A Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer

Time to objective response was defined as the time from first dose of talazoparib to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per prostate cancer working Group 3 (PCWG3). Soft tissue response is defined as a best overall response of CR or PR per RECIST 1.1 by independent central review. RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than 10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than 10 mm short axis); PR: at least 30 % decrease in sum of diameters of target lesions taking as reference baseline sum diameters.

DOR was defined as the time from the first objective evidence of soft tissue response (CR or PR, whichever is earlier) per RECIST 1.1 and no evidence of confirmed bone disease progression per PCWG3 to the date of first objective evidence of radiographic progression or death due to any cause without evidence of radiographic progression, whichever occurs first. RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than 10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than 10 mm short axis); PR: at least 30 % decrease in sum of diameters of target lesions taking as reference baseline sum diameters.

Percentage of participants with PSA response of >= 50% was reported in this outcome measure. PSA response was calculated as a decline from baseline PSA (ng/mL) by at least 50% measured by central laboratory.

Percentage of participants with conversion of CTC count was defined as percentage of participants with a CTC count >= 5 CTC per 7.5 milliliter (mL) of blood at baseline that decreased to < 5 CTC per 7.5 mL of blood any time on study.

Percentage of participants with a null CTC count was defined as percentage of participants with CTC count >=1 CTC per 7.5 mL of blood at baseline that decreased to CTC = 0 per 7.5 mL of blood any time on study.

Percentage of participants with CTC count <5 CTC per 7.5 mL of blood at baseline those who showed an increased CTC count, compared to baseline, any time on study was reported in this study.

Time to PSA progression was defined as the time from first dose of study treatment to the date of PSA progression, which was subsequently confirmed. The time from first dose of talazoparib to the date that a >=25% increase in PSA with an absolute increase of >=2micogram per liter (2 nanogram per mL) above the nadir (or baseline for participants with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained >=3 weeks (21 days) later. Kaplan-Meier method was used for analysis.

Radiographic PFS was defined as the time from date of first dose of talazoparib to first objective evidence of radiographic progression as assessed in soft tissue per modified RECIST 1.1 or confirmed progression in bone per PCWG3 guidelines by independent central review or death without documented radiographic progression, whichever occurs first.

OS was defined as the time from start date (the date of first dose of treatment) to the date of death due to any cause. Participants who had not died were censored at the date of last contact. Kaplan-Meier method was used for analysis.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included both serious AEs and all non-serious AEs. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Treatment discontinuation was defined as permanent cessation of study drug treatment administration.

Vital sign abnormalities criteria included: 1) Systolic blood pressure (SBP) in millimeters of mercury (mmHg): absolute result greater than (>) 180 mmHg and increase from baseline greater than or equal to (>=) 40 mmHg or absolute result < 90 mmHg and decrease from baseline > 30 mmHg; 2) Diastolic blood pressure (DBP) (mmHg): absolute result > 110 mmHg and increase from baseline >= 30 mmHg or absolute result < 50 mmHg and decrease from baseline > 20 mmHg or >= 20 mmHg increase from baseline; 3) Heart rate in beats per minutes (bpm): absolute result < 50 bpm and decrease from baseline > 20 bpm or absolute result > 120 bpm and increase from baseline > 30 bpm; Weight in kilogram: > 10% decrease from baseline.

Hematology parameters included anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, Leukocytosis and white blood cell decreased. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or non-invasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

Chemistry parameters:alanine aminotransferase increased(inc), alkaline phosphatase inc, aspartate aminotransferase inc, blood bilirubin inc, chronic kidney disease, creatinine inc, gamma-glutamyl transferase (GGT) inc, hypercalcemia, Hyperglycemia, hyperkalemia, hypermagnesemia, hypocalcemia, Hyponatremia, hypoglycemia, hypokalemia, hypomagnesemia, hypernatremia, Hypoalbuminemia and hypophosphatemia. Severity was graded as Grade(G)1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G2:moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G3:severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G4:life-threatening consequence, urgent intervention indicated; G5: death related to AEs.

Number of participants with dose modification due to adverse events was reported.

Time deterioration is based on BPI-SF question 3: "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 24 hours." Pain intensity was to be answered on a range of 0 to 10, where 0 corresponded to no pain and 10 worst pain. Time to this event is defined as the time from the date of first dose of study treatment to onset of pain progression, where pain progression is defined as a 2-point or more increase from baseline in the question 3 score. Kaplan-Meier method was used for analysis. Average of all assessments visits is reported in this outcome measure.

BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-SF have 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10; '0=No pain and 10=Pain as bad as you can imagine'. Measure can be scored by item, with lower scores being indicative of less pain or pain interference. BPI-SF question 3 was related to participant experiencing pain at its worst in last 24 hours, score range 0 to 10, where large values corresponded to worse outcomes.

The EQ-5D VAS score was a participant rated questionnaire where participants rated how they felt at assessment visit on a vertical VAS that ranged from 0 (worst imaginable health state) to 100 (best imaginable health state), with higher scores indicating a better health condition.

EQ-5D-5L: participant rated assessed level of current health using 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety, and depression. EQ-5D mobility domain had 5 responses: no problem, slight problem, moderate problem, severe problem and extreme problem.

EQ-5D-5L: participant rated assessed level of current health using 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety, and depression. EQ-5D self-care domain had 5 responses: no problem, slight problem, moderate problem, severe problem and extreme problem.

EQ-5D-5L: participant rated assessed level of current health using 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety, and depression. EQ-5D usual activities domain had 5 responses: no problem, slight problem, moderate problem, severe problem and extreme problem.

EQ-5D-5L: participant rated assessed level of current health using 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety, and depression. EQ-5D pain and discomfort domain had 5 responses: no problem, slight problem, moderate problem, severe problem and extreme problem.

EQ-5D-5L: participant rated assessed level of current health using 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety, and depression. EQ-5D anxiety and depression domain had 5 responses: no problem, slight problem, moderate problem, severe problem and extreme problem.

Ctrough was defined as pre-dose plasma concentration during dosing and observed directly from data.

Plasma concentration was measured 2 hours after dosing and observed directly from data.