Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer

OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS.

OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS.

Time to pain progression was defined as the time from randomization to the first occurrence of confirmed clinically meaningful cancer-related pain progression event. Cancer-related pain progression refers to pain onset for participants who were asymptomatic at baseline or pain worsening for those who were mildly symptomatic at baseline. Pain severity was graded on a 10-point numeric rating scale [NRS], with 0=no pain and 10=severe pain. Pain severity progression was defined as a ≥ 2-point absolute increase from baseline. KM estimates were used to determine the median time to pain progression.

Time to pain progression was defined as the time from randomization to the first occurrence of confirmed clinically meaningful cancer-related pain progression event. Cancer-related pain progression refers to pain onset for participants who were asymptomatic at baseline or pain worsening for those who were mildly symptomatic at baseline. Pain severity was graded on a 10-point NRS, with 0=no pain and 10=severe pain. Pain severity progression was defined as a ≥ 2-point absolute increase from baseline. KM estimates were used to determine the median time to pain progression.

Time to initiation of cytotoxic chemotherapy was defined as the time interval from the date of randomization to the date of initiation of cytotoxic chemotherapy (use of antineoplastic agents: docetaxel, cabazitaxel, mitoxantrone, estramustine, cisplatin, carboplatin, cyclophosphamide, doxorubicin, mitomycin, irinotecan, 5-fluorouracil, gemcitabine, or etoposide) for PC. KM estimates were used to determine the median time to initiation of cytotoxic chemotherapy.

Time to initiation of cytotoxic chemotherapy was defined as the time interval from the date of randomization to the date of initiation of cytotoxic chemotherapy (use of antineoplastic agents: docetaxel, cabazitaxel, mitoxantrone, estramustine, cisplatin, carboplatin, cyclophosphamide, doxorubicin, mitomycin, irinotecan, 5-fluorouracil, gemcitabine, or etoposide) for PC. KM estimates were used to determine the median time to initiation of cytotoxic chemotherapy.

Time to function deterioration=time from date of randomization to date of 10-point or more score decrease on either EORTC QLQ-C30 5-item PF/2-item RF scale scores, held for two consecutive assessments or death within 28 days, whichever occurs first. EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of participant functioning (physical,emotional,role,cognitive\&social), 3 symptom scales (fatigue,nausea\&vomiting,pain), global health/quality of life (GHS/QoL)\&6 single items (dyspnea,insomnia,appetite loss,constipation,diarrhea\&financial difficulties). PF scale has 5 questions about participants physical functioning\&daily activities. RF scale has 2 questions about work/daily activities\&hobbies/leisurely activities. PF\&RF are scored on a 4-point scale (1=Not at All to 4=Very Much). Obtained scores are linearly transformed to score range of 0-100, where higher scores indicate a higher response level (better PF)\&better functioning/support.

Time to function deterioration=time from date of randomization to date of 10-point or more score decrease on either EORTC QLQ-C30 5-item PF/2-item RF scale scores, held for two consecutive assessments or death within 28 days, whichever occurs first. EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of participant functioning (physical,emotional,role,cognitive \& social), 3 symptom scales (fatigue,nausea\&vomiting,pain), GHS/QoL \& 6 single items (dyspnea,insomnia,appetite loss,constipation,diarrhea \& financial difficulties). PF scale has 5 questions about participants physical functioning \& daily activities. RF scale has 2 questions about work/daily activities \& hobbies/leisurely activities. PF\&RF are scored on a 4-point scale (1=Not at All to 4=Very Much). Obtained scores are linearly transformed to score range of 0-100, where higher scores indicate a higher response level (better PF) \& better functioning/support.

Time to PSA progression was defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression was defined as a PSA increase that was ≥ 25% and ≥ 2 nanograms per milliliters (ng/mL) above the baseline or the nadir, which was confirmed by a second value ≥ 3 weeks later. KM estimate was used to determine the median time to PSA.

Time to PSA progression was defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression was defined as a PSA increase that was ≥ 25% and ≥ 2 ng/mL above the baseline or the nadir, which was confirmed by a second value ≥ 3 weeks later. KM estimate was used to determine the median time to PSA.

Time to first opioid use was defined as the time interval from the date of randomization to the date of an initiation of opioid analgesic use for cancer-related pain, and consumption reported on at least 7 consecutive days. KM estimate was used to determine the median time to first opioid use.

Time to first opioid use was defined as the time interval from the date of randomization to the date of an initiation of opioid analgesic use for cancer-related pain, and consumption reported on at least 7 consecutive days. KM estimate was used to determine the median time to first opioid use.

Time to SSE was defined as the time from randomization to the first occurrence of an SSE. A SSE was defined using one of the following: use of external-beam radiotherapy to relieve skeletal symptoms (including initiation of radium-223 to treat symptoms of bone metastases); occurrence of a new symptomatic pathological bone fracture (vertebral or non-vertebral); clinically apparent occurrence of spinal cord compression, or a tumor-related orthopedic surgical intervention. KM estimates were used to determine the median time to SSE.

Time to SSE was defined as the time from randomization to the first occurrence of an SSE. A SSE was defined using one of the following: use of external-beam radiotherapy to relieve skeletal symptoms (including initiation of radium-223 to treat symptoms of bone metastases); occurrence of a new symptomatic pathological bone fracture (vertebral or non-vertebral); clinically apparent occurrence of spinal cord compression, or a tumor-related orthopedic surgical intervention. KM estimates were used to determine the median time to SSE.

ORR was defined as the percentage of participants who had an objective response (OR) with measurable disease at baseline. An OR was defined as a complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 and PCWG3 criteria in participants with measurable disease at baseline. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. An estimate of ORR was calculated for each treatment arm, and its 95% CI was calculated using the Clopper-Pearson method. Percentages have been rounded off.

ORR was defined as the percentage of participants who had an OR with measurable disease at baseline. An OR was defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 and PCWG3 criteria in participants with measurable disease at baseline. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. An estimate of ORR was calculated for each treatment arm, and its 95% CI was calculated using the Clopper-Pearson method. Percentage have been rounded off.

DOCR was defined as the time from the first documented OR (CR or PR) to documented PD as determined by the investigator using RECIST v1.1 and PCWG3 criteria, or death from any cause, whichever occurred first. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. DOR was estimated using the KM methodology.

DOCR was defined as the time from the first documented OR (CR or PR) to documented PD as determined by the investigator using RECIST v1.1 and PCWG3 criteria, or death from any cause, whichever occured first. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. DOR was estimated using the KM methodology.

PSA response rate was defined as the percentage of participants achieving a PSA decline ≥ 50% from baseline. Participants without a post-baseline PSA assessment were considered to be non-responders. Percentages have been rounded off.

PSA response rate was defined as the percentage of participants achieving a PSA decline ≥ 50% from baseline. Participants without a post-baseline PSA assessment were considered to be non-responders. Percentages have been rounded off.

rPFS was defined as time from date of randomization to the first occurrence of documented PD, as assessed by the investigator using the PCWG3 criteria or death from any cause, whichever occurs first. PD for soft tissue was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later.

An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs. Percentages have been rounded off.

Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.

Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.