Clinical Development of Rucaparib Rucaparib is an investigational [PDF]

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Rucaparib is an investigational product and not approved by any health authority. Conclusions about efficacy and safety cannot be made

Clinical Development of Rucaparib

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Development of HRD/LOH Signature

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Development Strategy

Initial goal: Identify all rucaparib

responsive patients using tumor DNA sequence data

Partnership with Foundation Medicine
Conduct trials in all-comer populations,

not just gBRCAmut

Focus on ovarian cancer
Initial hypothesis: HRD patients will

respond to rucaparib

− gBRCAmut - known − sBRCAmut - not known − BRCAWT but HRD (“BRCA-like”); not known

Key issue: Defining BRCA-like

All Ovarian Cancer Patients BRCAmut HRD

gBRCAmut = germline mutation sBRCAmut = somatic BRCA mutation BRCAWT = BRCA wild type HRD = homologous recombination deficient 3

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BRCA1/2

RAD51

PALB2

PARP Inhibitors are Synthetically Lethal to BRCAmut and BRCA-Like Tumor Cells with Homologous Recombination Deficiency (HRD)

Cell death Cell deficient in HR Cell survival Cell proficient in HR P A R P I N H I B I T O R

HR is a complex process requiring coordinated function of many gene products Genetic and epigenetic dysregulation cause HRD, resulting in tumor tissue BRCAmut and BRCA-like tumors that are sensitive to PARP inhibitors

HR, homologous recombination; HRD, HR-deficient; PALB2, partner and localizer of BRCA2; RAD51, homolog of the bacterial RecA protein. Kristeleit R, et al. ECC-ESMO 2015. Abstract 2700.

4 | Confidential

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Loss of Heterozygosity (LOH) is a Marker of Genomic Scarring in HRD Ovarian Cancer

Loss of heterozygosity (LOH) is a large-scale (Mbp) chromosomal event resulting in the

loss of varying lengths of DNA that represents a phenotypic marker of Homologous Recombination Deficiency (HRD).

Increased LOH correlates with BRCA mutation and platinum sensitivity in HGSOC
LOH can be quantified by analysis of single nucleotide polymorphisms (SNPs) across

the genome

Clovis partnered with Foundation Medicine to develop a CoDx evaluating tumor

genome-wide LOH and BRCA mutation status

Normal chromosome pair (diploid) Chromosome pair with LOH

AAAAAAAAAAAAAAAAAAAAA BBBBBBBBBBBBBBBBBBBBB AAAAAAAAAAAAAAAAAAAAA BAABBBBBBBBBBBBBAABBB

SNP profile of normal:

LOH, loss of heterozygosity; NGS, next generation sequencing; SNP, single nucleotide polymorphism. Swisher E, et al. AACR 2014. Abstract CT339; McNeish I, et al. IGCS 2014. Abstract 0211.

SNP profile of LOH : 5

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BRCAmut BRCA-like Biomarker Negative

Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCA-like signature will respond to rucaparib. Hypothesis 2: Ovarian cancer patients who are “Biomarker Negative” (ie, with low genomic LOH) will not respond to rucaparib.

BRCAwt

TCGA and AOCS ovarian genomic data and overall survival data was used to develop LOH cutoff to

prospectively identify HGSOC patients with a BRCA-like signature in ARIEL2 study

NGS=next-generation sequencing; mut=mutation; wt=wild type.

Genome-Wide LOH Quantified by FoundationOne SNP NGS is employed for Prospective Patient Selection in ARIEL Studies

Kristeleit R et al. Presented at ECC-ESMO 2015. Abstract 2700.

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HGSOC Patients can be Classified into Three Molecular Subgroups: BRCAmut, BRCA-like, Biomarker Negative

Frequency of Tumors Extent of Genomic LOH

Genomic LOH cutoff

Biomarker Negative BRCA-like

BRCAwt BRCAmut

Kristeleit R et al. Presented at ECC-ESMO 2015. Abstract 2700

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Summary

BRCA-like phenotype considers the whole genomic signature of patients with ovarian cancer to

predict treatment response to PARP inhibitors − HRD leads to LOH across the genome, the extent of which is used to define BRCA-like phenotype

Clovis Oncology and Foundation Medicine have collaborated to develop an NGS-based HRD

companion diagnostic test − This HRD test incorporating analyses of both tumor tissue BRCAmut and BRCA-like (in later version) signatures may identify additional patients with ovarian cancer who may be likely to respond to rucaparib

The ARIEL clinical development program is underway and aims to identify and prospectively test

the utility of the HRD diagnostic test in the treatment (ARIEL2) and maintenance (ARIEL3) settings

NGS, next-generation sequencing.

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Rucaparib Company-Sponsored Clinical Development Program

BRCAmut, BRCA mutant; HRD, homologous recombination deficiency; PK, pharmacokinetics; AR; androgen-receptor

CO-338-010 NCT01482715 Treatment setting Part 1

Phase I Dose escalation Any solid tumor

Part 2 Part 3

PK

ARIEL2/CO-338-017 NCT01891344 Treatment setting Part 1 Part 2 ARIEL3/ CO-338-014 NCT01968213

Maintenance setting

ARIEL4 Treatment setting 2A (Phase II)

Platinum sensitive
Relapsed ovarian

cancer (germline BRCAmut)

2–4 prior

treatments

2B (Phase II)

Relapsed ovarian

cancer (germline or somatic BRCAmut)

≥3 prior

chemotherapy regimens

Phase II

Development of

HRD signature

Relapsed
varian cancer
Platinum

sensitive

All comers

(Known germline BRCAmut)

>1 prior platinum-

based treatment

Phase III

Randomized;

blinded rucaparib (maintenance) vs placebo after response to platinum-based chemotherapy

Confirmatory study
≥2 prior platinum-

based treatments

Phase III

Randomized;

rucaparib vs chemotherapy

Confirmatory study

Phase II

Refinement of

HRD signature

Relapsed
varian cancer
All comers
≥3 prior

chemotherapy regimens

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TRITON 2 Treatment setting TRITON 3 Treatment setting Phase II

Metastatic

castrate-resistant prostate cancer

Biomarker

selected

>2 prior therapies

including AR- targeted and taxane

Phase III

Metastatic

castrate-resistant prostate cancer

Biomarker

selected

Chemo-naïve,

progression following one AR- targeted therapy

Randomised:

Rucaparib v chemotherapy or AR-targeted therapy

Ovarian Cancer Prostate Cancer

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Investigator Initiated Trials (IIT’s)

Clovis Oncology supports ethical, independent, investigator initiated research designed to advance scientific knowledge of the

disease state, patient populations and medical treatments in alignment with Clovis Oncology’s clinical and non-clinical areas of interest as outlined in the previous slides.

Clovis Oncology supports the funding of IIT’s with defined processes and governance measures in place, with independent

investigators and co-operative groups. The IIT is conducted independently of Clovis Oncology with the following focus:

Identify all rucaparib responsive patients using tumor DNA sequence data
Conduct trials in all-comer populations, not just gBRCAmut
Company sponsored studies and supportive studies in ovarian and prostate cancer indications
Identify which Homologous Recombination Deficient (HRD) patients will respond to rucaparib and defining “BRCA-like” tumours
Identify combination therapies which may provide incremental patient benefit
Approval of an IIT in a specific indication does not preclude other IIT proposals being considered in that indication provided there is

strong clinical or non clinical rationale for the question, that has not already been addressed.

Areas where IIT’s have been supported as of October 2016 include HER2(-), BRCAmut or BRCAwt/LOHHigh breast cancer; neoadjuvant triple

negative breast cancer ; 1L maintenance oesophago-gastric and 1L maintenance ovarian cancer, Prostate cancer, Pancreatic cancer, Solid Tumour Basket studies, Mesothelioma and Radiotherapy Combinations. This list is being constantly updated as new proposals are received and reviewed and therefore is a snap shot view. Investigators should discuss proposals with Clovis Oncology when an IIT concept is being developed.

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Clinical Activity of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib in Patients with High-Grade Ovarian Carcinoma and a BRCA Mutation: Analysis of Pooled Data from Study 10 (Parts 1, 2a, and 3) and ARIEL2 (Parts 1 and 2)

Rebecca S. Kristeleit,1 Ronnie Shapira-Frommer,2 Ana Oaknin,3 Judith Balmaña,3 Isabelle Ray-Coquard,4 Susan Domchek,5 Anna V. Tinker,6 Cesar Castro,7 Stephen Welch,8 Andres Poveda,9 Kathy Bell-McGuinn,10 Gottfried Konecny,11 Heidi Giordano,12 Lara Maloney,12 Sandra Goble,12 Lindsey Rolfe,12 Amit M. Oza13

1University College London, Cancer Institute, London, UK; 2Sheba Medical Center, Ramat Gan, Israel; 3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4GINECO, Centre Léon Bérard and University Claude Bernard, Lyon, France; 5University of Pennsylvania,

Philadelphia, PA, USA; 6British Columbia Cancer Agency, Vancouver, BC, Canada; 7Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA; 8Division of Medical Oncology, London Regional Cancer Program, London, ON, Canada; 9Clinical Area of Gynecologic Oncology, Valencian Institute of Oncology, Valencia, Spain; 10Memorial Sloan-Kettering Cancer Center, New York, NY, USA;

11University of California Los Angeles, Los Angeles, CA, USA; 12Clovis Oncology, Inc., Boulder, CO, USA; 13Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

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Background

Approximately 14%–18% of epithelial ovarian cancers harbour a germline BRCA1
r BRCA2 mutation (BRCAmut); 5%–7% harbour a somatic BRCAmut1–3
The PARP inhibitor rucaparib has demonstrated clinical activity in BRCAmut high-

grade ovarian carcinoma (HGOC) in two phase 2 studies in the treatment setting4,5

Data from these studies, Study 10 (NCT01482715) and ARIEL2 (NCT01891344),

were combined for an integrated efficacy and safety analysis

– These analyses further characterise the clinical benefit of rucaparib (600 mg BID) in the treatment setting in patients with BRCAmut HGOC who have received ≥2 prior chemotherapy regimens

1. The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-15; 2. Pennington KP et al. Clin Cancer Res. 2014;20:764-75; 3.

Moschetta M et al. Ann Oncol. 2016;27:1449-55; 4. Shapira-Frommer R et al. Eur J Cancer. 2015;51:S545; abstract 2746;

5. Coleman RL et al. J Clin Oncol. 2016;4(suppl 15):abstract 5540

BID, twice daily.

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Efficacy and Safety Populations

Criteria

Diagnosis of ovarian cancer (inclusive of primary peritoneal

and fallopian tube cancer)

Enrolled at 600 mg BID dosing level and received ≥1 dose of

rucaparib 600 mg Criteria

Received ≥2 prior chemotherapies, including ≥2

platinum-based regimens

Had a deleterious germline BRCA or somatic BRCA mutation
Enrolled at 600 mg BID dosing level and received ≥1 dose of

rucaparib 600 mg Study 10 (NCT01482715) n=62 n=42 ARIEL2 (NCT01891344) n=315 n=64 Safety Population (n=377) Efficacy Population (n=106)

Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).

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Patient Characteristics

Efficacy population n=106 Safety population n=377 Median age (range), years 59 (33–84) 62 (31–86) ECOG Performance Status, n (%) 65 (61.3) 233 (61.8) 1 41 (38.7) 144 (38.2) Cancer type, n (%) Epithelial ovarian 91 (85.8) 305 (80.9) Primary peritoneal 6 (5.7) 39 (10.3) Fallopian 9 (8.5) 33 (8.8) BRCA mutation, n (%) Germline 88 (83.0) 108 (28.6) Somatic 13 (12.3) 23 (6.1) Origin uncertain 5 (4.7) 12 (3.2) No mutation 0 (0.0) 234 (62.1) BRCA gene mutation, n (%) BRCA1 67 (63.2) NA BRCA2 39 (36.8) NA

Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). ECOG, Eastern Cooperative Oncology Group; NA, not applicable.

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Patient Characteristics

Efficacy population n=106 Safety population n=377 Median number of prior chemotherapies (range) 3 (2–6) 2 (1–7) 1 prior therapy, n (%) 127 (33.7) 2 prior therapies, n (%) 41 (38.7) 85 (22.5) ≥3 prior therapies, n (%) 65 (61.3) 165 (43.8) Median number of platinum-based therapies (range) 2 (2–5) 2 (1–5) 1 prior platinum-based therapy, n (%) 131 (34.7) 2 prior platinum-based therapies, n (%) 60 (56.6) 144 (38.2) ≥3 prior platinum-based therapies, n (%) 46 (43.4) 102 (27.1) PFI from latest platinum regimen, n (%) <6 months 27 (25.5) 90 (23.9) ≥6–12 months 56 (52.8) 152 (40.3) >12 months 23 (21.7) 129 (34.2) Missing 6 (1.6) Platinum response (most recent therapy), n (%) Sensitive (recurrence after PFI ≥6 months) 79 (74.5) 283 (75.1) Resistant (recurrence after PFI <6 months) 20 (18.9) 67 (17.8) Refractory (progression on platinum, PFI <2 months) 7 (6.6) 26 (6.9) Unknown 1 (0.3)

Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). PFI, progression-free interval.

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Progression-Free Survival in the Efficacy Population

At risk (events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56)

Median (months) 95% CI Range 10.0 7.3–12.5 0.0–22.1+ + Censored; Censoring rate: 47%

Of 106 patients, 50 did not have an event of disease progression or death at the data cutoff dates

– Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease progression or death at the data cutoff dates

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CI, confidence interval.

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Progression-Free Survival in the Efficacy Population

Median (months) 95% CI Range 10.0 7.3–12.5 0.0–22.1+ + Censored; Censoring rate: 47% Progression-free at 6 months: 79%

Progression-free at 12 months: 41%

At risk (events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56)

Of 106 patients, 50 did not have an event of disease progression or death at the data cutoff dates

– Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease progression or death at the data cutoff dates

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CI, confidence interval.

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Investigator-Assessed ORR in the Efficacy Population

Parameter Study 10 n=42 ARIEL2 n=64 Efficacy population n=106 n (%) [95% CI] Investigator-assessed RECIST ORR (confirmed CR+PR) 25 (59.5) [43.3–74.4] 32 (50.0) [37.2–62.8] 57 (53.8) [43.8–63.5] CR 4 (9.5) 5 (7.8) 9 (8.5) PR 21 (50.0) 27 (42.2) 48 (45.3) SD 12 (28.6) 24 (37.5) 36 (34.0) PD 2 (4.8) 7 (10.9) 9 (8.5) NE 3 (7.1) 1 (1.6) 4 (3.8) Investigator-assessed RECIST/GCIG CA-125 ORR 75 (70.8) [61.1–79.2]

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

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Response by Subgroups

ORR, % (95% CI)

53.8 (43.8–63.5) 53.4 (42.5–64.1) 46.2 (19.2–74.9) 80.0 (28.4–99.5) 53.7 (41.1–66.0) 53.8 (37.2–69.9) 68.3 (51.9–81.9) 53.8 (43.8–63.5) 65.0 (51.6–76.9) 53.8 (43.8–63.5) 18.5 (6.3–38.1) 62.5 (48.6–75.1) 73.9 (51.6–89.8) 0 (0.0–41.0) 25.0 (8.7–49.1) 65.8 (54.3–76.1)

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).

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Best Response for Target Lesions in the Efficacy Population

*Three patients did not have a post baseline scan; †For unconfirmed responses; includes the best percent change from baseline up to and including the first

verall response of progressive disease.

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). + + + ++ ++ ++++ + + + + + + + + ++ + ++ + +++++ ++ + ++++

120
100
80
60
40
20

20 40 60 80 Change from Baseline in Sum of the Diameter of Target Lesions† (%)

N=103* + = Ongoing BRCA1 BRCA2

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Best Response for Target Lesions in the Efficacy Population

+ + + ++ ++ ++++ + + + + + + + + ++ + ++ + +++++ ++ + ++++

120
100
80
60
40
20

20 40 60 80 Change from Baseline in Sum of the Diameter of Target Lesions† (%)

N=103* + = Ongoing BRCA1 BRCA2 BRCA mutation origin uncertain Somatic BRCA mutation Germline BRCA mutation

*Three patients did not have a post baseline scan; †For unconfirmed responses; includes the best percent change from baseline up to and including the first

verall response of progressive disease.

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).

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Duration of Response in the Efficacy Population

Median (months) 95% CI Range 9.2 6.6–11.7 1.7–19.8+ + Censored; censoring rate: 47%

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).

At risk (events) 57 (0) 57 (0) 52 (1) 50 (1) 44 (4) 41 (5) 27 (15) 25 (16) 19 (19) 17 (20) 12 (23) 11 (24) 9 (26) 6 (28) 3 (29) 2 (29) 2 (29) 2 (29) 2 (29) 1 (30) 0 (30)

Of the 57 patients with a response, 27 did not have an event of disease progression or death at the data cutoff dates

– Of these 27 patients, 20 were still on treatment, and 7 discontinued treatment for reasons other than disease progression

r death at the data cutoff dates

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Safety Summary: All Ovarian Cancer Patients Who Received ≥1 Dose

f Rucaparib 600 mg

Parameter Ovarian cancer patients n=377 Any all-grade AE, n (%) 377 (100.0) Treatment-related all-grade AE, n (%) 360 (95.5) Any grade ≥3 AE, n (%) 229 (60.7) Treatment-related grade ≥3 AE, n (%) 177 (46.9) AE leading to dose interruption, n (%) 221 (58.6) AE leading to dose reduction, n (%) 173 (45.9) Treatment-related AE leading to dose reduction, n (%) 167 (44.3) AE leading to treatment discontinuation*, n (%) 50 (13.3) Treatment-related AE leading to discontinuation, n (%) 30 (8.0) Any AE leading to death, n (%) 9 (2.4) Malignant neoplasm progression, n (%) 8 (2.1) Nonprogression AE leading to death, n (%) 1 (0.3)†

*Excludes patients who discontinued due to disease progression; †Patient died of sepsis, which was assessed by the investigator as not related to rucaparib. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016) AE, adverse event.

Median dose intensity (actual dose received/first dose received) was 0.92 (range, 0.1–1.3)
Primary reasons for dose reduction: anemia/decreased hemoglobin (17.2%), asthenia/fatigue (14.1%), and nausea (11.1%)
Primary reasons for treatment discontinuation: asthenia/fatigue (2.4%), small intestinal obstruction (1.9%), and nausea (1.3%)

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Treatment-Emergent Adverse Events: ≥20% All Grade

Term Ovarian cancer patients n=377 All grade, n (%) Grade 3/4, n (%) Nausea 290 (76.9) 19 (5.0) Asthenia/fatigue* 289 (76.7) 41 (10.9) Vomiting 174 (46.2) 15 (4.0) Anaemia* 165 (43.8) 94 (24.9) ALT/AST increased* 156 (41.4) 41 (10.9) Constipation 150 (39.8) 6 (1.6) Decreased appetite 148 (39.3) 10 (2.7) Dysgeusia 148 (39.3) 1 (0.3) Diarrhoea 130 (34.5) 9 (2.4) Abdominal Pain 119 (31.6) 13 (3.4) Dyspnoea 81 (21.5) 2 (0.5) Thrombocytopoenia* 79 (21.0) 17 (4.5) Blood creatinine increased 79 (21.0) 2 (0.5)

Myelodysplastic syndrome/acute myeloid leukemia was reported in <1% of patients

*Combined terms. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016) ALT, alanine aminotransferase; AST; aspartate aminotransferase.

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Laboratory Abnormalities: Shifts from Baseline

Term Ovarian cancer patients n=375* Any worsening shift from baseline, n (%) Maximum shift to grade 3/4, n (%) Increase in creatinine 347 (92.5) 5 (1.3) Increase in ALT 279 (74.4) 47 (12.5) Increase in AST 276 (73.6) 17 (4.5) Decrease in haemoglobin 251 (66.9) 88 (23.5) Decrease in lymphocytes† 168 (45.3) 26 (7.0) Increase in cholesterol‡ 150 (41.0) 9 (2.5) Decrease in platelets 147 (39.2) 23 (6.1) Decrease in neutrophils 132 (35.2) 37 (9.9)

Increases in AST (SGOT) and ALT (SGPT) levels normalised over time with continued treatment
Elevations in creatinine likely result from inhibition of the renal transporters MATE1 and MATE2-K

*Data shown for patients with both baseline and post-baseline results; †n=371; ‡n=366. Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.

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Conclusions

Rucaparib is active in patients with germline or somatic BRCAmut high-grade ovarian cancer

who have received ≥2 prior chemotherapies in the treatment setting

– Response rates were highest in patients who had a PFI ≥6 months (65.8%) or were limited to 2 prior lines of therapy (68.3%) – Response to rucaparib was durable (median duration of response, 9.2 months; 95% CI 6.6–11.7)

Rucaparib has a manageable safety profile

– Adverse events were managed with treatment interruption or dose modification

Two randomised, phase 3 confirmatory trials are ongoing

– In the maintenance setting in patients with relapsed high-grade ovarian cancer (ARIEL3; NCT01968213) – In the treatment setting in comparison to standard chemotherapy (ARIEL4; NCT02855944)