BI836845 Plus Enzalutamide in Castrate Resistant Prostate Cancer (CRPC)

Maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period.

Time frame: From first administration of xentuzumab up to start of Cycle 2, up to 28 days.

Population: MTD-set: The MTD set defined the set of patients in the Phase Ib escalation part who were fully evaluable for determination of the MTD in the first treatment course. 1 patient in the 1000 mg Xentuzumab + 160 mg Enzalutamide arm was not evaluable for the MTD determination due to missed doses. Phase Ib escalation part.

Number of patients with DLTs were used to determine the maximum tolerated dose (MTD) in the Phase Ib escalation part. The MTD in this study was defined as the highest protocol dose level of xentuzumab in combination with enzalutamide, at which no more than 1 out of 6 patients in a cohort experienced a DLT during the MTD evaluation period.

Time frame: From first administration of xentuzumab up to start of Cycle 2, up to 28 days.

Population: MTD-set: The MTD set defined the set of patients in the Phase Ib escalation part who were fully evaluable for determination of the MTD in the first treatment course. 1 patient in the 1000 mg Xentuzumab + 160 mg Enzalutamide arm was not evaluable for the MTD determination due to missed doses. Phase Ib escalation part.

The primary endpoint of the Phase Ib expansion part was PSA response. PSA response was defined as a decline in PSA value \>50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. The date of response was the date that the first 50% (or greater) decline was observed. Number of participants with response is reported.

Time frame: At Cycle 1 Day 1 before study treatment and from Cycle 3 Day 1 and Day 1 of every cycle thereafter until the end of treatment, up to 35 months.

Population: Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Phase Ib expansion part.

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS \[days\] = date of outcome - date of randomisation + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of randomisation + 1.

Time frame: From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.

Population: Randomised Set (RS): All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

Changes in circulating tumour cells (CTC) response - CTC reduction from \>=5 to \<5 cells per 7.5 mL blood for at least one post-baseline time point. Number of participants with CTC Response (yes/no) is reported.

Time frame: Prior to study drug administration at Day 1 Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 Cycle 5, Day 1 Cycle 7 and every 12 weeks thereafter, up to end of treatment. Up to 35 months.

Population: Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Only participants with baseline CTC value \>= 5 cells per 7.5mL were included in the analysis. Phase Ib expansion part.

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: (according to modified RECIST version 1.1 or PCWG2) PFS \[days\] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of first treatment administration + 1.

Time frame: From first treatment administration of any study medication until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1114 days.

Population: Treated Set (TS): All patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Phase Ib expansion part.

CTC reduction is defined as CTC decline from ≥5 to \<5 cells per 7.5 mL blood for at least one post-baseline time-point. Patients with a CTC value \< 5 cells per 7.5mL blood at baseline, or with missing baseline values were not taken into consideration for this endpoint. Baseline value is the value collected before a patient starts treatment with trial medication. Number of participants per category is reported.

Time frame: Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.

Population: Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only patients with baseline CTC value \>=5 cells per 7.5mL were included in the analysis. Phase II part.

CTC status (≥5 or \<5 cells per 7.5mL blood) at Week 12. Number of participants per category is reported.

Time frame: At Week 12.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

Maximum decline in CTC counts (in number of cells) compared with baseline that occurred at any point after treatment start , defined as the difference between the minimum post-baseline CTC value and the baseline CTC value. Patients with missing baseline value are considered missing for this criterion. Baseline value is the value collected before a patient starts treatment with trial medication. Positive values for maximum decline in CTC are possible in case no decline in CTC occurred. This indicates an increase in CTC.

Time frame: Prior to study drug administration at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1 and then every 12 weeks thereafter, until end of treatment. Up to 40.1 months.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only participants with baseline CTC value were included in the analysis. Phase II part.

Maximum decline in (PSA) compared to baseline. The maximum decline in PSA is defined as the change in PSA between the baseline PSA value and the minimum post-baseline PSA value. The change from baseline is defined as: Change from baseline in PSA (ng/mL) = PSA value post-baseline - PSA value at baseline. Maximum decline in PSA is defined as: Maximum decline in PSA (ng/mL) = min(PSA value post-baseline) - PSA value at baseline.

Time frame: At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Population: Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only participants with non-missing values were included in the analysis. Phase II part.

Overall survival (OS) defined as the time from randomisation to death from any cause. Median survival time in months is reported. Overall survival at cut-off date for final analysis (24-Oct-2019) is reported.

Time frame: From randomisation until radiological tumor progression or death from any cause (until cut-off date for final analysis), whichever occurred earlier, up to 1269 days.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

Percentage change in PSA from baseline to Week 12. Percentage change in PSA from baseline to week 12 of treatment is defined as: Percentage change in PSA (%) = 100\*(PSA value at week 12 - PSA value at baseline)/PSA value at baseline For this assessment, it is allowed to take a value: * until one week later than week 12, in case the PSA assessment was delayed * one day earlier due to the one day window allowed by the protocol Values from assessments between day 84 and day 92 after first treatment administration will therefore be taken into account (according to the protocol schedule for visits at week 12).

Time frame: At baseline and at Week 12.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Only participants with non-missing values were included in the analysis. Phase II part.

PSA response - defined as a decline in PSA value \>50% (which is confirmed by a second value 3 to 4 weeks apart). PSA response was defined as a decline in PSA value \>50% compared to baseline which was confirmed by the next available value occurring at least 3 weeks later. The confirmatory value had to be at least 50% lower than the baseline, but could be higher than the first PSA value taken into account for response. However the confirmatory value was not allowed to be 50% higher than this first PSA value. If it was ≥ 50% higher than the first PSA value, the next available sample was to be taken to determine if response had been achieved. Number of participants with response is reported.

Time frame: At Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Population: Randomised Set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

PFS was defined as the time from randomisation until radiological tumour progression in bone (based on Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria) or soft tissue (based on modified RECIST 1.1) or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. Median PFS time in months is reported. PFS was calculated as follows: For patients with 'event' as an outcome for PFS: (according to modified RECIST version 1.1 or PCWG2) PFS \[days\] = date of outcome - date of first treatment administration + 1. For patients with 'censored' as an outcome for PFS (according to modified RECIST version 1.1 or PCWG2): PFS (censored) \[days\] = date of outcome - date of first treatment administration + 1.

Time frame: From randomisation until radiological tumor progression or death from any cause, whichever occurred earlier, up to 1269 days.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.

For the definition of time to PSA progression, the following rules are used: * Decline from baseline in PSA before increasing: Time to PSA progression is defined as the time from the date of randomisation until the date where a 25% or greater increase in PSA and an absolute increase of 2 ng/mL or more from baseline, is documented (which is confirmed by the next available value occurring at least 3 weeks later). * No decline from baseline in PSA: Time to PSA progression is defined as the time from the date of randomisation until the date where a 25% or greater increase in PSA and an absolute increase of 2 ng/mL or more from baseline, is documented. However, only values after 12 weeks of therapy are considered. Time to PSA progression \[days\] = date of PSA progression - date of randomisation + 1. For patients not presenting with PSA progression or being lost to follow-up: Time to PSA progression (censored) \[days\] = date of censoring - date of randomisation + 1.

Time frame: At screening, at Cycle 1 Day 1 and from Cycle 3 Day 1 and at Day 1 of every cycle thereafter until end of treatment, up to 40.1 months.

Population: Randomised Set: All randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with enzalutamide or enzalutamide alone. Phase II part.