OlympiAD: Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02000622
• Collaborator: Myriad Genetic Laboratories, Inc. (Industry), Merck Sharp & Dohme LLC (Industry)
• Enrollment: 302
• Locations: 172
• Arms: 2
• Anticipated Duration (Months): 105.1
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This open label, randomised, controlled, multi-centre phase III study will assess the efficacy and safety of single agent olaparib vs standard of care based on physician's choice of capecitabine, vinorelbine or eribulin in metastatic breast cancer patients with gBRCA 1/2 mutations.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Metastatic; BRCA 1 Gene Mutation; BRCA 2 Gene Mutation	Drug: Olaparib; Drug: Physician's choice chemotherapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to Assess the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.
• Actual Study Start Date: Mar 27, 2014
• Actual Primary Completion Date: Dec 9, 2016
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olaparib Olaparib tablet 300mg bd po	Drug: Olaparib; Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 mL of water.
Active Comparator: Physician's choice chemotherapy Capecitabine 2500 mg/m2 d1-14 q 21, or Vinorelbine 30 mg/m2 d1,8 q 21, or Eribulin 1.4 mg/m2 d1,8 q 21	Drug: Physician's choice chemotherapy; Investigators will declare one of the following regimens: Capecitabine 2500 mg/m2 po daily (divided in 2 doses) x 14 days, repeat every 21 days Vinorelbine 30 mg/m2 IV Day 1 and Day 8, repeat every 21 days Eribulin 1.4 mg/m2 IV Day 1 and Day 8, repeat every 21 days

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) [Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.]

   Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Time to Second Progression or Death (PFS2) [Second progression status reviewed every 8 weeks following the first objective radiological progression as per investigator assessment. Assessed up to a maximum of 30 months.]

   Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination.

2. Overall Survival (OS) [Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 30 months.]

   Time from randomisation until death due to any cause.

3. Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) [Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.]

   Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR.

4. Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) [EORTC QLQ-C30 assessments performed at baseline then every ~6 weeks until objective radiological disease progression. Assessed up to a maximum of 30 months.]

   Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL.

5. Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm [Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.]

   Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).

6. Overall Survival (OS) at Final OS [Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 40 months.]

   Time from randomisation until death due to any cause.

7. Overall Survival (OS) at Extended OS [Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.]

   Time from randomisation until death due to any cause.

Other Outcome Measures

1. Time to First Subsequent Cancer Therapy or Death (TFST) [Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.]

   Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.

2. Time to Second Subsequent Cancer Therapy or Death (TSST) [Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.]

   Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.

3. Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS [Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.]

   Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.

4. Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS [Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.]

   Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious.

• Histologically or cytologically confirmed breast cancer with evidence of metastatic disease.

• Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting.

• Prior platinum allowed as long as no breast cancer progression occurred on treatment or if given in adjuvant/neoadjuvant setting at least 12 months from last dose to study entry elapsed.

• ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy.

• ECOG performance status 0-1.

• Adequate bone marrow, kidney and liver function.

Exclusion Criteria:

• Prior treatment with PARP inhibitor.

• Patients with HER2 positive disease.

• More than 2 prior lines of chemotherapy for metastatic breast cancer.

• Untreated and/or uncontrolled brain metastases.

• Prior malignancy unless curatively treated and disease-free for > 5 years prior to study entry. Prior adequately treated non-melanoma skin cancer, in situ cancer of the cervix, DCIS or stage I grade 1 endometrial cancer allowed.

• Known HIV (Human Immunodeficiency Virus) infection.

• Pregnant or breast-feeding women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	San Diego	California	United States	92123
2	Research Site	Santa Rosa	California	United States	95403
3	Research Site	Whittier	California	United States	90602
4	Research Site	Denver	Colorado	United States	80204
5	Research Site	New Haven	Connecticut	United States	06510
6	Research Site	Washington	District of Columbia	United States	20007
7	Research Site	Jacksonville	Florida	United States	32224
8	Research Site	Orlando	Florida	United States	32804
9	Research Site	Plantation	Florida	United States	33324
10	Research Site	Columbus	Georgia	United States	31904
11	Research Site	Marietta	Georgia	United States	30060
12	Research Site	Chicago	Illinois	United States	60612
13	Research Site	Niles	Illinois	United States	60714
14	Research Site	Wichita	Kansas	United States	67214
15	Research Site	Lafayette	Louisiana	United States	70506
16	Research Site	Boston	Massachusetts	United States	02114
17	Research Site	Boston	Massachusetts	United States	02118
18	Research Site	Boston	Massachusetts	United States	02215
19	Research Site	Detroit	Michigan	United States	48201
20	Research Site	Grand Rapids	Michigan	United States	49503
21	Research Site	Rochester	Minnesota	United States	55905-0001
22	Research Site	Saint Louis Park	Minnesota	United States	55416
23	Research Site	Jackson	Mississippi	United States	39202
24	Research Site	Columbia	Missouri	United States	65212
25	Research Site	Saint Louis	Missouri	United States	63131
26	Research Site	Lebanon	New Hampshire	United States	03756
27	Research Site	Commack	New York	United States	11725
28	Research Site	Harrison	New York	United States	10604
29	Research Site	New York	New York	United States	10021
30	Research Site	New York	New York	United States	10065
31	Research Site	Rockville Centre	New York	United States	11570
32	Research Site	Syracuse	New York	United States	13210
33	Research Site	Cincinnati	Ohio	United States	45267
34	Research Site	Cleveland	Ohio	United States	44106
35	Research Site	Cleveland	Ohio	United States	44195
36	Research Site	Portland	Oregon	United States	97213
37	Research Site	Philadelphia	Pennsylvania	United States	19104
38	Research Site	Sayre	Pennsylvania	United States	18840
39	Research Site	Germantown	Tennessee	United States	38138
40	Research Site	Houston	Texas	United States	77030
41	Research Site	Tyler	Texas	United States	75701
42	Research Site	Burlington	Vermont	United States	05401
43	Research Site	Plovdiv		Bulgaria	4000
44	Research Site	Plovdiv		Bulgaria	4004
45	Research Site	Sofia		Bulgaria	1233
46	Research Site	Sofia		Bulgaria	1303
47	Research Site	Sofia		Bulgaria	1330
48	Research Site	Sofia		Bulgaria	1504
49	Research Site	Varna		Bulgaria	9010
50	Research Site	Vratza		Bulgaria	3000
51	Research Site	Beijing		China	100006
52	Research Site	Beijing		China	100021
53	Research Site	Beijing		China	100142
54	Research Site	Changchun		China	130061
55	Research Site	Changsha		China	410013
56	Research Site	Chengdu		China	610041
57	Research Site	Dalian		China	116011
58	Research Site	Guangzhou		China	510060
59	Research Site	Hangzhou		China	310022
60	Research Site	Harbin		China	150081
61	Research Site	Nanjing		China	210009
62	Research Site	Shanghai		China	200025
63	Research Site	Shanghai		China	200032
64	Research Site	Shenyang		China	110016
65	Research Site	Tianjin		China	300060
66	Research Site	Brno		Czechia	656 53
67	Research Site	Olomouc		Czechia	775 20
68	Research Site	Praha 2		Czechia	128 08
69	Research Site	Caen Cedex		France	14076
70	Research Site	Montpellier		France	34298
71	Research Site	Rouen		France	76038
72	Research Site	Strasbourg Cedex		France	67065
73	Research Site	Villejuif		France	94800
74	Research Site	Budapest		Hungary	1032
75	Research Site	Budapest		Hungary	1083
76	Research Site	Budapest		Hungary	1115
77	Research Site	Budapest		Hungary	1122
78	Research Site	Budapest		Hungary	1145
79	Research Site	Nyíregyháza		Hungary	4400
80	Research Site	Veszprém		Hungary	8200
81	Research Site	Bologna		Italy	40138
82	Research Site	Napoli		Italy	80131
83	Research Site	Padova		Italy	35128
84	Research Site	Roma		Italy	00144
85	Research Site	Roma		Italy	00168
86	Research Site	Rozzano		Italy	20089
87	Research Site	Chuo-ku		Japan	104-0045
88	Research Site	Chuo-ku		Japan	104-8560
89	Research Site	Fukuoka-shi		Japan	811-1395
90	Research Site	Kagoshima-shi		Japan	892-0833
91	Research Site	Nagoya-shi		Japan	464-8681
92	Research Site	Osaka-city		Japan	540-0006
93	Research Site	Sapporo-shi		Japan	003-0804
94	Research Site	Shinagawa-ku		Japan	142-8666
95	Research Site	Suita-city		Japan	565-0871
96	Research Site	Cheongju-si		Korea, Republic of	28644
97	Research Site	Daegu		Korea, Republic of	41404
98	Research Site	Incheon		Korea, Republic of	21565
99	Research Site	Seongnam-si		Korea, Republic of	13620
100	Research Site	Seoul		Korea, Republic of	03080
101	Research Site	Seoul		Korea, Republic of	03722
102	Research Site	Seoul		Korea, Republic of	135-710
103	Research Site	Seoul		Korea, Republic of	158-710
104	Research Site	Estado de México		Mexico	50080
105	Research Site	Merida		Mexico	97000
106	Research Site	Merida		Mexico	97133
107	Research Site	Mexico		Mexico	6760
108	Research Site	Mérida		Mexico	97070
109	Research Site	San Juan del Rio		Mexico	76800
110	Research Site	Cusco		Peru	CUSCO 01
111	Research Site	Lima		Peru	LIMA 01
112	Research Site	Lima		Peru	Lima 18
113	Research Site	Lima		Peru	LIMA 27
114	Research Site	Lima		Peru	LIMA 34
115	Research Site	Lima		Peru	LIMA 41
116	Research Site	San Borja		Peru	LIMA 41
117	Research Site	Elbląg		Poland	82-300
118	Research Site	Gdańsk		Poland	80-214
119	Research Site	Grzepnica		Poland	72-003
120	Research Site	Tarnobrzeg		Poland	39-400
121	Research Site	Warszawa		Poland	01-748
122	Research Site	Warszawa		Poland	03-291
123	Research Site	Łódź		Poland	93-513
124	Research Site	Bucharest		Romania	013811
125	Research Site	Bucuresti		Romania	011171
126	Research Site	Bucuresti		Romania	030171
127	Research Site	Cluj Napoca		Romania	400015
128	Research Site	Cluj-Napoca		Romania	400015
129	Research Site	Arkhangelsk		Russian Federation	163045
130	Research Site	Ivanovo		Russian Federation	153040
131	Research Site	Moscow		Russian Federation	115478
132	Research Site	Omsk		Russian Federation	644013
133	Research Site	Saint Petersburg		Russian Federation	195257
134	Research Site	Saint Petersburg		Russian Federation	195271
135	Research Site	Saint Petersburg		Russian Federation	197022
136	Research Site	Saransk		Russian Federation	430005
137	Research Site	St-Petersburg		Russian Federation	197758
138	Research Site	St.Petersburg		Russian Federation	191014
139	Research Site	Yaroslavl		Russian Federation	150054
140	Research Site	Barcelona		Spain	08003
141	Research Site	Córdoba		Spain	14004
142	Research Site	Granada		Spain	18014
143	Research Site	Madrid		Spain	28034
144	Research Site	Majadahonda		Spain	28222
145	Research Site	Oviedo		Spain	33011
146	Research Site	Sevilla		Spain	41013
147	Research Site	Valencia		Spain	46026
148	Research Site	Zaragoza		Spain	50009
149	Research Site	Bern		Switzerland	CH-3010
150	Research Site	Lausanne		Switzerland	CH-1011
151	Research Site	Zürich		Switzerland	CH-8063
152	Research Site	Kaohsiung		Taiwan	80756
153	Research Site	Taichung		Taiwan	407
154	Research Site	Taipei		Taiwan	10048
155	Research Site	Taipei		Taiwan	10449
156	Research Site	Taipei		Taiwan	11217
157	Research Site	Taoyuan		Taiwan	333
158	Research Site	Adana		Turkey	1260
159	Research Site	Ankara		Turkey	06230
160	Research Site	Edirne		Turkey	22030
161	Research Site	Gaziantep		Turkey	27310
162	Research Site	Istanbul		Turkey	34390
163	Research Site	Izmir		Turkey	35100
164	Research Site	Kayseri		Turkey	38039
165	Research Site	Konya		Turkey	42080
166	Research Site	Mersin		Turkey	33110
167	Research Site	Aberdeen		United Kingdom	AB25 2ZN
168	Research Site	Colchester		United Kingdom	CO4 5JL
169	Research Site	Coventry		United Kingdom	CV2 2DX
170	Research Site	London		United Kingdom	W6 8RF
171	Research Site	Manchester		United Kingdom	M20 4BX
172	Research Site	Plymouth		United Kingdom	PL6 8DH.

Sponsors and Collaborators

• AstraZeneca
• Myriad Genetic Laboratories, Inc.
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Mark Robson, MD, Memorial Sloan-Kettering Cancer Center, New York

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Redacted Protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02000622
• Other Study ID Numbers: D0819C00003; 2013-005137-20
• First Posted: Dec 4, 2013
• Last Update Posted: Jul 6, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: Breast Cancer; Metastatic; Olaparib; BRCA; PARP inhibitor; HER2; chemotherapy
• Additional relevant MeSH terms: Breast Neoplasms; Olaparib

Study Results

Participant Flow

Recruitment Details	The first patient was enrolled on 27 March 2014 and the last patient on 30 October 2015. Patients were randomized at 125 centres across 19 countries in North America, South America, Europe and Asia.
Pre-assignment Detail	Screening occurred in 2 parts. Part 1: patients with unknown BRCA status were tested by Myriad. Part 1 screening failures were mostly due to no BRCA1/2 mutation detected. Part 2: patients with a known germline BRCA mutation were screened. 302 patients were randomized.

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description
Period Title: Overall Study
STARTED	205	97
COMPLETED	36	17
NOT COMPLETED	169	80

Baseline Characteristics

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	205	97	302
Age (Years) [Median (Full Range) ]
Age (years)	44	45	44
Age, Customized (Count of Participants)
<50	138 67.3%	63 64.9%	201 66.6%
>=50-<65	56 27.3%	30 30.9%	86 28.5%
>=65	11 5.4%	4 4.1%	15 5%
Sex: Female, Male (Count of Participants)
Female	200 97.6%	95 97.9%	295 97.7%
Male	5 2.4%	2 2.1%	7 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.5%	1 1%	4 1.3%
Asian	66 32.2%	28 28.9%	94 31.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.5%	4 4.1%	5 1.7%
White	134 65.4%	63 64.9%	197 65.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.5%	1 1%	2 0.7%
Region of Enrollment (Count of Participants)
BULGARIA	4 2%	4 4.1%	8 2.6%
CHINA	32 15.6%	9 9.3%	41 13.6%
CZECH REPUBLIC	11 5.4%	1 1%	12 4%
FRANCE	5 2.4%	4 4.1%	9 3%
HUNGARY	10 4.9%	0 0%	10 3.3%
ITALY	17 8.3%	7 7.2%	24 7.9%
JAPAN	15 7.3%	9 9.3%	24 7.9%
KOREA	11 5.4%	9 9.3%	20 6.6%
MEXICO	1 0.5%	4 4.1%	5 1.7%
PERU	3 1.5%	1 1%	4 1.3%
POLAND	10 4.9%	5 5.2%	15 5%
ROMANIA	1 0.5%	1 1%	2 0.7%
RUSSIAN FEDERATION	10 4.9%	5 5.2%	15 5%
SPAIN	7 3.4%	6 6.2%	13 4.3%
SWITZERLAND	6 2.9%	2 2.1%	8 2.6%
TAIWAN	1 0.5%	1 1%	2 0.7%
TURKEY	8 3.9%	6 6.2%	14 4.6%
UNITED KINGDOM	8 3.9%	4 4.1%	12 4%
UNITED STATES	45 22%	19 19.6%	64 21.2%
Receptor status (Count of Participants)
ER and/or PgR positive	103 50.2%	49 50.5%	152 50.3%
ER and PgR negative	102 49.8%	48 49.5%	150 49.7%
Received prior chemotherapy for metastatic breast cancer (Count of Participants)
Yes	146 71.2%	69 71.1%	215 71.2%
No	59 28.8%	28 28.9%	87 28.8%
Received prior platinum for breast cancer (Count of Participants)
Yes	60 29.3%	26 26.8%	86 28.5%
No	145 70.7%	71 73.2%	216 71.5%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)
Description	Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	7.0	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments	Study is sized to provide 90% power to detect a true treatment effect of PFS hazard ratio 0.653.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments	A priori threshold for statistical significance (2-sided) is 0.05.
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

2. Secondary Outcome

Title	Time to Second Progression or Death (PFS2)
Description	Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination.
Time Frame	Second progression status reviewed every 8 weeks following the first objective radiological progression as per investigator assessment. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	13.2	9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments	PFS2 tested using a multiple testing procedure with a recycling strategy. With 157 PFS2 events, a priori threshold for statistical significance (2-sided) was 0.008.
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from randomisation until death due to any cause.
Time Frame	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	19.3	19.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5665
	Comments	OS tested using a multiple testing procedure with a recycling strategy. With 140 OS events, a priori threshold for statistical significance (2-sided) was 0.018.
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

4. Secondary Outcome

Title	Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)
Description	Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR.
Time Frame	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Evaluable For Response (EFR) Analysis Set consisting of all randomised patients with measurable disease at baseline, i.e. at least one measurable target lesion assessed by blinded independent central review (BICR)

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	167	66
Number [Participants]	100 48.8%	19 19.6%

5. Secondary Outcome

Title	Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)
Description	Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL.
Time Frame	EORTC QLQ-C30 assessments performed at baseline then every ~6 weeks until objective radiological disease progression. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Subset of Full Analysis Set (FAS) consisting of all randomised patients with an evaluable baseline EORTC QLQ-C30 assessment and at least one evaluable post-baseline assessment

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	191	73
Mean (95% Confidence Interval) [Score on a scale]	3.9	-3.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0035
	Comments
	Method	Mixed Models Analysis
	Comments	Variables for treatment, visit, treatment-visit interaction, adjusted for baseline global health status/QoL score, baseline score-visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.5
	Confidence Interval	(2-Sided) 95%; 2.5 to 12.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean difference >0 favours olaparib.

6. Secondary Outcome

Title	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm
Description	Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).
Time Frame	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Subset of Full Analysis Set (FAS) consisting of all randomised patients who were confirmed as Myriad CDx gBRCAm

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	202	95
Median (95% Confidence Interval) [Months]	7.4	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

7. Other Pre-specified Outcome

Title	Time to First Subsequent Cancer Therapy or Death (TFST)
Description	Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.
Time Frame	Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	9.4	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments	Supportive analysis to PFS.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.24 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

8. Other Pre-specified Outcome

Title	Time to Second Subsequent Cancer Therapy or Death (TSST)
Description	Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.
Time Frame	Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	14.3	10.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments	Supportive analysis to PFS2.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

9. Secondary Outcome

Title	Overall Survival (OS) at Final OS
Description	Time from randomisation until death due to any cause.
Time Frame	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 40 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	19.3	17.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5131
	Comments	OS tested using a multiple testing procedure with a recycling strategy. With 192 OS events, a priori threshold for statistical significance was 0.045.
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

10. Secondary Outcome

Title	Overall Survival (OS) at Extended OS
Description	Time from randomisation until death due to any cause.
Time Frame	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	19.3	17.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4167
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

11. Other Pre-specified Outcome

Title	Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS
Description	Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.
Time Frame	Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	9.4	4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments	Supportive analysis to PFS.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

12. Other Pre-specified Outcome

Title	Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS
Description	Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.
Time Frame	Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisting of all randomised patients

Arm/Group Title	Olaparib 300 mg bd	Chemotherapy
Arm/Group Description	Olaparib 300 mg bd tablets	Physician's choice of chemotherapy; capecitabine, vinorelbine, or eribulin
Measure Participants	205	97
Median (95% Confidence Interval) [Months]	14.3	10.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib 300 mg bd, Chemotherapy
	Comments	Supportive analysis to PFS2.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments	Stratified by received prior chemotherapy for metastatic breast cancer (yes/no) and receptor status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 favours olaparib.

Adverse Events

Time Frame	Adverse events and serious adverse events were collected throughout the study until study completion (up to a maximum of 30 months). They are reported from date of first dose of study treatment until the earliest of 30 days after last dose of study treatment and data cut-off.
Adverse Event Reporting Description	Adverse events and serious adverse events are reported in the Safety Analysis Set including all patients who received at least one dose of study treatment (n=296). Six patients on the chemotherapy arm did not receive any study treatment and therefore are excluded from the Safety Analysis Set, leaving n=91 patients on the chemotherapy arm. All cause mortality is reported in the Full Analysis Set (n=302).
Arm/Group Title	Olaparib 300 mg bd		Chemotherapy
Arm/Group Description	Description (Arm-group)		Description (Arm-group)
All Cause Mortality
	Olaparib 300 mg bd		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	159/205 (77.6%)		73/97 (75.3%)
Serious Adverse Events
	Olaparib 300 mg bd		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/205 (18%)		15/91 (16.5%)
Blood and lymphatic system disorders
Anaemia	5/205 (2.4%)	7	2/91 (2.2%)	2
Febrile bone marrow aplasia	0/205 (0%)	0	1/91 (1.1%)	1
Febrile neutropenia	0/205 (0%)	0	2/91 (2.2%)	2
Neutropenia	0/205 (0%)	0	1/91 (1.1%)	1
Thrombocytopenia	1/205 (0.5%)	1	0/91 (0%)	0
Cardiac disorders
Atrial fibrillation	1/205 (0.5%)	1	0/91 (0%)	0
Ear and labyrinth disorders
Vertigo	1/205 (0.5%)	1	0/91 (0%)	0
Gastrointestinal disorders
Ascites	0/205 (0%)	0	1/91 (1.1%)	1
Diarrhoea	0/205 (0%)	0	1/91 (1.1%)	1
Nausea	0/205 (0%)	0	1/91 (1.1%)	1
Vomiting	0/205 (0%)	0	1/91 (1.1%)	1
General disorders
Malaise	0/205 (0%)	0	1/91 (1.1%)	1
Pyrexia	3/205 (1.5%)	3	0/91 (0%)	0
Hepatobiliary disorders
Bile duct stone	0/205 (0%)	0	1/91 (1.1%)	1
Immune system disorders
Drug hypersensitivity	0/205 (0%)	0	1/91 (1.1%)	1
Infections and infestations
Appendicitis	1/205 (0.5%)	1	0/91 (0%)	0
Biliary sepsis	0/205 (0%)	0	1/91 (1.1%)	1
Cellulitis staphylococcal	1/205 (0.5%)	1	0/91 (0%)	0
Gastrointestinal infection	1/205 (0.5%)	1	0/91 (0%)	0
Pneumonia	2/205 (1%)	2	0/91 (0%)	0
Pyelonephritis	1/205 (0.5%)	1	0/91 (0%)	0
Sepsis	1/205 (0.5%)	1	0/91 (0%)	0
Streptococcal sepsis	0/205 (0%)	0	1/91 (1.1%)	1
Injury, poisoning and procedural complications
Hip fracture	1/205 (0.5%)	1	0/91 (0%)	0
Radiation skin injury	0/205 (0%)	0	1/91 (1.1%)	1
Tibia fracture	1/205 (0.5%)	1	0/91 (0%)	0
Investigations
Neutrophil count decreased	2/205 (1%)	2	0/91 (0%)	0
Platelet count decreased	2/205 (1%)	4	0/91 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/205 (0%)	0	1/91 (1.1%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/205 (0.5%)	1	0/91 (0%)	0
Back pain	1/205 (0.5%)	1	0/91 (0%)	0
Intervertebral disc protrusion	1/205 (0.5%)	1	0/91 (0%)	0
Vertebral foraminal stenosis	1/205 (0.5%)	1	0/91 (0%)	0
Nervous system disorders
Central nervous system lesion	1/205 (0.5%)	1	0/91 (0%)	0
Epilepsy	1/205 (0.5%)	1	0/91 (0%)	0
Headache	1/205 (0.5%)	1	0/91 (0%)	0
Intracranial pressure increased	1/205 (0.5%)	1	0/91 (0%)	0
Seizure	2/205 (1%)	5	0/91 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/205 (2%)	4	0/91 (0%)	0
Pleural effusion	1/205 (0.5%)	1	1/91 (1.1%)	1
Pulmonary embolism	1/205 (0.5%)	1	1/91 (1.1%)	1
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/205 (0.5%)	2	0/91 (0%)	0
Vascular disorders
Aortic aneurysm	1/205 (0.5%)	1	0/91 (0%)	0
Embolism	0/205 (0%)	0	1/91 (1.1%)	1
Pelvic venous thrombosis	1/205 (0.5%)	1	0/91 (0%)	0
Phlebitis	0/205 (0%)	0	1/91 (1.1%)	1
Venous thrombosis	0/205 (0%)	0	1/91 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Olaparib 300 mg bd		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	196/205 (95.6%)		85/91 (93.4%)
Blood and lymphatic system disorders
Anaemia	76/205 (37.1%)	129	21/91 (23.1%)	29
Leukopenia	23/205 (11.2%)	55	9/91 (9.9%)	40
Lymphopenia	14/205 (6.8%)	30	1/91 (1.1%)	2
Neutropenia	37/205 (18%)	89	27/91 (29.7%)	78
Thrombocytopenia	13/205 (6.3%)	20	5/91 (5.5%)	5
Gastrointestinal disorders
Abdominal distension	7/205 (3.4%)	7	5/91 (5.5%)	6
Abdominal pain	14/205 (6.8%)	16	6/91 (6.6%)	7
Abdominal pain upper	15/205 (7.3%)	16	5/91 (5.5%)	5
Constipation	26/205 (12.7%)	30	12/91 (13.2%)	13
Diarrhoea	42/205 (20.5%)	68	19/91 (20.9%)	29
Dyspepsia	17/205 (8.3%)	20	4/91 (4.4%)	4
Nausea	119/205 (58%)	175	31/91 (34.1%)	40
Stomatitis	16/205 (7.8%)	23	10/91 (11%)	10
Vomiting	66/205 (32.2%)	127	13/91 (14.3%)	18
General disorders
Asthenia	19/205 (9.3%)	28	12/91 (13.2%)	15
Fatigue	61/205 (29.8%)	80	22/91 (24.2%)	23
Mucosal inflammation	5/205 (2.4%)	5	6/91 (6.6%)	7
Pyrexia	27/205 (13.2%)	35	16/91 (17.6%)	20
Infections and infestations
Influenza	14/205 (6.8%)	15	4/91 (4.4%)	4
Nasopharyngitis	17/205 (8.3%)	26	3/91 (3.3%)	5
Upper respiratory tract infection	27/205 (13.2%)	40	9/91 (9.9%)	16
Urinary tract infection	13/205 (6.3%)	14	3/91 (3.3%)	3
Investigations
Alanine aminotransferase increased	24/205 (11.7%)	39	16/91 (17.6%)	19
Aspartate aminotransferase increased	20/205 (9.8%)	29	15/91 (16.5%)	19
Gamma-glutamyltransferase increased	13/205 (6.3%)	14	5/91 (5.5%)	5
Neutrophil count decreased	21/205 (10.2%)	49	17/91 (18.7%)	43
Platelet count decreased	10/205 (4.9%)	19	6/91 (6.6%)	10
White blood cell count decreased	33/205 (16.1%)	75	19/91 (20.9%)	40
Metabolism and nutrition disorders
Decreased appetite	35/205 (17.1%)	41	11/91 (12.1%)	14
Musculoskeletal and connective tissue disorders
Arthralgia	22/205 (10.7%)	27	9/91 (9.9%)	9
Back pain	29/205 (14.1%)	32	8/91 (8.8%)	9
Musculoskeletal chest pain	11/205 (5.4%)	11	5/91 (5.5%)	5
Musculoskeletal pain	13/205 (6.3%)	13	4/91 (4.4%)	4
Myalgia	8/205 (3.9%)	8	9/91 (9.9%)	10
Pain in extremity	15/205 (7.3%)	19	3/91 (3.3%)	3
Nervous system disorders
Dizziness	18/205 (8.8%)	18	7/91 (7.7%)	8
Dysgeusia	17/205 (8.3%)	22	6/91 (6.6%)	6
Headache	41/205 (20%)	51	14/91 (15.4%)	15
Peripheral sensory neuropathy	3/205 (1.5%)	3	9/91 (9.9%)	10
Psychiatric disorders
Insomnia	13/205 (6.3%)	14	7/91 (7.7%)	8
Respiratory, thoracic and mediastinal disorders
Cough	35/205 (17.1%)	40	6/91 (6.6%)	7
Dyspnoea	15/205 (7.3%)	19	9/91 (9.9%)	10
Skin and subcutaneous tissue disorders
Alopecia	7/205 (3.4%)	8	12/91 (13.2%)	13
Palmar-plantar erythrodysaesthesia syndrome	1/205 (0.5%)	1	19/91 (20.9%)	25
Pruritus	6/205 (2.9%)	6	5/91 (5.5%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.