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Clinical Trial Results:
A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination With Talazoparib in Subjects With BRCA or ATM Mutant Tumors

Summary
EudraCT number	2018-000345-39
Trial protocol	GB NL FR BE DK ES IT
Global end of trial date	03 Feb 2023

Results information
Results version number	v1(current)
This version publication date	16 Sep 2023
First version publication date	16 Sep 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B9991032

ISRCTN number

US NCT number

NCT03565991

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Feb 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Feb 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to evaluate objective response rate (ORR) of avelumab in combination with talazoparib, in subjects with locally advanced or metastatic solid tumors harboring BRCA1, BRCA2 or ATM defect.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Jun 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

52 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Italy: 31

Country: Number of subjects enrolled

Japan: 9

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

United States: 126

Worldwide total number of subjects

200

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

135

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 270 subjects were screened for this study, 202 subjects were enrolled and assigned to study treatment but 2 subjects never started the treatment. In total 200 subjects were treated (159 in Cohort 1 and 41 in Cohort 2).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)

Arm description

Subjects with locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes were enrolled in Cohort 1. Talazoparib was self-administered orally at a starting dose of 1 mg Once Daily (QD) for subjects with normal renal function or mild renal impairment until End of Treatment. Subjects with moderate renal impairment received starting dose of 0.75 mg QD. Avelumab was administered as a 1-hour Intravenous (IV) infusion Every 2 Weeks (Q2W) on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Avelumab was administered as a 1-hour IV infusion Q2W at a dose of 800 mg.

Investigational medicinal product name

Talazoparib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Talazoparib was administered orally at 1 mg QD for subjects with normal renal function or mild renal impairment until End of Treatment. Talazoparib was administered orally at 0.75 mg QD for subjects with moderate renal impairment.

Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)

Arm description

Subjects with locally advanced or metastatic solid tumors with one or more defects in the ATM gene without concurrent BRCA1/2 defect were enrolled in Cohort 2. Talazoparib was self-administered orally at a starting dose of 1 mg QD for subjects with normal renal function or mild renal impairment until End of Treatment. Subjects with moderate renal impairment received starting dose of 0.75 mg QD. Avelumab was administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Avelumab was administered as a 1-hour IV infusion Q2W at a dose of 800 mg.

Investigational medicinal product name

Talazoparib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Started	159	41
Completed	1	0
Not completed	158	41
Adverse event, serious fatal	1	-
Adverse event, not serious	4	1
Consent withdrawn by subject	2	6
Global deterioration of health status	14	4
Death	3	-
Adverse event, serious non-fatal	2	1
Unspecified	11	-
Progressive disease	121	29

Baseline characteristics

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Reporting group title

Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)

Reporting group description

Reporting group title

Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)

Reporting group description

Reporting group values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)	Total
Number of subjects	159	41	200
Age Categorical
Units: Subjects
< 65 years	110	25	135
65 - <75 years	34	11	45
75 - <85 years	15	3	18
>=85 years	0	2	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	57.35 ( 12.88 )	61.76 ( 12.47 )	-
Sex: Female, Male
Units: Subjects
Female	108	24	132
Male	51	17	68
Race/Ethnicity, Customized
Units: Subjects
Black or African American	8	3	11
American Indian or Alaska Native	1	0	1
Asian	15	0	15
White	117	37	154
Not reported	18	1	19
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	11	2	13
Not Hispanic or Latino	131	39	170
Unknown or Not Reported	17	0	17

Subject analysis set title

Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib

Subject analysis set type

Full analysis

Subject analysis set description

Talazoparib was self-administered orally QD at a dose of 1 mg QD for subjects with normal renal function or mild renal impairment until End of Treatment. Subjects with moderate renal impairment received 0.75 mg QD. Avelumab was administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication.

Subject analysis sets values	Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib
Number of subjects	200
Age Categorical
Units: Subjects
< 65 years	135
65 - <75 years	45
75 - <85 years	18
>=85 years	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.25 ( 12.89 )
Sex: Female, Male
Units: Subjects
Female	132
Male	68
Race/Ethnicity, Customized
Units: Subjects
Black or African American	11
American Indian or Alaska Native	1
Asian	15
White	154
Not reported	19
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	13
Not Hispanic or Latino	170
Unknown or Not Reported	17

End points

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Reporting group title

Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)

Reporting group description

Reporting group title

Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)

Reporting group description

Subject analysis set title

Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Percentage of Subjects With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)

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End point title

Percentage of Subjects With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) ^[1]

End point description

For subjects with solid tumors except metastatic Castration Resistant Prostate Cancer (mCRPC),OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors version 1.1(RECIST v1.1),both confirmed by repeat assessments performed >=4 weeks after the criteria for response were first met.For subjects with mCRPC, OR was defined as the percentage of subjects with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per Prostate Cancer Working Group3(PCWG3) criteria.CR was defined as complete disappearance of all target&non-target lesions with the exception of nodal disease.PR was defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions.Non-target PR lesions must be non-Progressive Disease (PD),which was unequivocal progression of pre-existing lesions.The analysis set included all enrolled subjects with >=1 dose of study treatment.

End point type

Primary

End point timeframe

From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to approximately 24 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Percentage of subjects
number (confidence interval 95%)	27.7 (20.9 to 35.3)	7.3 (1.5 to 19.9)

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation where subjects administered a product. TEAEs were those events with onset dates occurring during the on-treatment period. A Serious Adverse Event (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomaly/birth defect. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a subject who received study drug. TEAEs were graded using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Subjects
TEAEs	156	40
treatment-related TEAEs	148	34
grade >=3 TEAEs	114	22
grade >=3 treatment-related TEAEs	85	17
SAEs	50	7
treatment-related SAEs	12	4
TEAEs leading to all study drugs' discontinuation	5	2
treatment-related TEAEs (study drugs discontinue)	0	1
TEAEs leading to death	14	2
treatment-related TEAEs leading to death	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period

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End point title

Number of Subjects With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period

End point description

The laboratory results were graded according to the CTCAE v4.03. The number and percentage of subjects with newly occurring or worsening hematology abnormalities to Grade>=1 during the on-treatment period were summarized. Per NCI CTCAE toxicity grading v4.03, Grade 1(G1) = mild; Grade 2(G2) = moderate; Grade 3(G3) = severe; Grade 4(G4) = life-threatening; Grade 5(G5) = death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy -1 day). The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment. Abbreviations: APTTP=activated partial thromboplastin time prolonged; HI=hemoglobin increased; INR=International Normalized Ratio; LCD=lymphocyte count decreased; LCI=lymphocyte count increased; NCD=neutrophil count decreased; N/W=new or worsened; PCD=platelet count decreased; WBCD=white blood cell decreased.

End point type

Secondary

End point timeframe

From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159 ^[2]	41 ^[3]
Units: Subjects
N/W to G1 (Parameter: APTTP) (n=5,1)	0	0
N/W to G2 (Parameter: APTTP) (n=5,1)	0	0
N/W to G3 (Parameter: APTTP) (n=5,1)	0	0
N/W to G4 (Parameter: APTTP) (n=5,1)	0	0
N/W to G1 (Parameter: anemia) (n=151,40)	27	9
N/W to G2 (Parameter: anemia) (n=151,40)	33	6
N/W to G3 (Parameter: anemia) (n=151,40)	61	12
N/W to G4 (Parameter: anemia) (n=151,40)	0	0
N/W to G1 (Parameter: HI) (n=157,41)	1	0
N/W to G2 (Parameter: HI) (n=157,41)	0	0
N/W to G3 (Parameter: HI) (n=157,41)	0	0
N/W to G4 (Parameter: HI) (n=157,41)	0	0
N/W to G1 (Parameter: INR) (n=6,0)	1	0
N/W to G2 (Parameter: INR) (n=6,0)	0	0
N/W to G3 (Parameter: INR) (n=6,0)	0	0
N/W to G4 (Parameter: INR) (n=6,0)	0	0
N/W to G1 (Parameter: LCD) (n=154,40)	15	6
N/W to G2 (Parameter: LCD) (n=154,40)	58	15
N/W to G3 (Parameter: LCD) (n=154,40)	34	7
N/W to G4 (Parameter: LCD) (n=154,40)	3	0
N/W to G1 (Parameter: LCI) (n=156,41)	0	0
N/W to G2 (Parameter: LCI) (n=156,41)	3	0
N/W to G3 (Parameter: LCI) (n=156,41)	1	0
N/W to G4 (Parameter: LCI) (n=156,41)	0	0
N/W to G1 (Parameter: NCD) (n=154,40)	15	2
N/W to G2 (Parameter: NCD) (n=154,40)	42	8
N/W to G3 (Parameter: NCD) (n=154,40)	16	4
N/W to G4 (Parameter: NCD) (n=154,40)	3	1
N/W to G1 (Parameter: PCD) (n=152,41)	59	16
N/W to G2 (Parameter: PCD) (n=152,41)	16	3
N/W to G3 (Parameter: PCD) (n=152,41)	14	4
N/W to G4 (Parameter: PCD) (n=152,41)	11	1
N/W to G1 (Parameter: WBCD) (n=156,41)	45	14
N/W to G2 (Parameter: WBCD) (n=156,41)	52	11
N/W to G3 (Parameter: WBCD) (n=156,41)	15	5
N/W to G4 (Parameter: WBCD) (n=156,41)	2	0

Notes
[2] - Subjects with available data (n=X, X in category titles) were analyzed.
[3] - Subjects with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Number of Subjects With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period

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End point title

Number of Subjects With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period

End point description

The laboratory results were graded according to the CTCAE v4.03. The number and percentage of subjects with newly occurring or worsening chemistry abnormalities to Grade >=1 during the on-treatment period were summarized. As per NCI CTCAE toxicity grading v4.03, Grade1(G1)=mild; Grade2(G2)=moderate; Grade3(G3)=severe; Grade4(G4)=life-threatening; Grade5(G5)=death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30days + last dose of study treatment, start day of new anti-cancer drug therapy -1day). The safety analysis set included all enrolled subjects who received at least 1 dose of study treatment. Abbreviations: ALTI=alanine aminotransferase increased; ALPI=alkaline phosphatase increased; ASTI=aspartate aminotransferase increased; BBI=blood bilirubin increased; CPKI=creatine phosphokinase increased; CI=creatinine increased; GGTI=gamma glutamyl transferase increased; LI=lipase increased; SAI=serum amylase increased.

End point type

Secondary

End point timeframe

From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159 ^[4]	41 ^[5]
Units: Subjects
N/W to G1 (Parameter: ALTI) (n=152,41)	30	10
N/W to G2 (Parameter: ALTI) (n=152,41)	6	0
N/W to G3 (Parameter: ALTI) (n=152,41)	3	3
N/W to G4 (Parameter: ALTI) (n=152,41)	1	0
N/W to G1 (Parameter: ALPI) (n=153,41)	25	12
N/W to G2 (Parameter: ALPI) (n=153,41)	21	5
N/W to G3 (Parameter: ALPI) (n=153,41)	7	1
N/W to G4 (Parameter: ALPI) (n=153,41)	1	0
N/W to G1 (Parameter: ASTI) (n=150,40)	35	5
N/W to G2 (Parameter: ASTI) (n=150,40)	13	2
N/W to G3 (Parameter: ASTI) (n=150,40)	2	4
N/W to G4 (Parameter: ASTI) (n=150,40)	1	0
N/W to G1 (Parameter: BBI) (n=154,40)	7	2
N/W to G2 (Parameter: BBI) (n=154,40)	7	2
N/W to G3 (Parameter: BBI) (n=154,40)	2	1
N/W to G4 (Parameter: BBI) (n=154,40)	0	0
N/W to G1 (Parameter: CPKI) (n=151,41)	22	3
N/W to G2 (Parameter: CPKI) (n=151,41)	8	1
N/W to G3 (Parameter: CPKI) (n=151,41)	2	3
N/W to G4 (Parameter: CPKI) (n=151,41)	0	1
N/W to G1 (Parameter: CI) (n=153,40)	87	24
N/W to G2 (Parameter: CI) (n=153,40)	12	4
N/W to G3 (Parameter: CI) (n=153,40)	1	0
N/W to G4 (Parameter: CI) (n=153,40)	1	0
N/W to G1 (Parameter: GGTI) (n=147,40)	23	8
N/W to G2 (Parameter: GGTI) (n=147,40)	16	5
N/W to G3 (Parameter: GGTI) (n=147,40)	26	7
N/W to G4 (Parameter: GGTI) (n=147,40)	1	1
N/W to G1 (Parameter: hypercalcemia) (n=156,41)	11	4
N/W to G2 (Parameter: hypercalcemia) (n=156,41)	0	0
N/W to G3 (Parameter: hypercalcemia) (n=156,41)	1	0
N/W to G4 (Parameter: hypercalcemia) (n=156,41)	0	0
N/W to G1 (Parameter: hyperglycemia) (n=155,41)	23	5
N/W to G2 (Parameter: hyperglycemia) (n=155,41)	2	0
N/W to G3 (Parameter: hyperglycemia) (n=155,41)	3	2
N/W to G4 (Parameter: hyperglycemia) (n=155,41)	1	0
N/W to G1 (Parameter: hyperkalemia) (n=156,40)	13	3
N/W to G2 (Parameter: hyperkalemia) (n=156,40)	6	0
N/W to G3 (Parameter: hyperkalemia) (n=156,40)	1	0
N/W to G4 (Parameter: hyperkalemia) (n=156,40)	1	0
N/W to G1 (Parameter: hypermagnesemia) (n=155,41)	9	4
N/W to G2 (Parameter: hypermagnesemia) (n=155,41)	0	0
N/W to G3 (Parameter: hypermagnesemia) (n=155,41)	3	0
N/W to G4 (Parameter: hypermagnesemia) (n=155,41)	0	0
N/W to G1 (Parameter: hypernatremia) (n=156,41)	8	1
N/W to G2 (Parameter: hypernatremia) (n=156,41)	0	0
N/W to G3 (Parameter: hypernatremia) (n=156,41)	0	0
N/W to G4 (Parameter: hypernatremia) (n=156,41)	0	0
N/W to G1 (Parameter: hypoalbuminemia) (n=150,39)	21	6
N/W to G2 (Parameter: hypoalbuminemia) (n=150,39)	10	2
N/W to G3 (Parameter: hypoalbuminemia) (n=150,39)	2	1
N/W to G4 (Parameter: hypoalbuminemia) (n=150,39)	0	0
N/W to G1 (Parameter: hypocalcemia) (n=153,41)	27	2
N/W to G2 (Parameter: hypocalcemia) (n=153,41)	6	1
N/W to G3 (Parameter: hypocalcemia) (n=153,41)	3	0
N/W to G4 (Parameter: hypocalcemia) (n=153,41)	0	0
N/W to G1 (Parameter: hypoglycemia) (n=155,41)	10	4
N/W to G2 (Parameter: hypoglycemia) (n=155,41)	1	0
N/W to G3 (Parameter: hypoglycemia) (n=155,41)	0	0
N/W to G4 (Parameter: hypoglycemia) (n=155,41)	0	0
N/W to G1 (Parameter: hypokalemia) (n=155,41)	0	0
N/W to G2 (Parameter: hypokalemia) (n=155,41)	24	8
N/W to G3 (Parameter: hypokalemia) (n=155,41)	4	1
N/W to G4 (Parameter: hypokalemia) (n=155,41)	0	0
N/W to G1 (Parameter: hypomagnesemia) (n=156,41)	24	5
N/W to G2 (Parameter: hypomagnesemia) (n=156,41)	2	0
N/W to G3 (Parameter: hypomagnesemia) (n=156,41)	1	0
N/W to G4 (Parameter: hypomagnesemia) (n=156,41)	1	0
N/W to G1 (Parameter: hyponatremia) (n=153,40)	29	10
N/W to G2 (Parameter: hyponatremia) (n=153,40)	0	0
N/W to G3 (Parameter: hyponatremia) (n=153,40)	11	2
N/W to G4 (Parameter: hyponatremia) (n=153,40)	0	0
N/W to G1 (Parameter: hypophosphatemia) (n=153,41)	0	0
N/W to G2 (Parameter: hypophosphatemia) (n=153,41)	18	4
N/W to G3 (Parameter: hypophosphatemia) (n=153,41)	2	1
N/W to G4 (Parameter: hypophosphatemia) (n=153,41)	0	0
N/W to G1 (Parameter: LI) (n=157,41)	13	4
N/W to G2 (Parameter: LI) (n=157,41)	9	3
N/W to G3 (Parameter: LI) (n=157,41)	7	2
N/W to G4 (Parameter: LI) (n=157,41)	2	1
N/W to G1 (Parameter: SAI) (n=156,41)	16	3
N/W to G2 (Parameter: SAI) (n=156,41)	1	2
N/W to G3 (Parameter: SAI) (n=156,41)	2	2
N/W to G4 (Parameter: SAI) (n=156,41)	1	1

Notes
[4] - Subjects with available data (n=X, X in category titles) were analyzed.
[5] - Subjects with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Serum Maximum Concentration (Cmax) for Avelumab

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End point title

Serum Maximum Concentration (Cmax) for Avelumab

End point description

Cmax was defined as maximum observed plasma concentration. The determination method of Cmax was observing directly from data. The avelumab PK concentration analysis set included all subjects (Cohort 1 and Cohort 2 combined) who received at least 1 dose of study intervention and had at least one concentration measurement for avelumab. Number of subjects analyzed = number of subjects evaluable for this OM. Number analyzed = subjects evaluable at the specific time point.

End point type

Secondary

End point timeframe

One hour post-dose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1

End point values	Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib
Number of subjects analysed	199 ^[6]
Units: mcg/mL
geometric mean (geometric coefficient of variation)
CYCLE1DAY1 (n=161)	223.0 ( 39 )
CYCLE1DAY15 (n=146)	221.6 ( 38 )
CYCLE3DAY1 (n=114)	225.6 ( 34 )
CYCLE6DAY1 (n=79)	222.3 ( 37 )
CYCLE12DAY1 (n=35)	248.2 ( 25 )
CYCLE18DAY1 (n=17)	265.9 ( 20 )
CYCLE24DAY1 (n=9)	286.1 ( 21 )

Notes
[6] - Subjects with available data (n=X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Serum Lowest (Trough) Concentration (Ctrough) of Avelumab

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End point title

Serum Lowest (Trough) Concentration (Ctrough) of Avelumab

End point description

Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. The lower limit of quantification (LLQ) was 0.2 mcg/mL. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented. The avelumab PK concentration analysis set included all subjects (Cohort 1 and Cohort 2 combined) who received at least 1 dose of study intervention and had at least one concentration measurement for avelumab. Number of subjects analyzed = number of subjects evaluable for this OM. Number analyzed = subjects evaluable at the specific time point.

End point type

Secondary

End point timeframe

Predose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1

End point values	Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib
Number of subjects analysed	199 ^[7]
Units: microgram(mcg)/milliliter(mL)
geometric mean (geometric coefficient of variation)
CYCLE1DAY1 (n=180)	99999 ( 99999 )
CYCLE1DAY15 (n=164)	21.06 ( 58 )
CYCLE3DAY1 (n=110)	32.65 ( 63 )
CYCLE6DAY1 (n=83)	36.23 ( 60 )
CYCLE12DAY1 (n=35)	41.80 ( 60 )
CYCLE18DAY1 (n=16)	35.19 ( 54 )
CYCLE24DAY1 (n=10)	37.21 ( 54 )

Notes
[7] - 99999 is entered for data not presented. n=subjects analyzed with available data.

No statistical analyses for this end point

Secondary: Plasma Ctrough for Talazoparib

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End point title

Plasma Ctrough for Talazoparib

End point description

Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented. Evaluable subjects were subjects with non-missing Ctrough concentrations at each specific time point and meeting 2 conditions: subjects received 14 consecutive days of talazoparib dose without dosing interruption prior to sample collection (except on Cycle 1 Day 1) and sample collection within 24 hours ± 10% (2 hours and 24 minutes) after the previous day's dose and no more than 5 minutes (0.083 hours) after the administration of the dose on the day of PK sample collection. Predose PK samples on Cycle 1 Day 1 must have been collected prior to dose. The analysis set included all subjects who received at least 1 dose of study intervention and had at least one Ctrough concentration measurement for talazoparib.

End point type

Secondary

End point timeframe

Predose on Cycle 1 Days 1, 15 and Cycle 3 Day 1

End point values	Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib
Number of subjects analysed	199 ^[8]
Units: picogram(pg)/mL
geometric mean (geometric coefficient of variation)
CYCLE1DAY1 (Starting Dose: 1 mg QD) (n=170)	99999 ( 99999 )
CYCLE1DAY15 (Starting Dose: 1 mg QD) (n=62)	4649 ( 61 )
CYCLE3DAY1 (Starting Dose: 1 mg QD) (n=30)	3313 ( 113 )
CYCLE1DAY1 (Starting Dose: 0.75 mg QD) (n=16)	99999 ( 99999 )
CYCLE1DAY15 (Starting Dose: 0.75 mg QD) (n=2)	7612 ( 99999 )
CYCLE3DAY1 (Starting Dose: 0.75 mg QD) (n=4)	4314 ( 42 )

Notes
[8] - 99999 is entered for data not presented or not estimable. n=subjects analyzed with available data.

No statistical analyses for this end point

Secondary: Number of Subjects by Avelumab Anti-drug Antibody (ADA) Categories

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End point title

Number of Subjects by Avelumab Anti-drug Antibody (ADA) Categories

End point description

Blood samples were assayed for ADA. ADA never-positive=no positive ADA results at any time point. ADA ever-positive=at least one positive ADA result at any time point. Baseline ADA positive=a positive ADA result at baseline. Treatment-boosted ADA=a positive ADA result at baseline and the titer >=8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA=subject was ADA-negative at baseline and had at least one positive post-baseline ADA result; or had at least one positive post-baseline ADA result if no baseline sample. Transient ADA response=subjects with treatment-induced ADA had (a single positive ADA result or duration between first and last positive result <16weeks) and ADA result at the last assessment was not positive. Persistent ADA response=subjects with treatment-induced ADA had duration between first & last positive ADA result >=16weeks or a positive ADA result at the last assessment. Analysis population=subjects with >=1 ADA sample for avelumab.

End point type

Secondary

End point timeframe

Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159 ^[9]	40 ^[10]
Units: Subjects
ADA never-positive (n=159,40)	153	39
ADA ever-positive (n=159,40)	6	1
Baseline ADA positive (n=150,38)	5	1
Treatment-boosted ADA (n=143,37)	0	0
Treatment-induced ADA (n=147,38)	1	0
Transient ADA response (n=147,38)	1	0
Persistent ADA response (n=147,38)	0	0

Notes
[9] - Subjects with available data (n=X, X in category titles) were analyzed.
[10] - Subjects with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Plasma Post-dose Concentrations for Talazoparib

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End point title

Plasma Post-dose Concentrations for Talazoparib

End point description

In this OM, the post-dose concentrations for talazoparib in plasma were reported. The Analysis Population included all subjects (Cohort 1 and Cohort 2 combined) who received at least 1 dose of talazoparib, had at least one non-missing concentration measurement at any collection scheduled time point, received 14 consecutive days of talazoparib dose without dosing interruption prior to sample collection (except on Cycle 1 Day 1) and sample collection was performed within ± 10% (12 minutes) of nominal time post-dose.

End point type

Secondary

End point timeframe

Postdose (samples collected within 2 hours post dose plus/minus 12 minutes) on Days 1,15 of Cycle 1, and Day 1 of Cycle 3

End point values	Avelumab 800 mg Intravenous (IV) Q2W plus talazoparib
Number of subjects analysed	106 ^[11]
Units: pg/mL
geometric mean (geometric coefficient of variation)
CYCLE1DAY1 (Starting Dose: 1 mg QD) (n=76)	1833 ( 275 )
CYCLE1DAY15 (Starting Dose: 1 mg QD) (n=51)	7985 ( 79 )
CYCLE3DAY1 (Starting Dose: 1 mg QD) (n=22)	7800 ( 69 )
CYCLE1DAY1 (Starting Dose: 0.75 mg QD) (n=6)	1663 ( 100 )
CYCLE1DAY15 (Starting Dose: 0.75 mg QD) (n=6)	12590 ( 47 )
CYCLE3DAY1 (Starting Dose: 0.75 mg QD) (n=3)	8366 ( 53 )

Notes
[11] - Subjects with available data (n=X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Number of Subjects With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive

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End point title

Number of Subjects With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive

End point description

Nab ever-positive was defined as at least one positive Nab result at any time point. Samples positive for ADA with persistent treatment-induced ADA response could be analyzed for Nab. The immunogenicity analysis set included subjects who had at least 1 Nab sample collected for avelumab. Nabs data were not collected due to insufficient number of subjects with persistent treatment-induced ADA response. Therefore, the number of subjects analyzed for this OM was 0.

End point type

Secondary

End point timeframe

Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	0 ^[12]	0 ^[13]
Units: Subjects

Notes
[12] - Data were not collected due to insufficient subjects with persistent treatment-induced ADA response.
[13] - Data were not collected due to insufficient subjects with persistent treatment-induced ADA response.

No statistical analyses for this end point

Secondary: Percentage of Subjects With Confirmed OR as Assessed by The Investigator

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End point title

Percentage of Subjects With Confirmed OR as Assessed by The Investigator

End point description

For subjects with solid tumors, except mCRPC, OR was defined as a CR or PR per RECIST v1.1, both confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. For subjects with mCRPC, OR was defined as the percentage of subjects with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per PCWG3 criteria. Per RECIST v1.1, CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Non-target PR lesions must be non-PD, where PD was unequivocal progression of pre-existing lesions.

End point type

Secondary

End point timeframe

From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Percentage of subjects
number (confidence interval 95%)	34.6 (27.2 to 42.5)	14.6 (5.6 to 29.2)

No statistical analyses for this end point

Secondary: DoR as Assessed by Investigator

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End point title

DoR as Assessed by Investigator

End point description

For subjects with solid tumors, except mCRPC: DoR was defined for subjects with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. For subjects with mCRPC:DoR was defined for subjects with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3. The analysis population included all enrolled subjects who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by investigator.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	55	6
Units: Months
median (confidence interval 95%)	8.8 (7.5 to 10.7)	7.1 (5.5 to 9.7)

No statistical analyses for this end point

Secondary: Duration of Response (DoR) as Assessed by BICR

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End point title

Duration of Response (DoR) as Assessed by BICR

End point description

For subjects with solid tumors, except mCRPC: DoR was defined for subjects with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occured first. For subjects with mCRPC: DoR was defined for subjects with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occured first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3. The analysis population included all enrolled subjects who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by BICR.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	44 ^[14]	3 ^[15]
Units: Months
median (confidence interval 95%)	12.5 (7.5 to 99999)	99999 (6.7 to 99999)

Notes
[14] - Reason for 99999: the upper limit of the confidence interval (CI) is not crossing the 50% bound.
[15] - Reason for 99999: the median and upper limit of the CI are not crossing the 50% bound.

No statistical analyses for this end point

Secondary: TTR as Assessed by Investigator

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End point title

TTR as Assessed by Investigator

End point description

For subjects with solid tumors, except mCRPC: TTR was defined for subjects with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For subjects with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a BOR of CR or PR per RECIST v1.1. The analysis population included all enrolled subjects who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by investigator.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	55	6
Units: Months
median (full range (min-max))	1.84 (1.5 to 18.4)	3.99 (1.9 to 14.0)

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR) as Assessed by BICR

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End point title

Time to Tumor Response (TTR) as Assessed by BICR

End point description

For subjects with solid tumors, except mCRPC: TTR was defined for subjects with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For subjects with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a Best Overall Response (BOR) of CR or PR per RECIST v1.1. The analysis population included all enrolled subjects who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by BICR.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	44	3
Units: Months
median (full range (min-max))	1.82 (1.5 to 12.1)	5.52 (1.6 to 16.8)

No statistical analyses for this end point

Secondary: Overall Survival (OS) for All Subjects

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End point title

Overall Survival (OS) for All Subjects

End point description

OS was defined as the time from the first dose of study treatment to the date of death. Subjects without an event (death) were censored at the date of last contact. All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment. Subjects were classified according to the cohort assigned at enrollment.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Months
median (confidence interval 95%)	11.9 (10.1 to 13.7)	16.4 (12.8 to 21.9)

No statistical analyses for this end point

Secondary: PFS as Assessed by Investigator

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End point title

PFS as Assessed by Investigator

End point description

For subjects with solid tumors, except mCRPC: PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For subjects with mCRPC: PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated per PCWG3, or death, whichever occurred first. All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled subjects who received at least 1 dose of study treatment. Subjects were classified according to the cohort assigned at enrollment.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Months
median (confidence interval 95%)	5.3 (3.7 to 5.6)	3.7 (2.1 to 7.4)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) as Assessed by BICR

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End point title

Progression Free Survival (PFS) as Assessed by BICR

End point description

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Months
median (confidence interval 95%)	3.7 (3.1 to 5.4)	3.5 (1.8 to 5.5)

No statistical analyses for this end point

Secondary: Number of Subjects With Confirmed PSA Response

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End point title

Number of Subjects With Confirmed PSA Response

End point description

For subjects with mCRPC, PSA response was defined as confirmed PSA decline >=50% compared to baseline. PSA response was calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must have been confirmed by a second consecutive value at least 3 weeks later. The analysis population included all subjects with mCRPC who received at least 1 dose of study intervention.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	26	5
Units: Subjects	17	2

No statistical analyses for this end point

Secondary: Time to Prostate-Specific Antigen (PSA) Progression for Subjects With mCRPC

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End point title

Time to Prostate-Specific Antigen (PSA) Progression for Subjects With mCRPC

End point description

For subjects with mCRPC, time to PSA progression was defined as the time from the first dose to the date that a >=25% increase in PSA with an absolute increase of >=2 μg/L (2 ng/mL) above the nadir (or baseline for subjects with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained >=3 weeks (21 days) later. The analysis population included all subjects with mCRPC who received at least 1 dose of study intervention.

End point type

Secondary

End point timeframe

Baseline up to approximately 24 months

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	26	5 ^[16]
Units: Months
median (confidence interval 95%)	6.5 (3.7 to 12.7)	11.3 (3.7 to 99999)

Notes
[16] - The upper limit of the CI is not crossing the 50% bound, thus 99999 is entered.

No statistical analyses for this end point

Secondary: Number of Subjects With Circulating Tumor Cell (CTC) Count Conversion

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End point title

Number of Subjects With Circulating Tumor Cell (CTC) Count Conversion

End point description

For subjects with mCRPC, CTC count conversion was defined as a decrease in CTC count from >=5 CTC per 7.5 mL of blood at baseline to <5 CTC per 7.5 mL of blood anytime on study. The analysis population included all enrolled subjects with mCRPC who received at least 1 dose of study treatment, and with CTC count >=5 CTC per 7.5 mL of blood at baseline.

End point type

Secondary

End point timeframe

Day 1 of Cycle 1 to Cycle 4

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	13	2
Units: Subjects	11	1

No statistical analyses for this end point

Secondary: Number of Subjects With Cancer Antigen 125 (CA-125) Response

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End point title

Number of Subjects With Cancer Antigen 125 (CA-125) Response

End point description

For subjects with ovarian cancer, CA-125 response was defined as at least a 50% reduction in CA-125 levels from baseline. The response must have been confirmed and maintained for at least 28 days. The analysis population included all subjects with ovarian cancer who received at least 1 dose of study intervention.

End point type

Secondary

End point timeframe

Baseline, Day 1 of each treatment Cycle, maximum up to 4.3 years approximately

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	26	3
Units: Subjects	9	0

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue

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End point title

Number of Subjects With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue

End point description

PD-L1 expression on tumor and infiltrating immune cells was measured by immunohistochemistry (IHC). PD-L1 expression level was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. This OM reported the number of subjects classified as positive according to scoring algorithms and cut-offs established from external sources. The biomarker analysis set included all subjects who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.

End point type

Secondary

End point timeframe

Baseline

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Subjects	27	0

No statistical analyses for this end point

Secondary: Number of Subjects With Different Status for Defects in BRCA1, BRCA2 and ATM

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End point title

Number of Subjects With Different Status for Defects in BRCA1, BRCA2 and ATM

End point description

Subjects were enrolled in the two cohorts based on BRCA 1/2 and ATM defect status assessed by the local laboratory. The subject BRCA and ATM status was assessed retrospectively by central laboratory, that may differ from the status assessed by the local laboratory. The ATM subjects with a negative ATM status per the central laboratory were reported to have a positive ATM status per the local laboratory. Therefore, subjects with negative ATM status might have been included in the ATM defect cohort. For defects in BRCA1, BRCA2 and ATM by central laboratory analysis, subjects were classified as positive, negative, not analyzable or missing. The number of subjects in each category of BRCA 1 defect, BRCA 2 defect, BRCA 1 or BRCA 2 defect and ATM defect were presented. The biomarker analysis set included all subjects who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.

End point type

Secondary

End point timeframe

Baseline

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Subjects
BRCA1 status positive	52	0
BRCA1 status negative	65	29
BRCA1 status not analyzable	21	4
BRCA1 status missing	21	8
BRCA2 status positive	53	1
BRCA2 status negative	64	28
BRCA2 status not analyzable	21	4
BRCA2 status missing	21	8
BRCA status positive	105	1
BRCA status negative	12	28
BRCA status not analyzable	21	4
BRCA status missing	21	8
ATM status positive	2	26
ATM status negative	115	3
ATM status not analyzable	21	4
ATM status missing	21	8

No statistical analyses for this end point

Secondary: Number of Subjects by Status of Tumor Mutational Burden (TMB) at Baseline

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End point title

Number of Subjects by Status of Tumor Mutational Burden (TMB) at Baseline

End point description

TMB was defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing. TMB categories were defined as high, low for a number of mutations per megabase >=10 and <10, respectively. The TMB category ‘Not analyzable’ included subjects with available samples but not evaluable. The TMB category ‘Missing’ included subjects with no sample available. The number of subjects in each category at only baseline were tabulated. The biomarker analysis set included all subjects who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.

End point type

Secondary

End point timeframe

Baseline

End point values	Cohort 1 (BReast CAncer Gene [BRCA] 1/2 defect)	Cohort 2 (Ataxia Telangiectasia Mutated [ATM] defect)
Number of subjects analysed	159	41
Units: Subjects
TMB status high	9	2
TMB status low	95	23
TMB status not analyzable	34	8
TMB status missing	21	8

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately.

Adverse event reporting additional description

The same event may appear as both an AE and an SAE. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and nonserious event during the study. Total number at risk below refers to the number of subjects evaluable for SAEs or AEs.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Cohort 2 (ATM defect)

Reporting group description

Reporting group title

Cohort 1 (BRCA 1/2 defect)

Reporting group description

Subjects with locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes were enrolled in Cohort 1. Talazoparib was self-administered orally at a starting dose of 1 mg QD for subjects with normal renal function or mild renal impairment until End of Treatment. Subjects with moderate renal impairment received starting dose of 0.75 mg QD. Avelumab was administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication.

Serious adverse events	Cohort 2 (ATM defect)	Cohort 1 (BRCA 1/2 defect)
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 41 (17.07%)	50 / 159 (31.45%)
number of deaths (all causes)	3	15
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Malignant neoplasm progression
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	2 / 41 (4.88%)	8 / 159 (5.03%)
occurrences causally related to treatment / all	0 / 2	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 41 (2.44%)	2 / 159 (1.26%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 41 (0.00%)	3 / 159 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 41 (0.00%)	3 / 159 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 41 (4.88%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 41 (4.88%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	5 / 6	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin T increased
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fracture
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrioventricular block complete
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 41 (0.00%)	2 / 159 (1.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 41 (0.00%)	2 / 159 (1.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 41 (4.88%)	4 / 159 (2.52%)
occurrences causally related to treatment / all	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow disorder
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 41 (2.44%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 41 (0.00%)	2 / 159 (1.26%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eye disorder
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 41 (0.00%)	3 / 159 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Nausea
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestine polyp
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 41 (0.00%)	2 / 159 (1.26%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver injury
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary tract obstruction
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral obstruction
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 41 (2.44%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Musculoskeletal and connective tissue disorders
Osteitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial abdominal infection
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Clostridial infection
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 41 (2.44%)	4 / 159 (2.52%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 41 (0.00%)	3 / 159 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 41 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 41 (2.44%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 41 (2.44%)	0 / 159 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 2 (ATM defect)	Cohort 1 (BRCA 1/2 defect)
Total subjects affected by non serious adverse events
subjects affected / exposed	40 / 41 (97.56%)	153 / 159 (96.23%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	3 / 41 (7.32%)	2 / 159 (1.26%)
occurrences all number	4	4
Vascular disorders
Hot flush
subjects affected / exposed	3 / 41 (7.32%)	1 / 159 (0.63%)
occurrences all number	3	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 41 (4.88%)	27 / 159 (16.98%)
occurrences all number	2	57
Chills
subjects affected / exposed	5 / 41 (12.20%)	17 / 159 (10.69%)
occurrences all number	6	22
Fatigue
subjects affected / exposed	19 / 41 (46.34%)	50 / 159 (31.45%)
occurrences all number	23	89
Influenza like illness
subjects affected / exposed	2 / 41 (4.88%)	10 / 159 (6.29%)
occurrences all number	2	12
Oedema peripheral
subjects affected / exposed	4 / 41 (9.76%)	12 / 159 (7.55%)
occurrences all number	4	13
Pyrexia
subjects affected / exposed	3 / 41 (7.32%)	28 / 159 (17.61%)
occurrences all number	4	35
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 41 (12.20%)	19 / 159 (11.95%)
occurrences all number	6	23
Dyspnoea
subjects affected / exposed	8 / 41 (19.51%)	34 / 159 (21.38%)
occurrences all number	9	53
Nasal congestion
subjects affected / exposed	1 / 41 (2.44%)	10 / 159 (6.29%)
occurrences all number	1	11
Productive cough
subjects affected / exposed	3 / 41 (7.32%)	8 / 159 (5.03%)
occurrences all number	3	10
Psychiatric disorders
Insomnia
subjects affected / exposed	5 / 41 (12.20%)	21 / 159 (13.21%)
occurrences all number	6	22
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 41 (17.07%)	16 / 159 (10.06%)
occurrences all number	11	27
Aspartate aminotransferase increased
subjects affected / exposed	6 / 41 (14.63%)	18 / 159 (11.32%)
occurrences all number	13	31
Blood bilirubin increased
subjects affected / exposed	3 / 41 (7.32%)	8 / 159 (5.03%)
occurrences all number	5	12
Blood creatine phosphokinase increased
subjects affected / exposed	4 / 41 (9.76%)	7 / 159 (4.40%)
occurrences all number	12	8
Blood creatinine increased
subjects affected / exposed	5 / 41 (12.20%)	3 / 159 (1.89%)
occurrences all number	10	5
Lymphocyte count decreased
subjects affected / exposed	3 / 41 (7.32%)	2 / 159 (1.26%)
occurrences all number	4	21
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 41 (7.32%)	9 / 159 (5.66%)
occurrences all number	3	21
Neutrophil count decreased
subjects affected / exposed	5 / 41 (12.20%)	21 / 159 (13.21%)
occurrences all number	10	55
Weight decreased
subjects affected / exposed	2 / 41 (4.88%)	10 / 159 (6.29%)
occurrences all number	3	13
White blood cell count decreased
subjects affected / exposed	4 / 41 (9.76%)	12 / 159 (7.55%)
occurrences all number	9	24
Platelet count decreased
subjects affected / exposed	11 / 41 (26.83%)	25 / 159 (15.72%)
occurrences all number	19	71
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	3 / 41 (7.32%)	22 / 159 (13.84%)
occurrences all number	3	23
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 41 (2.44%)	19 / 159 (11.95%)
occurrences all number	1	24
Headache
subjects affected / exposed	6 / 41 (14.63%)	35 / 159 (22.01%)
occurrences all number	6	48
Peripheral sensory neuropathy
subjects affected / exposed	3 / 41 (7.32%)	5 / 159 (3.14%)
occurrences all number	3	5
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	4 / 41 (9.76%)	20 / 159 (12.58%)
occurrences all number	6	57
Anaemia
subjects affected / exposed	18 / 41 (43.90%)	81 / 159 (50.94%)
occurrences all number	52	269
Thrombocytopenia
subjects affected / exposed	5 / 41 (12.20%)	27 / 159 (16.98%)
occurrences all number	8	62
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	6 / 41 (14.63%)	5 / 159 (3.14%)
occurrences all number	6	5
Abdominal pain
subjects affected / exposed	6 / 41 (14.63%)	30 / 159 (18.87%)
occurrences all number	8	42
Ascites
subjects affected / exposed	3 / 41 (7.32%)	1 / 159 (0.63%)
occurrences all number	3	2
Constipation
subjects affected / exposed	8 / 41 (19.51%)	39 / 159 (24.53%)
occurrences all number	10	52
Diarrhoea
subjects affected / exposed	10 / 41 (24.39%)	36 / 159 (22.64%)
occurrences all number	16	75
Dyspepsia
subjects affected / exposed	3 / 41 (7.32%)	10 / 159 (6.29%)
occurrences all number	3	11
Nausea
subjects affected / exposed	21 / 41 (51.22%)	73 / 159 (45.91%)
occurrences all number	27	102
Vomiting
subjects affected / exposed	11 / 41 (26.83%)	39 / 159 (24.53%)
occurrences all number	16	48
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 41 (7.32%)	19 / 159 (11.95%)
occurrences all number	3	20
Pruritus
subjects affected / exposed	1 / 41 (2.44%)	10 / 159 (6.29%)
occurrences all number	1	13
Dry skin
subjects affected / exposed	4 / 41 (9.76%)	5 / 159 (3.14%)
occurrences all number	5	5
Endocrine disorders
Hypothyroidism
subjects affected / exposed	5 / 41 (12.20%)	10 / 159 (6.29%)
occurrences all number	8	11
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 41 (26.83%)	30 / 159 (18.87%)
occurrences all number	13	37
Back pain
subjects affected / exposed	10 / 41 (24.39%)	21 / 159 (13.21%)
occurrences all number	16	23
Myalgia
subjects affected / exposed	2 / 41 (4.88%)	16 / 159 (10.06%)
occurrences all number	2	18
Neck pain
subjects affected / exposed	2 / 41 (4.88%)	9 / 159 (5.66%)
occurrences all number	3	12
Pain in extremity
subjects affected / exposed	5 / 41 (12.20%)	7 / 159 (4.40%)
occurrences all number	5	11
Infections and infestations
Sinusitis
subjects affected / exposed	3 / 41 (7.32%)	1 / 159 (0.63%)
occurrences all number	3	1
Upper respiratory tract infection
subjects affected / exposed	3 / 41 (7.32%)	12 / 159 (7.55%)
occurrences all number	3	13
Urinary tract infection
subjects affected / exposed	7 / 41 (17.07%)	11 / 159 (6.92%)
occurrences all number	8	14
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	12 / 41 (29.27%)	33 / 159 (20.75%)
occurrences all number	19	41
Hypokalaemia
subjects affected / exposed	5 / 41 (12.20%)	8 / 159 (5.03%)
occurrences all number	11	13

More information

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Were there any global substantial amendments to the protocol? Yes

15 Nov 2018

1. Based on limitations in utility of this and/or complexity to collect this exploratory endpoint, irRECIST assessments and any associated elements were removed or revised accordingly. 2. To help facilitate study conduct, the Schedule of Activities has been modified with a -1 day window for the baseline physical examination and a +/ 3 day window (formerly +/- 2 day) for treatment visits. 3. To help facilitate study conduct, the Schedule of Activities and Section 7.8 has been modified to clarify that Patient Reported Outcome assessments are not required when not available in a language understood by the patient, and to provide a window for shipment of pre-treatment tumor tissue. 4. The background section has been updated with health authority approvals for Avelumab and Talazoparib. 5. Consistent with the updated Avelumab Investigator’s Brochure (version 8, 16 May 2018), the protocol was revised to update background information and recommendation for management of Grade 1 to 2 immune-related rash was updated. 6. Consistent with the updated Talazoparib Investigator’s Brochure (dated August 2018), the protocol was revised to provide updated background information on clinical experience and pharmacokinetic information, to increase the duration of contraception use, and to simplify language regarding prohibited medication P-gp inhibitors. 7. Preliminary safety information and the recommended phase 2 dose from the B9991025 study has been added to the Background, Allocation to Treatment and Talazoparib administration sections. 8. Use of a Patient Enrollment Verification Form has been added.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination With Talazoparib in Subjects With BRCA or ATM Mutant Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)

Primary: Percentage of Subjects With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period

Secondary: Number of Subjects With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period

Secondary: Number of Subjects With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period

Secondary: Number of Subjects With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period

Secondary: Serum Maximum Concentration (Cmax) for Avelumab

Secondary: Serum Maximum Concentration (Cmax) for Avelumab

Secondary: Serum Lowest (Trough) Concentration (Ctrough) of Avelumab

Secondary: Serum Lowest (Trough) Concentration (Ctrough) of Avelumab

Secondary: Plasma Ctrough for Talazoparib

Secondary: Plasma Ctrough for Talazoparib

Secondary: Number of Subjects by Avelumab Anti-drug Antibody (ADA) Categories

Secondary: Number of Subjects by Avelumab Anti-drug Antibody (ADA) Categories

Secondary: Plasma Post-dose Concentrations for Talazoparib

Secondary: Plasma Post-dose Concentrations for Talazoparib

Secondary: Number of Subjects With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive

Secondary: Number of Subjects With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive

Secondary: Percentage of Subjects With Confirmed OR as Assessed by The Investigator

Secondary: Percentage of Subjects With Confirmed OR as Assessed by The Investigator

Secondary: DoR as Assessed by Investigator

Secondary: DoR as Assessed by Investigator

Secondary: Duration of Response (DoR) as Assessed by BICR

Secondary: Duration of Response (DoR) as Assessed by BICR

Secondary: TTR as Assessed by Investigator

Secondary: TTR as Assessed by Investigator

Secondary: Time to Tumor Response (TTR) as Assessed by BICR

Secondary: Time to Tumor Response (TTR) as Assessed by BICR

Secondary: Overall Survival (OS) for All Subjects

Secondary: Overall Survival (OS) for All Subjects

Secondary: PFS as Assessed by Investigator

Secondary: PFS as Assessed by Investigator

Secondary: Progression Free Survival (PFS) as Assessed by BICR

Secondary: Progression Free Survival (PFS) as Assessed by BICR

Secondary: Number of Subjects With Confirmed PSA Response

Secondary: Number of Subjects With Confirmed PSA Response

Secondary: Time to Prostate-Specific Antigen (PSA) Progression for Subjects With mCRPC

Secondary: Time to Prostate-Specific Antigen (PSA) Progression for Subjects With mCRPC

Secondary: Number of Subjects With Circulating Tumor Cell (CTC) Count Conversion

Secondary: Number of Subjects With Circulating Tumor Cell (CTC) Count Conversion

Secondary: Number of Subjects With Cancer Antigen 125 (CA-125) Response

Secondary: Number of Subjects With Cancer Antigen 125 (CA-125) Response

Secondary: Number of Subjects With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue

Secondary: Number of Subjects With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue

Secondary: Number of Subjects With Different Status for Defects in BRCA1, BRCA2 and ATM

Secondary: Number of Subjects With Different Status for Defects in BRCA1, BRCA2 and ATM

Secondary: Number of Subjects by Status of Tumor Mutational Burden (TMB) at Baseline

Secondary: Number of Subjects by Status of Tumor Mutational Burden (TMB) at Baseline

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination With Talazoparib in Subjects With BRCA or ATM Mutant Tumors