Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02987543
• Collaborator: Merck Sharp & Dohme LLC (Industry), Foundation Medicine, Inc. (Other), Myriad Genetics, Inc. (Industry)
• Enrollment: 387
• Locations: 205
• Arms: 2
• Anticipated Duration (Months): 70.7
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-resistant Prostate Cancer	Drug: olaparib; Drug: enzalutamide; Drug: abiraterone acetate; Drug: abiraterone acetate; Drug: enzalutamide	Phase 3

Detailed Description

This is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status.

Approximately 340 subjects will be randomized 2:1 (olaparib : investigator choice of enzalutamide or abiraterone acetate) into the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 387 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Open Label, Randomized Study to Assess the Efficacy and Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment With a New Hormonal Agent and Have Homologous Recombination Repair Gene Mutations (PROfound)
• Actual Study Start Date: Feb 6, 2017
• Actual Primary Completion Date: Jun 4, 2019
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olaparib Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. Subjects will be administered study treatment orally at a dose of 300 mg twice daily (bid). The planned dose of 300 mg bid will be made up of two x 150 mg tablets twice daily, with 100 mg tablets used to manage dose reductions	Drug: olaparib; 300 mg (2x 150 mg tablets) twice daily; Other Names: Lynparza
Active Comparator: Enzalutamide OR abiraterone acetate Enzalutamide: Enzalutamide is available as capsules or tablets containing 40 mg of enzalutamide. Subjects will be administered study treatment orally at a dose of 160 mg once daily. Abiraterone acetate with prednisone: Abiraterone acetate is available as tablets containing 250 mg or 500 mg of abiraterone acetate. Subjects will be administered study treatment orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg administered twice daily orally. Prednisolone is permitted for use instead of prednisone if necessary.	Drug: enzalutamide; 160 mg (4 x 40 mg capsules) once daily; Other Names: XTANDI ; Drug: abiraterone acetate; 1,000 mg (4 x 250 mg tablets) once daily; Other Names: ZYTIGA ; Drug: abiraterone acetate; 1,000 mg (2 x 500 mg tablets) once daily; Other Names: ZYTIGA ; Drug: enzalutamide; 160 mg (4 x 40 mg tablets) once daily; Other Names: XTANDI

Outcome Measures

Primary Outcome Measures

1. Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only [Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).]

   The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a >=20% increase in the sum of diameters of target lesions and an absolute increase of >=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as >= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, >=6 weeks later, must show >=2 more new bone lesions (for a total of >=4 new bone lesions since baseline).

Secondary Outcome Measures

1. Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only [Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).]

   ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = >=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.

2. Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B [Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).]

   The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.

3. Time to Pain Progression - Cohort A Only [Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).]

   Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain [Item 3] and Analgesic Quantification Algorithm [AQA] score.

4. Overall Survival (OS) - Cohort A Only [Approximately 35 months after the first patient was randomised.]

   Number of Participants with Overall Survival (OS) - Cohort A only.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion criteria

1. Histologically confirmed diagnosis of prostate cancer.

2. Documented evidence of metastatic castration resistant prostate cancer (mCRPC).

3. Subjects must have progressed on prior new hormonal agent (e.g. abiraterone acetate and/or enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC .

4. Ongoing therapy with LHRH analog or bilateral orchiectomy.

5. Radiographic progression at study entry while on androgen deprivation therapy (or after bilateral orchiectomy).

6. Qualifying HRR mutation in tumor tissue.

Exclusion criteria

1. Any previous treatment with PARP inhibitor, including olaparib.

2. Subjects who have any previous treatment with DNA-damaging cytotoxic chemotherapy, except if for non-prostate cancer indication and last dose > 5 years prior to randomization.

3. Other malignancy (including MDS and MGUS) within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥5 years.

4. Subjects with known brain metastases.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anchorage	Alaska	United States	99503
2	Research Site	Tucson	Arizona	United States	85704
3	Research Site	Tucson	Arizona	United States	85741
4	Research Site	Duarte	California	United States	91010
5	Research Site	San Diego	California	United States	92161
6	Research Site	Santa Barbara	California	United States	93105
7	Research Site	Washington	District of Columbia	United States	20007
8	Research Site	Tampa	Florida	United States	33612
9	Research Site	Atlanta	Georgia	United States	30318
10	Research Site	Chicago	Illinois	United States	60611
11	Research Site	Jeffersonville	Indiana	United States	47130
12	Research Site	New Orleans	Louisiana	United States	70112
13	Research Site	Baltimore	Maryland	United States	21287
14	Research Site	Towson	Maryland	United States	21204
15	Research Site	Omaha	Nebraska	United States	68130
16	Research Site	Las Vegas	Nevada	United States	89135
17	Research Site	Albany	New York	United States	12208
18	Research Site	Bronx	New York	United States	10468
19	Research Site	Brooklyn	New York	United States	11201
20	Research Site	Syracuse	New York	United States	13210
21	Research Site	Durham	North Carolina	United States	27710
22	Research Site	Salisbury	North Carolina	United States	28144
23	Research Site	Columbus	Ohio	United States	43230
24	Research Site	Oklahoma City	Oklahoma	United States	73104
25	Research Site	Springfield	Oregon	United States	97477
26	Research Site	Tualatin	Oregon	United States	97062
27	Research Site	Charleston	South Carolina	United States	29401
28	Research Site	Charleston	South Carolina	United States	29425
29	Research Site	Myrtle Beach	South Carolina	United States	29572
30	Research Site	Germantown	Tennessee	United States	38138
31	Research Site	Nashville	Tennessee	United States	37232
32	Research Site	San Antonio	Texas	United States	78229
33	Research Site	Salt Lake City	Utah	United States	84112
34	Research Site	Salt Lake City	Utah	United States	84148
35	Research Site	Spokane	Washington	United States	99202
36	Research Site	Wheeling	West Virginia	United States	26003
37	Research Site	Buenos Aires		Argentina	1426
38	Research Site	Buenos Aires		Argentina	C1118AAT
39	Research Site	Buenos Aires		Argentina	C1120AAT
40	Research Site	Caba		Argentina	C1280AEB
41	Research Site	La Rioja		Argentina	5300
42	Research Site	Rosario		Argentina	2000
43	Research Site	Adelaide		Australia	5000
44	Research Site	Box Hill		Australia	3128
45	Research Site	Clayton		Australia	3168
46	Research Site	Greenslopes		Australia	4120
47	Research Site	Herston		Australia	4029
48	Research Site	Macquarie University		Australia	2109
49	Research Site	Melbourne		Australia	3000
50	Research Site	Nedlands		Australia	6009
51	Research Site	Randwick		Australia	2031
52	Research Site	Waratah		Australia	2298
53	Research Site	Graz		Austria	8036
54	Research Site	Linz		Austria	4020
55	Research Site	Salzburg		Austria	5020
56	Research Site	Wien		Austria	1020
57	Research Site	Wien		Austria	1090
58	Research Site	Barretos		Brazil	14784-400
59	Research Site	Belo Horizonte		Brazil	30110-022
60	Research Site	Curitiba		Brazil	80530-010
61	Research Site	Florianópolis		Brazil	88034-000
62	Research Site	Passo Fundo		Brazil	99010-080
63	Research Site	Porto Alegre		Brazil	90160-093
64	Research Site	Porto Alegre		Brazil	90610-000
65	Research Site	Recife		Brazil	50040-000
66	Research Site	Ribeirao Preto		Brazil	14015-140
67	Research Site	Rio de Janeiro		Brazil	22793-080
68	Research Site	Santo Andre		Brazil	09060-650
69	Research Site	São José do Rio Preto		Brazil	15090-000
70	Research Site	São Paulo		Brazil	01321-001
71	Research Site	São Paulo		Brazil	03102-002
72	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
73	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
74	Research Site	Vancouver	British Columbia	Canada	V5Z 4E6
75	Research Site	Hamilton	Ontario	Canada	L8V 5C2
76	Research Site	Oakville	Ontario	Canada	L6H 3P1
77	Research Site	Toronto	Ontario	Canada	M4N 3M5
78	Research Site	Toronto	Ontario	Canada	M5G 2M9
79	Research Site	Chicoutimi	Quebec	Canada	G7H 5H6
80	Research Site	Montreal	Quebec	Canada	H2X 3E4
81	Research Site	Montreal	Quebec	Canada	H4A 3J1
82	Research Site	Saskatoon	Saskatchewan	Canada	S7N 4H4
83	Research Site	Quebec		Canada	G1R 2J6
84	Research Site	Odense C		Denmark	5000
85	Research Site	BESANCON Cedex		France	25030
86	Research Site	Bordeaux Cedex		France	33000
87	Research Site	Caen		France	14000
88	Research Site	Lille		France	59020
89	Research Site	Lyon Cedex 08		France	69008
90	Research Site	Marseille cedex 09		France	13273
91	Research Site	Montpellier		France	34298
92	Research Site	Paris		France	75014
93	Research Site	Poitiers Cedex		France	86021
94	Research Site	Saint Herblain		France	44805
95	Research Site	Toulouse Cedex 09		France	31100
96	Research Site	Vandoeuvre les Nancy		France	54519
97	Research Site	Villejuif		France	94805
98	Research Site	Bergisch Gladbach		Germany	51465
99	Research Site	Berlin		Germany	13055
100	Research Site	Bremen		Germany	28277
101	Research Site	Duisburg		Germany	47179
102	Research Site	Düsseldorf		Germany	40225
103	Research Site	Hamburg		Germany	22399
104	Research Site	Heidelberg		Germany	69120
105	Research Site	Holzminden		Germany	37603
106	Research Site	Jena		Germany	07747
107	Research Site	Köln		Germany	50968
108	Research Site	Magdeburg		Germany	39120
109	Research Site	Nürnberg		Germany	90491
110	Research Site	Nürtingen		Germany	72622
111	Research Site	Tübingen		Germany	72076
112	Research Site	Wuppertal		Germany	42109
113	Research Site	Haifa		Israel	31096
114	Research Site	Jerusalem		Israel	91120
115	Research Site	Kfar Saba		Israel	95847
116	Research Site	Petach-Tikva		Israel	4941492
117	Research Site	Ramat Gan		Israel	5265601
118	Research Site	Zerifin		Israel	70300
119	Research Site	Ancona		Italy	60126
120	Research Site	Arezzo		Italy	52100
121	Research Site	Bari		Italy	70124
122	Research Site	Brescia		Italy	25100
123	Research Site	Meldola		Italy	47014
124	Research Site	Milano		Italy	20133
125	Research Site	Milano		Italy	20141
126	Research Site	Modena		Italy	41124
127	Research Site	Napoli		Italy	80131
128	Research Site	Trento		Italy	38100
129	Research Site	Bunkyo-ku		Japan	113-8431
130	Research Site	Bunkyo-ku		Japan	113-8510
131	Research Site	Bunkyo-ku		Japan	113-8603
132	Research Site	Fukuoka		Japan	812-8582
133	Research Site	Hirosaki-shi		Japan	036-8563
134	Research Site	Kanazawa-shi		Japan	920-8641
135	Research Site	Kashihara-shi		Japan	634-8522
136	Research Site	Kashiwa		Japan	277-8577
137	Research Site	Kawagoe-shi		Japan	350-8550
138	Research Site	Kita-gun		Japan	761-0793
139	Research Site	Koto-ku		Japan	135-8550
140	Research Site	Kyoto-shi		Japan	606-8507
141	Research Site	Maebashi-shi		Japan	371-8811
142	Research Site	Matsuyama-shi		Japan	791-0280
143	Research Site	Minato-ku		Japan	105-8471
144	Research Site	Mitaka-shi		Japan	181-8611
145	Research Site	Miyazaki-shi		Japan	889-1692
146	Research Site	Nagasaki-shi		Japan	852-8501
147	Research Site	Nagoya-shi		Japan	464-8681
148	Research Site	Nagoya-shi		Japan	466-8560
149	Research Site	Osaka-shi		Japan	541-8567
150	Research Site	Osaka-shi		Japan	545-8586
151	Research Site	Osakasayama-shi		Japan	589-8511
152	Research Site	Sagamihara-shi		Japan	252-0375
153	Research Site	Sakura-shi		Japan	285-8741
154	Research Site	Sapporo-shi		Japan	060-8648
155	Research Site	Shinjuku-ku		Japan	160-8582
156	Research Site	Suita-shi		Japan	565-0871
157	Research Site	Sunto-gun		Japan	411-8777
158	Research Site	Yokohama-shi		Japan	232-0024
159	Research Site	Busan		Korea, Republic of	49241
160	Research Site	Daegu		Korea, Republic of	41404
161	Research Site	Goyang-si		Korea, Republic of	10408
162	Research Site	Gwangju		Korea, Republic of	61469
163	Research Site	Seoul		Korea, Republic of	03722
164	Research Site	Seoul		Korea, Republic of	05505
165	Research Site	Seoul		Korea, Republic of	06273
166	Research Site	Seoul		Korea, Republic of	06351
167	Research Site	Seoul		Korea, Republic of	06591
168	Research Site	Amsterdam		Netherlands	1066 CX
169	Research Site	Hilversum		Netherlands	1213 XZ
170	Research Site	Leiden		Netherlands	2333 ZA
171	Research Site	Nijmegen		Netherlands	6525 GA
172	Research Site	Tilburg		Netherlands	5042 AD
173	Research Site	Zwolle		Netherlands	8025 AB
174	Research Site	Lørenskog		Norway	N-1478
175	Research Site	Gerona		Spain	17007
176	Research Site	Madrid		Spain	08035
177	Research Site	Madrid		Spain	28040
178	Research Site	Madrid		Spain	28041
179	Research Site	Malaga		Spain	29010
180	Research Site	Oviedo		Spain	33011
181	Research Site	Sevilla		Spain	41009
182	Research Site	Göteborg		Sweden	413 45
183	Research Site	Solna		Sweden	171 64
184	Research Site	Changhua City		Taiwan	50006
185	Research Site	Kaohsiung		Taiwan	807
186	Research Site	Kaohsiung		Taiwan	833
187	Research Site	Taichung		Taiwan	404
188	Research Site	Taichung		Taiwan	40705
189	Research Site	Tainan		Taiwan	70403
190	Research Site	Taipei		Taiwan	10002
191	Research Site	Taipei		Taiwan	112
192	Research Site	Taoyuan City		Taiwan	333
193	Research Site	Adana		Turkey	01120
194	Research Site	Ankara		Turkey	06230
195	Research Site	Ankara		Turkey	06340
196	Research Site	Ankara		Turkey	06590
197	Research Site	Edirne		Turkey	22030
198	Research Site	Istanbul		Turkey	34030
199	Research Site	Istanbul		Turkey	34365
200	Research Site	Karsiyaka		Turkey	35575
201	Research Site	London		United Kingdom	EC1M 6BQ
202	Research Site	London		United Kingdom	NW1 2PG
203	Research Site	Manchester		United Kingdom	M20 4BX
204	Research Site	Romford		United Kingdom	RM7 0BE
205	Research Site	Sutton		United Kingdom	SM25PT

Sponsors and Collaborators

• AstraZeneca
• Merck Sharp & Dohme LLC
• Foundation Medicine, Inc.
• Myriad Genetics, Inc.

Investigators

• Principal Investigator: Johann de Bono, M.D., Ph.D., The Institute of Cancer Research, United Kingdom
• Principal Investigator: Maha Hussain, M.D., FACP, FASCO, Northwestern University, United States of America

Study Documents (Full-Text)

• Study Protocol - Mar 7, 2019
• Statistical Analysis Plan - Jul 4, 2019

More Information

Additional Information:

• CSP redacted
• redacted SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02987543
• Other Study ID Numbers: D081DC00007
• First Posted: Dec 9, 2016
• Last Update Posted: Jun 15, 2022
• Last Verified: May 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: metastatic castration-resistant prostate cancer (mCRPC); homologous recombination repair (HRR)
• Additional relevant MeSH terms: Prostatic Neoplasms; Olaparib; Abiraterone Acetate

Study Results

Participant Flow

Recruitment Details	Subjects were divided into two cohorts based on HRR gene mutation status. Subjects with mutations in either BRCA1, BRCA2, or ATM are in Cohort A whereas subjects with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1,CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) are in Cohort B.

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA	Cohort B Olaparib 300mg bd	Cohort B Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Period Title: Overall Study
STARTED	162	83	94	48
COMPLETED	0	0	0	0
NOT COMPLETED	162	83	94	48

Baseline Characteristics

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA	Cohort B Olaparib 300mg bd	Cohort B Investigators Choice of NHA	Total
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)	Total of all reporting groups
Overall Participants	162	83	94	48	387
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.0 (8.23)	68.1 (7.36)	69.2 (8.79)	70.3 (7.83)	68.6 (8.15)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	162 100%	83 100%	94 100%	48 100%	387 100%
Race/Ethnicity, Customized (Number) [Number]
White	109 67.3%	55 66.3%	54 57.4%	30 62.5%	248 64.1%
Black or African American	2 1.2%	1 1.2%	5 5.3%	0 0%	8 2.1%
Asian	43 26.5%	19 22.9%	26 27.7%	17 35.4%	105 27.1%
Other	1 0.6%	1 1.2%	1 1.1%	0 0%	3 0.8%
Missing	7 4.3%	7 8.4%	8 8.5%	1 2.1%	23 5.9%

Outcome Measures

1. Secondary Outcome

Title	Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only
Description	ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = >=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.
Time Frame	Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).

Outcome Measure Data

Analysis Population Description

Evaluable for response

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Measure Participants	84	43
Response	28 17.3%	1 1.2%
No response	56 34.6%	42 50.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A Olaparib 300mg bd, Cohort A Investigators Choice of NHA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	20.86
	Confidence Interval	(2-Sided) 95%; 4.18 to 379.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B
Description	The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
Time Frame	Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Measure Participants	256	131
Median (95% Confidence Interval) [Months]	5.82	3.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A Olaparib 300mg bd, Cohort A Investigators Choice of NHA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Pain Progression - Cohort A Only
Description	Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain [Item 3] and Analgesic Quantification Algorithm [AQA] score.
Time Frame	Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Measure Participants	162	83
Median (95% Confidence Interval) [Months]	NA	9.92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A Olaparib 300mg bd, Cohort A Investigators Choice of NHA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0192
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Survival (OS) - Cohort A Only
Description	Number of Participants with Overall Survival (OS) - Cohort A only.
Time Frame	Approximately 35 months after the first patient was randomised.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Measure Participants	162	83
Died	91 56.2%	57 68.7%
Alive at data cut-off	49 30.2%	21 25.3%
Terminated prior to death (withdrawn consent)	22 13.6%	5 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A Olaparib 300mg bd, Cohort A Investigators Choice of NHA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0175
	Comments	2-sided p-value
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only
Description	The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a >=20% increase in the sum of diameters of target lesions and an absolute increase of >=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as >= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, >=6 weeks later, must show >=2 more new bone lesions (for a total of >=4 new bone lesions since baseline).
Time Frame	Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A Olaparib 300mg bd	Cohort A Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets	either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
Measure Participants	162	83
Median (95% Confidence Interval) [Months]	7.39	3.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A Olaparib 300mg bd, Cohort A Investigators Choice of NHA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.25 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the time of signature of informed consent throughout the treatment period (median duration of treatment of 7.5 and 3.9 months for Olaparib and Investigators Choice of NHA respectively) up to and including the 30-day follow-up period
Adverse Event Reporting Description	There were 131 subjects randomised to the Investigators Choice of NHA treatment group (Full Analysis Set), however 1 of these subjects did not receive treatment (resulting in 130 in the Safety Analysis Set). Hence, for the Investigators Choice of NHA, the Total number at risk for all-cause mortality = 131 while the Total # at Risk by any Serious Adverse Event = 130 and the Total # at Risk by any Other Adverse Event = 130.
Arm/Group Title	Cohort A+B Olaparib 300mg bd		Cohort A+B Investigators Choice of NHA
Arm/Group Description	2x150mg film-coated tablets		either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
All Cause Mortality
	Cohort A+B Olaparib 300mg bd		Cohort A+B Investigators Choice of NHA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/256 (62.5%)		88/131 (67.2%)
Serious Adverse Events
	Cohort A+B Olaparib 300mg bd		Cohort A+B Investigators Choice of NHA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	94/256 (36.7%)		39/130 (30%)
Blood and lymphatic system disorders
Anaemia	23/256 (9%)	24	0/130 (0%)	0
Febrile neutropenia	1/256 (0.4%)	1	1/130 (0.8%)	1
Neutropenia	3/256 (1.2%)	3	0/130 (0%)	0
Pancytopenia	1/256 (0.4%)	1	0/130 (0%)	0
Thrombocytopenia	4/256 (1.6%)	6	0/130 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/256 (0.4%)	1	0/130 (0%)	0
Angina pectoris	1/256 (0.4%)	1	2/130 (1.5%)	2
Atrial fibrillation	1/256 (0.4%)	1	0/130 (0%)	0
Cardiac failure	0/256 (0%)	0	1/130 (0.8%)	1
Cardiac failure acute	1/256 (0.4%)	1	0/130 (0%)	0
Cardiomyopathy	0/256 (0%)	0	1/130 (0.8%)	1
Cardiopulmonary failure	2/256 (0.8%)	2	0/130 (0%)	0
Coronary ostial stenosis	1/256 (0.4%)	1	0/130 (0%)	0
Myocardial infarction	1/256 (0.4%)	1	0/130 (0%)	0
Right ventricular failure	1/256 (0.4%)	1	0/130 (0%)	0
Coronary artery stenosis	0/256 (0%)	0	1/130 (0.8%)	1
Endocrine disorders
Adrenal insufficiency	1/256 (0.4%)	1	0/130 (0%)	0
Eye disorders
Diplopia	1/256 (0.4%)	1	0/130 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/256 (0.4%)	1	0/130 (0%)	0
Diarrhoea	1/256 (0.4%)	1	0/130 (0%)	0
Diverticulum intestinal	1/256 (0.4%)	1	0/130 (0%)	0
Gastric perforation	0/256 (0%)	0	1/130 (0.8%)	1
Gastric ulcer	1/256 (0.4%)	1	0/130 (0%)	0
Gastric ulcer haemorrhage	0/256 (0%)	0	1/130 (0.8%)	1
Inguinal hernia	0/256 (0%)	0	1/130 (0.8%)	1
Nausea	2/256 (0.8%)	2	2/130 (1.5%)	2
Obstruction gastric	1/256 (0.4%)	1	0/130 (0%)	0
Obstructive pancreatitis	1/256 (0.4%)	1	0/130 (0%)	0
Small intestinal obstruction	0/256 (0%)	0	1/130 (0.8%)	1
Stress ulcer	1/256 (0.4%)	1	0/130 (0%)	0
Vomiting	4/256 (1.6%)	4	1/130 (0.8%)	1
Duodenal ulcer perforation	0/256 (0%)	0	1/130 (0.8%)	1
General disorders
Asthenia	4/256 (1.6%)	4	1/130 (0.8%)	1
Death	0/256 (0%)	0	1/130 (0.8%)	1
Fatigue	2/256 (0.8%)	2	0/130 (0%)	0
General physical health deterioration	0/256 (0%)	0	1/130 (0.8%)	1
Pain	1/256 (0.4%)	1	0/130 (0%)	0
Pyrexia	3/256 (1.2%)	3	2/130 (1.5%)	3
Sudden death	1/256 (0.4%)	1	0/130 (0%)	0
Hepatobiliary disorders
Budd-Chiari syndrome	1/256 (0.4%)	1	0/130 (0%)	0
Cholangitis	1/256 (0.4%)	1	0/130 (0%)	0
Cholecystitis acute	1/256 (0.4%)	1	0/130 (0%)	0
Infections and infestations
Anal abscess	0/256 (0%)	0	1/130 (0.8%)	1
Cellulitis of male external genital organ	1/256 (0.4%)	1	0/130 (0%)	0
Cystitis	0/256 (0%)	0	1/130 (0.8%)	1
Gastroenteritis	0/256 (0%)	0	1/130 (0.8%)	1
Infection	0/256 (0%)	0	1/130 (0.8%)	1
Nasopharyngitis	1/256 (0.4%)	1	0/130 (0%)	0
Neutropenic sepsis	0/256 (0%)	0	1/130 (0.8%)	1
Pharyngitis	1/256 (0.4%)	1	0/130 (0%)	0
Pneumonia	11/256 (4.3%)	13	4/130 (3.1%)	4
Pyelonephritis	1/256 (0.4%)	1	0/130 (0%)	0
Sepsis	3/256 (1.2%)	3	3/130 (2.3%)	3
Septic shock	1/256 (0.4%)	1	0/130 (0%)	0
Urinary tract infection	5/256 (2%)	6	4/130 (3.1%)	4
Urosepsis	0/256 (0%)	0	1/130 (0.8%)	1
Pneumocystis jirovecii pneumoni	1/256 (0.4%)	1	0/130 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/256 (0.4%)	1	0/130 (0%)	0
Concussion	1/256 (0.4%)	1	0/130 (0%)	0
Cystitis radiation	1/256 (0.4%)	1	0/130 (0%)	0
Fall	1/256 (0.4%)	1	2/130 (1.5%)	2
Femur fracture	3/256 (1.2%)	3	0/130 (0%)	0
Fracture	1/256 (0.4%)	1	0/130 (0%)	0
Gastroenteritis radiation	1/256 (0.4%)	1	0/130 (0%)	0
Post-traumatic pain	1/256 (0.4%)	1	0/130 (0%)	0
Spinal compression fracture	1/256 (0.4%)	1	0/130 (0%)	0
Spinal fracture	1/256 (0.4%)	1	0/130 (0%)	0
Subdural haematoma	0/256 (0%)	0	1/130 (0.8%)	1
Metabolism and nutrition disorders
Decreased appetite	2/256 (0.8%)	2	0/130 (0%)	0
Dehydration	0/256 (0%)	0	3/130 (2.3%)	3
Hypocalcaemia	1/256 (0.4%)	1	0/130 (0%)	0
Hypoglycaemia	1/256 (0.4%)	1	0/130 (0%)	0
Hyponatraemia	2/256 (0.8%)	3	0/130 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/256 (0.4%)	1	0/130 (0%)	0
Back pain	1/256 (0.4%)	1	1/130 (0.8%)	1
Bone pain	2/256 (0.8%)	2	0/130 (0%)	0
Muscular weakness	2/256 (0.8%)	2	0/130 (0%)	0
Musculoskeletal chest pain	2/256 (0.8%)	2	0/130 (0%)	0
Musculoskeletal pain	1/256 (0.4%)	1	0/130 (0%)	0
Spinal stenosis	1/256 (0.4%)	1	0/130 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	0/256 (0%)	0	1/130 (0.8%)	1
Glioma	1/256 (0.4%)	1	0/130 (0%)	0
Transitional cell carcinoma	0/256 (0%)	0	1/130 (0.8%)	1
Nervous system disorders
Ballismus	0/256 (0%)	0	1/130 (0.8%)	1
Cerebral infarction	1/256 (0.4%)	1	0/130 (0%)	0
Cerebrovascular accident	3/256 (1.2%)	3	0/130 (0%)	0
Dizziness	1/256 (0.4%)	1	0/130 (0%)	0
Ischaemic stroke	0/256 (0%)	0	1/130 (0.8%)	1
Neuralgia	1/256 (0.4%)	1	0/130 (0%)	0
Spinal cord compression	1/256 (0.4%)	1	1/130 (0.8%)	1
Syncope	1/256 (0.4%)	1	0/130 (0%)	0
Psychiatric disorders
Confusional state	1/256 (0.4%)	1	0/130 (0%)	0
Delirium	1/256 (0.4%)	1	2/130 (1.5%)	2
Renal and urinary disorders
Acute kidney injury	1/256 (0.4%)	1	2/130 (1.5%)	2
Calculus bladder	1/256 (0.4%)	1	0/130 (0%)	0
Chronic kidney disease	0/256 (0%)	0	1/130 (0.8%)	1
Haematuria	3/256 (1.2%)	3	1/130 (0.8%)	1
Hydronephrosis	1/256 (0.4%)	1	1/130 (0.8%)	1
Nephrolithiasis	0/256 (0%)	0	1/130 (0.8%)	1
Renal failure	1/256 (0.4%)	1	0/130 (0%)	0
Renal impairment	1/256 (0.4%)	1	0/130 (0%)	0
Urinary retention	2/256 (0.8%)	2	0/130 (0%)	0
Urinary tract obstruction	0/256 (0%)	0	2/130 (1.5%)	2
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/256 (0.4%)	2	0/130 (0%)	0
Dyspnoea	4/256 (1.6%)	4	1/130 (0.8%)	1
Interstitial lung disease	1/256 (0.4%)	1	0/130 (0%)	0
Pleural effusion	0/256 (0%)	0	1/130 (0.8%)	1
Pneumonia aspiration	3/256 (1.2%)	3	0/130 (0%)	0
Pneumonitis	1/256 (0.4%)	1	0/130 (0%)	0
Pneumothorax	2/256 (0.8%)	2	0/130 (0%)	0
Pulmonary embolism	5/256 (2%)	5	1/130 (0.8%)	1
Respiratory failure	1/256 (0.4%)	1	0/130 (0%)	0
Skin and subcutaneous tissue disorders
Drug eruption	0/256 (0%)	0	1/130 (0.8%)	1
Skin ulcer	1/256 (0.4%)	1	0/130 (0%)	0
Vascular disorders
Arterial thrombosis	0/256 (0%)	0	1/130 (0.8%)	1
Deep vein thrombosis	0/256 (0%)	0	1/130 (0.8%)	1
Embolism	1/256 (0.4%)	1	0/130 (0%)	0
Orthostatic hypotension	1/256 (0.4%)	1	0/130 (0%)	0
Phlebitis	1/256 (0.4%)	1	0/130 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort A+B Olaparib 300mg bd		Cohort A+B Investigators Choice of NHA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	241/256 (94.1%)		112/130 (86.2%)
Blood and lymphatic system disorders
Anaemia	110/256 (43%)	154	20/130 (15.4%)	23
Lymphopenia	13/256 (5.1%)	15	1/130 (0.8%)	1
Neutropenia	13/256 (5.1%)	16	0/130 (0%)	0
Thrombocytopenia	18/256 (7%)	22	2/130 (1.5%)	2
Gastrointestinal disorders
Constipation	49/256 (19.1%)	52	19/130 (14.6%)	21
Diarrhoea	54/256 (21.1%)	71	9/130 (6.9%)	9
Dyspepsia	20/256 (7.8%)	23	3/130 (2.3%)	3
Nausea	109/256 (42.6%)	136	26/130 (20%)	28
Vomiting	49/256 (19.1%)	82	17/130 (13.1%)	19
Stomatitis	13/256 (5.1%)	14	2/130 (1.5%)	2
General disorders
Asthenia	37/256 (14.5%)	54	18/130 (13.8%)	19
Fatigue	68/256 (26.6%)	71	28/130 (21.5%)	28
Oedema peripheral	34/256 (13.3%)	36	10/130 (7.7%)	10
Pyrexia	15/256 (5.9%)	16	4/130 (3.1%)	4
Infections and infestations
Urinary tract infection	18/256 (7%)	22	12/130 (9.2%)	15
Investigations
Weight decreased	21/256 (8.2%)	21	7/130 (5.4%)	7
Metabolism and nutrition disorders
Decreased appetite	78/256 (30.5%)	88	24/130 (18.5%)	25
Musculoskeletal and connective tissue disorders
Arthralgia	25/256 (9.8%)	26	14/130 (10.8%)	16
Back pain	36/256 (14.1%)	44	17/130 (13.1%)	18
Musculoskeletal chest pain	14/256 (5.5%)	14	6/130 (4.6%)	7
Musculoskeletal pain	17/256 (6.6%)	18	6/130 (4.6%)	6
Pain in extremity	14/256 (5.5%)	18	6/130 (4.6%)	6
Nervous system disorders
Dizziness	17/256 (6.6%)	18	5/130 (3.8%)	5
Dysgeusia	18/256 (7%)	20	2/130 (1.5%)	2
Headache	16/256 (6.3%)	29	3/130 (2.3%)	3
Psychiatric disorders
Insomnia	14/256 (5.5%)	14	4/130 (3.1%)	4
Renal and urinary disorders
Haematuria	6/256 (2.3%)	7	10/130 (7.7%)	11
Respiratory, thoracic and mediastinal disorders
Cough	29/256 (11.3%)	32	3/130 (2.3%)	3
Dyspnoea	24/256 (9.4%)	25	4/130 (3.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.