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

Phase 3

Completed

Conditions: Metastatic Prostate Cancer

Interventions: Drug: Abiraterone
Drug: Ipatasertib
Drug: Placebo
Drug: Prednisone/Prednisolone

Registration Number: NCT03072238

Lead Sponsor: Hoffmann-La Roche

Brief Summary: The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in participants with metastatic castrate-resistant prostate cancer (mCRPC).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 1101

Inclusion Criteria

Eastern Collaborative Oncology Group (ECOG) performance status of 0 or 1 at screening
Adequate hematologic and organ function within 28 days before the first study treatment
Ability to comply with the study protocol, in the investigator's judgment
Willingness and ability of participants to use the electronic device to report selected study outcomes; Caregivers and site staff can assist with patient diary input but patient must be able to independently comprehend and answer the questionnaires
Life expectancy of at least 6 months
Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
For enrollment into the China extension cohort, residence in the People's Republic of China

Disease-specific Inclusion Criteria:

Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features
Consent to provide a formalin-fixed paraffin-embedded (FFPE) tissue block (preferred) or a minimum of 15 (20 preferred) freshly cut unstained tumor slides from the most recently collected, available tumor tissue accompanied by an associated pathology report (with tumor content information, Gleason score, and disease staging) for PTEN IHC and NGS testing and for other protocol-mandated secondary and exploratory assessments. If only 12-14 slides are available, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor. Cytologic or fine-needle aspiration samples are not acceptable. Tumor tissue from bone metastases is not acceptable
A valid PTEN IHC result (testingcentral laboratory tested with results directly sent to IxRS) (e.g., participants with an "invalid" or "failed" PTEN IHC result are not permitted to enroll)
Metastatic disease documented prior to randomization by clear evidence of bone lesions on bone scan and/or measurable soft tissue disease by computed tomography (CT) and/or magnetic resonance imaging (MRI) (at least one target lesion) according to RECIST v1.1
Asymptomatic or mildly symptomatic form of prostate cancer
Progressive disease before initiating study treatment
Ongoing androgen deprivation with gonadotropin-releasing hormone (GnRH) analog or bilateral orchiectomy, with serum testosterone <= 50 ng/dL (<= 1.7 nmol/L) within 28 days before randomization

Exclusion Criteria

Inability or unwillingness to swallow whole pills
History of malabsorption syndrome or other condition that would interfere with enteral absorption
Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
Need of more than 10 mg/day of prednisone or an equivalent dose of other anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to treat a chronic disease (e.g., rheumatic disorder)
Active infection requiring intravenous (IV) antibiotics within 14 days before Day 1, Cycle 1
Immunocompromised status because of current known active infection with HIV or because of the use of immunosuppressive therapies for other conditions
Major surgical procedure or significant traumatic injury within 28 days prior to Day 1, Cycle 1, or anticipation of the need for major surgery during study treatment
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), untreated coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), myocardial infarction or atrial thrombotic events within the past 6 months, severe unstable angina, New York Heart Association Class III and IV heart disease or depressed left ventricular ejection fraction (LVEF; previously documented LVEF < 50% without documentation of recovery), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
History of another malignancy within 5 years prior to randomization, except for either adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta, and low grade T1 tumors), or other malignancies where the patient has undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to have a recurrence rate of <5% at 5 years
Any other diseases, cardiovascular, pulmonary, or metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the participants at high risk from treatment complications.

Disease-Specific Exclusion Criteria:

Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the prostate
Any therapy including chemotherapy (e.g., docetaxel) or biological therapy (e.g., vaccine, immunotherapy) for the treatment of castration-resistant prostate cancer. Previous treatment with flutamide, steroidal anti-androgens, androgens, estrogens, bicalutamide, nilutamide, or 5-α reductase inhibitor is permitted.
Use of opioid medications for cancer-related pain, including codeine and dextropropoxyphene, currently or any time within 4 weeks of Day 1, Cycle 1
Prior treatment with abiraterone or other known potent CYP17 inhibitors (e.g., ketoconazole, orteronel) or investigational agents that block androgen synthesis. Previous treatment with itraconazole and fluconazole is permitted.
Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or experimental (e.g., ARN-509, ODM-201, or galeterone)
Prior treatment with flutamide (Eulexin®), steroidal anti-androgens (e.g., cyproterone acetate, chlormadinone acetate), androgens, or estrogens treatment within 4 weeks of Cycle 1, Day 1
Prior treatment with bicalutamide (Casodex®) or nilutamide (Nilandron®) within 6 weeks of Cycle 1, Day 1
Prior treatment with 5-alpha reductase inhibitors within 4 weeks of Cycle 1, Day 1
Prior treatment with systemic radiopharmaceuticals (e.g., radium-223 and strontium-89). Radiopharmaceuticals for the purpose of imaging are permitted. Focal palliative radiation to treat cancer-related pain is permitted provided that the last treatment with radiation is at least 14 days prior to Cycle 1, Day 1.
Prior treatment with approved or experimental therapeutic agents with known inhibition of the PI3K pathway, including PI3K inhibitors, AKT inhibitors, and mTOR inhibitors
Administration of an investigational therapeutic agent within 28 days of Cycle 1, Day 1
Known untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsant medications or corticosteroids for symptomatic control); a CT or MRI scan of the brain will be performed at screening if required by the local health authority
Any chronic therapy or use of food supplements that are strong CYP3A4/5 inducers or inhibitors or sensitive substrates of CYP3A or CYP2D6 with a narrow therapeutic window

Abiraterone-Specific Exclusion Criteria:

Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg)
History of pituitary or adrenal dysfunction
Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical therapy

Ipatasertib-Specific Exclusion Criteria:

Type 1 or Type 2 diabetes mellitus requiring insulin at study entry
History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active bowel inflammation (e.g., diverticulitis)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + Abiraterone	Prednisone/Prednisolone	Participants received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
Placebo + Abiraterone	Abiraterone	Participants received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
Placebo + Abiraterone	Placebo	Participants received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
Ipatasertib + Abiraterone	Prednisone/Prednisolone	Participants received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
Ipatasertib + Abiraterone	Abiraterone	Participants received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
Ipatasertib + Abiraterone	Ipatasertib	Participants received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

Primary Outcome Measures

Name	Time	Method
Investigator-assessed Radiographic Progression-free Survival (rPFS), Per Prostate Cancer Working Group 3 (PCWG3) Criteria in Phosphatase and Tensin Homolog (PTEN) Loss Population	Up to approximately 32 months	rPFS was defined as time from date of randomization to the first occurrence of documented disease progression (PD), as assessed by the investigator with use of 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 sum of diameters (SOD) of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 millimeters (mm) in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria. 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 according to the PCWG3 criteria. The Kaplan-Meier (KM) estimate was used to determine the median rPFS.
Investigator-assessed rPFS, Per PCWG3 Criteria in ITT Population	Up to approximately 32 months	rPFS was defined as time from date of randomization to the first occurrence of documented PD, as assessed by the investigator with use of 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 according to RECIST v1.1 criteria. 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 according to the PCWG3 criteria. The KM estimate was used to determine the median rPFS.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) in PTEN-loss Population	Up to approximately 6.5 years	OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS.
OS in ITT Population	Up to approximately 6.5 years	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 in PTEN-loss Population	Up to approximately 5.5 years	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 in ITT Population	Up to approximately 5.5 years	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 for Prostate Cancer (PC) in PTEN-loss Population	Up to approximately 5.5 years	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 for PC in ITT Population	Up to approximately 5.5 years	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 Per European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function (PF) Scale and Role Function (RF) Scale in PTEN-loss Population	Up to approximately 5.5 years	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 Per EORTC QLQ-C30 PF Scale and RF Scale in ITT Population	Up to approximately 5.5 years	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 Prostate-specific Antigen (PSA) Progression, Per the PCWG3 Criteria in PTEN-loss Population	Up to approximately 5.5 years	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, Per the PCWG3 Criteria in ITT Population	Up to approximately 5.5 years	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 in PTEN-loss Population	Up to approximately 5.5 years	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 in ITT Population	Up to approximately 5.5 years	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 in ITT Population	Up to approximately 5.5 years	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.
Objective Response Rate (ORR) Per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in PTEN-loss Population	Up to approximately 5.5 years	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 Per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in ITT Population	Up to approximately 5.5 years	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.
Duration of Confirmed Response (DOCR) in PTEN-loss Population	Up to approximately 5.5 years	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 in ITT Population	Up to approximately 5.5 years	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 in PTEN-loss Population	Up to approximately 5.5 years	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 in ITT Population	Up to approximately 5.5 years	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.
Investigator-assessed rPFS Per PCWG3 Criteria in PTEN-loss Population by Next-generation Sequencing (NGS)	Up to approximately 32 months	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.
Percentage of Participants With Adverse Events (AEs)	Up to 28 days after last study drug administration (approximately 6.5 years)	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 Concentrations of Ipatasertib at Specified Timepoints	1-3 hours post-dose (Cycle 1, Day 1; Cycle 1 Day 15 and Cycle 3 Day 1) and pre-dose at steady state (Cycle 1 Day 15, Cycle 3 Day 1, Cycle 6 Day 1) (each cycle length= 28 days)	Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.
Time to Symptomatic Skeletal Event (SSE) in PTEN-loss Population	Up to approximately 5.5 years	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.
Plasma Concentrations of Abiraterone at Specified Timepoints	Pre-dose at steady state in Cycle 1, Day 15 and Cycle 3 Day 1 (each cycle length= 28 days)	Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.

Trial Locations

Locations (176): Ironwood Cancer & Research Centers
🇺🇸
Chandler, Arizona, United States
Mayo Clinic Arizona
🇺🇸
Scottsdale, Arizona, United States
City of Hope
🇺🇸
Duarte, California, United States
USC Norris Cancer Center
🇺🇸
Los Angeles, California, United States
UC Irvine Medical Center
🇺🇸
Orange, California, United States
Stanford University
🇺🇸
Palo Alto, California, United States
Pacific Hematology Oncology Associates
🇺🇸
San Francisco, California, United States
University of Colorado Hospital - Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Yale Cancer Center
🇺🇸
New Haven, Connecticut, United States
Georgetown University Medical Center
🇺🇸
Washington, District of Columbia, United States
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Ironwood Cancer & Research Centers
🇺🇸Chandler, Arizona, United States