fixed-dose safety cohorts 500 mg Q3W or 1,000 mg Q6W (N=13) Part 2B: Expansion cohorts at RP2D 500 mg Q3W × 4; 1000 mg Q6W MSI-H endometrial cancer (N=65) Endometrial cancer (N=65) NSCLC (N=65) Nonendometrial MSI-H (N=100) Primary endpoint 2B1,2 ORR and DOR per irRECIST assessed by investigators DLT, dose-limiting toxicity; DOR, duration of response; irRECIST, Immune-related Response Evaluation Criteria in Solid Tumours; MSI-H, microsatellite instability-high; NSCLC, non–small cell lung cancer; ORR, objective response rate; PK, pharmacokinetic; Q2W, every 2 weeks; Q6W, every 6 weeks; RP2D, recommended Phase II dose. Oaknin A. Oral presentation at ESMO 2018; Munich, Germany, October 19–23, 2018.

GARNET: Safety1 Thirty-five patients with MSI-H EC received at least one treatment with TSR-042 The safety profile of the MSI-H EC cohort was consistent with the safety profile seen in the overall GARNET study Treatment-related TEAEs were reported in 65.7% of patients; Grade ≥3 treatment-related AEs were reported in 11.4% irAEs related to anti-PD-1 therapies2 were infrequent Serious treatment-related TEAEs were reported in 4 patients (11.4%) Grade ≥3 treatment-related TEAEs, MSI-H EC (n=35) Preferred term Subjects with at least 1 treatment-related Grade ≥3 TEAE, n (%) 4 (11.4) Alanine aminotransferase increased 1 (2.9) Anemia Aspartate aminotransferase increased Leukopenia Neutropenia AE, adverse event; EC, endometrial cancer; irAE, immune-related adverse event; MSI-H, microsatellite instability-high; PD-1, programmed cell death protein-1; TEAE, treatment-emergent adverse event. 1. Oaknin A. Oral presentation at ESMO 2018; Munich, Germany, October 19–23, Wang PF et al. Front Pharmacol 2017; 8: 730.

GARNET: Treatment response and efficacy of RP2D in MSI-H EC patients
Twenty-five patients with MSI-H EC were evaluable Data cut-off date July 2, 2018; patients had at least one tumor assessment or had discontinued treatment The overall response rate was 52% (95% CI: 31.3–72.2), including one patient with unconfirmed PR who is ongoing in the study Twelve out of the 13 responses (92.3%) are ongoing. Three patients with partial response have been receiving TSR-042 for >60 weeks. At RP2D, TSR-042 achieved serum concentrations at least 8-fold higher than required for full receptor occupancy throughout the treatment Best overall response by irRECIST MSI-H EC (n=25) Complete response, n (%) 1 (4) Partial response,* n (%) 12 (48) Stable disease, n (%) 3 (12) Progressive disease, n (%) 7 (28) Not evaluated/done, n (%) 2 (8) Overall response rate, % (95% CI) 52 (31.3–72.2) Disease control rate,† % (95% CI) 64 (42.5–82.0) 150 130 110 90 70 50 30 10 −10 −30 −50 −70 −90 −110 Percentage change (%) Subject Ongoing Treatment discontinued PD S N P C *11 confirmed and 1 unconfirmed PR. †C+P+PD+S. C, immune-related complete response; CI, confidence interval; irRECIST, Immune-related Response Evaluation Criteria in Solid Tumours; MSI-H EC, microsatellite instability-high endometrial cancer; N, non-evaluable; P, immune-related partial response; PD, immune-related progressive disease; PR, partial response; S, immune-related stable disease; RP2D, recommended Phase II dose. Oaknin A. Oral presentation at ESMO 2018; Munich, Germany, October 19–23, 2018.

FIRST: A Phase III comparison of platinum‑based therapy with TSR‑042 and niraparib versus standard of care platinum‑based therapy as first‑line treatment of Stage III/IV non‑mucinous epithelial ovarian cancer NCT Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib is not licensed for use in combination with bevacizumab. Please consult the summary of product characteristics.

FIRST: Study design Newly diagnosed patients with advanced Stage III/IV cancer Cycle 1: Carboplatin + paclitaxel ± bevacizumab Randomization (N=~720–960) Treatment 21-day cycle × 5 cycles Carboplatin + paclitaxel + placebo (TSR-042) Carboplatin + paclitaxel + placebo (TSR-042) Carboplatin + paclitaxel + TSR-042 ± Bevacizumab Maintenance up to 3 years Placebo (TSR-042) + placebo (niraparib) Placebo (TSR-042) + niraparib TSR-042 + niraparib ± Bevacizumab (i.e. maintenance doublets and triplets) Primary endpoint PFS by investigator-assessment per RECIST v1.1 criteria Secondary endpoint OS • PFS by BICR • HRQoL • Safety and tolerability • PFS by irRECIST Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.2 Niraparib is NOT licensed for the treatment of advanced ovarian cancer after front-line platinum-based therapy. Please consult the summary of product characteristics. Adaptive design anticipates evolving first-line standard of care: double-placebo maintenance arm may be transitioned to niraparib maintenance for BRCAmut (pending SOLO-1 success) and BRCAwt (pending PRIMA success) patients over time. BRCA, breast cancer susceptibility gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; HRD, homologous recombination deficiency; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours; BICR, blinded independent central review; irRECIST, Immune-related Response Evaluation Criteria in Solid Tumours; HRQoL, health-related quality of life; OS, overall survival. 1. ClinicalTrials.gov FIRST. Available at: Accessed October TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

AVANOVA: A Phase I/II trial of niraparib in combination with bevacizumab
NCT Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. Niraparib is not licensed for use in combination with bevacizumab. Please consult the summary of product characteristics.

AVANOVA: Study design Phase I1 Patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer Niraparib + bevacizumab combination therapy at escalating doses*,1 Primary endpoint Safety and tolerability of niraparib + bevacizumab combination Phase II1 Patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer, with high-grade serous or endometrioid histology Niraparib 300 mg monotherapy1,2 Niraparib 300 mg monotherapy + bevacizumab 15 mg/kg combination therapy1,2 Secondary endpoint DCR Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.3 Niraparib is not licensed for use in combination with bevacizumab. Please consult the summary of product characteristics. *To determine the recommended Phase III dose. DCR, disease control rate; PFS, progression-free survival. 1. ClinicalTrials.gov AVANOVA. Available at: Accessed October TESARO, Inc. Data on file. 3. TESARO UK Ltd. ZEJULA – summary of product characteristics; February 2018.

AVANOVA: Efficacy Disease control rate (CR + PR + SD) was achieved in 92% of patients Response rate (CR + PR) was achieved in 50% of patients PFS (median) was 49 weeks Response n (%) (N=12) CR 1 (8) PR 5 (42) SD PD PFS CR, complete response; PR, partial response; PD, progressive disease; PFS, progression-free survival; SD, stable disease. Mirza MR et al. Poster 953P at ESMO 2017; Madrid, Spain, September 8–12, 2017.

Niraparib: Looking forward
TESARO is committed to broadening the availability of niraparib to different groups of patients with recurrent ovarian cancer PRIMA will assess the efficacy of niraparib after response to front-line platinum therapy1 Ongoing Phase II/III studies aim to assess the efficacy of combining niraparib with other anticancer agents TOPACIO has shown niraparib + pembrolizumab combination therapy provides a clinical benefit in patients with platinum‑resistant/refractory disease, across biomarker- selected populations including BRCAwt and HRDneg2,3 No new safety signals were detected FIRST will investigate the efficacy of platinum‑based therapy + TSR‑042 and niraparib vs. standard of care platinum‑based therapy as first‑line treatment in patients with newly diagnosed Stage III/IV non‑mucinous epithelial ovarian cancer4 The investigator‑initiated AVANOVA study will investigate the efficacy of niraparib + bevacizumab combination therapy in patients with ovarian cancer5 BRCA, breast cancer susceptibility gene; BRCAwt, wild-type breast cancer susceptibility gene; HRD, homologous recombination deficiency; HRDneg, HRD negative. 1. González A et al. Poster presented at ESGO 2017; Vienna, Austria, November 4–7, Konstantinopoulos PA et al. Poster presented at ESMO 2017; Madrid, Spain, September 8–12, Konstantinopoulos PA et al. Presented at SGO 2018; New Orleans, LA, USA, March 24–27, ClinicalTrials.gov FIRST. Available at: Accessed October ClinicalTrials.gov AVANOVA. Available at: Accessed October 2018.

Day 1 close Patrik Zintl TESARO Bio GmbH, Zug, Switzerland
This meeting is organized and funded by TESARO Bio GmbH. November 2018 | NP-ZEJ-INT-0004

Thank you for your participation in Day 1
We hope today’s presentations and panel discussion have enabled you to: Learn about the key niraparib clinical trial data and how to apply these in the real‑world setting Think about the types of challenges and queries your colleagues may raise and how to address them Consider the available niraparib data and how these data can be used to overcome challenges and respond to queries

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