Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Docetaxel

Prednisone

Prednisolone

Olaparib

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Placebo

Abiraterone

Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.

Prednisone or prednisolone

This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and pharmacokinetics (PK) of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo given in addition to abiraterone. Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg twice daily (bid) will be administered with the abiraterone in this study.

This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and PK of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo-controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo in addition to abiraterone.

Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg bid will be administered with the abiraterone in this study, but throughout this protocol the treatment will be referred to simply as abiraterone.

For Part A of the study, 15 to 18 evaluable patients (Cohorts 1 and 2) are planned to be enrolled from approximately 4 sites in approximately 1 or 2 countries, and a further 12 patients may be recruited into a 3rd cohort if necessary.

For Part B of the study, approximately 140 patients who have received prior chemotherapy containing docetaxel will be randomised from approximately 40 sites in North America and Europe. Patients who have been dosed in Part A of the study may not participate in Part B.

Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer.

A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus Placebo When Given in Addition to Abiraterone Treatment in Patients With Metastatic Castrate-Resistant Prostate Cancer Who Have Received Prior Chemotherapy Containing Docetaxel

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

The safety and tolerability of olaparib in combination with abiraterone was assessed during Part A of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented.

Severity of AEs was assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) v4.0. AEs were assigned to a Grade from 1 through 5 as follows:

Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE.

'c-r' = causally related 'discont' = discontinuation.

DLTs were assessed by a Safety Review Committee (SRC) after a minimum of 3 patients had received at least 14 days of treatment in Part A.

A DLT was defined as any toxicity which was not a recognised AE of abiraterone or prednisolone, and was not attributable to the disease or disease-related processes under investigation, which occurred during a minimum period of 14 days treatment and which included: 1. haematological toxicity CTCAE v4.0 Grade 4 or higher present for more than 4 days (except anaemia); 2. non-haematological toxicity CTCAE v4.0 Grade 3 or higher including infection, corrected QT interval prolongation; 3. any other toxicity that was greater than that at baseline, was clinically significant and/or unacceptable, did not respond to supportive care, resulted in a disruption of dosing schedule of 7 days or more, or was judged to be a DLT by the SRC.

A DLT excluded alopecia and isolated laboratory changes of any grade without clinical sequelae or clinical significance.

The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (for soft tissue disease) and Prostate Cancer Working Group 2 (PCWG-2) (for bone disease) criteria, or death.

Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion.

Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit).

The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using RECIST version 1.1 (for soft tissue disease) and PCWG-2 (for bone disease) criteria, or death.

Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion.

Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit).

The percentage of patients with progression events is presented overall and according to RECIST 1.1 and/or PCWG-2 criteria, or death.

Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib Cmax,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone Cmax,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib tmax,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone tmax,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib Cmin,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone Cmin,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib AUCss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone AUCss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone.

Only patients with data available for analysis at each time point are presented.

The safety and tolerability of olaparib when given in combination with abiraterone was assessed during Part B of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented.

Severity of AEs was assessed using the NCI Common Terminology CTCAE v4.0. AEs were assigned to a Grade from 1 through 5 as follows:

Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE.

'c-r' = causally related. 'discont' = discontinuation. 'ola/pla' = olaparib/placebo.

The best percentage change from baseline in PSA levels was determined to assess the anti-tumour activity of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone.

The best percentage change was defined as the biggest reduction in PSA level compared with baseline or smallest increase in the absence of a decrease.

The percentages of patients with single visit responses and with confirmed responses are presented to assess the anti-tumour activity of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone.

A single visit response was defined as any post-dose visit PSA level reduced by 50% or more compared with baseline.

A confirmed response was defined as a reduction in PSA level of 50% or more on 2 consecutive occasions at least 4 weeks apart compared with baseline.

Patients may have had more than 1 single visit response or confirmed response but were counted once.

The median best percentage change from baseline in CTC levels was determined to assess the anti-tumour activity of olaparib when given in combination with abiraterone, compared with placebo given in addition to abiraterone.

The best percentage change was defined as the biggest CTC level reduction compared with baseline or smallest increase in the absence of a decrease.

The overall radiological ORR was calculated to assess the anti-tumour activity of olaparib in combination with abiraterone, compared with placebo in combination with abiraterone.

The best overall ORR was defined as the percentage of patients with at least 1 visit response of complete response (CR) or partial response (PR) in soft tissue disease assessed by RECIST 1.1 and also bone scan status of non-progressive disease or non-evaluable for their bone scans assessed by PCWG-2.

CR: Disappearance of all target lesions. Reduction of pathological lymph nodes to \<10 millimetres.

PR: At least a 30% decrease in the sum of diameters of target lesions from baseline.

The percentage of patients with a response is presented.

The TFST and TSST were determined to assess the anti-tumour activity of olaparib when given in combination with abiraterone, compared with placebo given in addition to abiraterone.

TFST was defined as the time from randomisation to the earlier of first subsequent anti-cancer therapy start date following study treatment discontinuation, or death.

TSST was defined as the time from randomisation to the earlier of the second subsequent anti-cancer therapy start date following study treatment discontinuation, or death.

OS was determined to assess the efficacy of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone.

OS was performed at the time of the analysis of rPFS, and the median OS, calculated using the Kaplan-Meier technique, is presented.

The efficacy of olaparib when given in combination with abiraterone was assessed by PFS2, defined by local standard clinical practice and included objective radiological progression by RECIST 1.1 (soft tissue), symptomatic progression, rise in PSA level or death in the absence of overall progression.

Merck Sharp & Dohme LLC

AstraZeneca

The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A. Part B safety analysis set consisted of all patients randomised into Part B of the study who received at least 1 dose of olaparib/placebo.

Patients received olaparib 200 mg bid and abiraterone 1000 mg once daily. Patients were assessed at Weeks 1, 2 and 4, then every 4 weeks up to Week 52, and every 12 weeks thereafter.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part A Cohort 1: Olaparib 200 mg + Abiraterone

If the combination of olaparib 200 mg + abiraterone 1000 mg was well tolerated (determined after a minimum of 14 days treatment in Cohort 1), patients were recruited into Cohort 2. Cohort 2 Group 1: patients received olaparib 300 mg bid alone for 3 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 5 days. Cohort 2 Group 2: patients received abiraterone 1000 mg once daily alone for 5 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 3 days. Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part A Cohort 2: Olaparib 300 mg + Abiraterone

Patients received the selected dose of olaparib 300 mg bid + abiraterone 1000 mg once daily. Patients were assessed every 4 weeks up to Week 52, and every 12 weeks thereafter.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part B: Olaparib + Abiraterone

Patients received placebo bid + abiraterone 1000 mg once daily. Patients were assessed every 4 weeks up to Week 52, and every 12 weeks thereafter.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part B: Placebo + Abiraterone

If the combination of olaparib 200 mg + abiraterone 1000 mg was well tolerated (determined after a minimum of 14 days treatment in Cohort 1), patients were recruited into Cohort 2.

Cohort 2 Group 1: patients received olaparib 300 mg bid alone for 3 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 5 days.

Cohort 2 Group 2: patients received abiraterone 1000 mg once daily alone for 5 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 3 days.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A and all patients randomised into Part B of the study who received at least 1 dose of study treatment.

Medical Director

Any AE c-r to olaparib + abiraterone

Any AE c-r to olaparib only

Any AE c-r to abiraterone only

Any AE CTCAE Grade 3 or higher

Any AE CTCAE Grade 3 or higher c-r to olaparib

Any AE CTCAE Grade 3 or higher c-r to abiraterone

Any AE with outcome = death

Any serious AE (SAE)

Any SAE c-r to olaparib

Any SAE c-r to abiraterone

Any AE causing discont of olaparib

Any AE causing discont of olaparib c-r to olaparib

Any AE causing discont olaparib c-r to abiraterone

The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A. Treatment group comparisons were based on the initial dose of olaparib actually received.

Part A: Percentage of Patients Experiencing Adverse Events (AEs)

Part A: Number of Patients With Dose Limiting Toxicities (DLTs)

The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.

Part B: Median Radiological Progression-Free Survival (rPFS) Time

The 1-sided p-value provides a test for rejecting the null hypothesis of no treatment effect versus the superiority alternative that patients on olaparib have a lower risk of progression compared with placebo.

Part B: Percentage of Patients With Progression Events or Death (rPFS)

Olaparib alone

Olaparib + abiraterone

Patients received olaparib 300 mg bid alone for 3 to 7 days to determine the steady state PK profile for olaparib. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 5 days to determine the PK profiles of both olaparib and abiraterone.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part A Cohort 2 Group 1: Olaparib, Olaparib + Abiraterone

Patients received abiraterone 1000 mg once daily alone for 5 to 7 days to determine the steady state PK profile for abiraterone. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 3 days to determine the PK profiles of both olaparib and abiraterone.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Part A Cohort 2 Group 2: Abiraterone, Olaparib + Abiraterone

The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.

Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

Abiraterone alone

Part A PK: Abiraterone Cmax,ss

Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss)

Part A PK: Abiraterone Tmax,ss

Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

Part A PK: Abiraterone Cmin,ss

Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)

Part A PK: Abiraterone AUCss

Any AE c-r to ola/pla + abiraterone

Any AE c-r to ola/pla only

Any AE CTCAE Grade 3 or higher c-r to ola/pla

Any AE with outcome = death c-r to ola/pla

Any AE with outcome = death c-r to abiraterone

Any SAE

Any SAE c-r to ola/pla

Any AE causing discont of ola/pla

Any AE causing discont of treatment c-r to ola/pla

Any AE causing discont treatment c-r abiraterone

Part B safety analysis set consisted of all patients randomised into Part B of the study who received at least 1 dose of olaparib/placebo.

Part B: Percentage of Patients Experiencing AEs

The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received. Only patients with data available for analysis are presented.

Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels

Single visit response

Confirmed response

Part B: Percentage of Patients With PSA Responses

Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level

The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received. Only patients with data available for analysis are presented. Only patients with measurable disease at baseline are included.

Part B: Percentage of Patients With at Least One Objective Response (Objective Response Rate [ORR])

Olapatib + abiraterone versus placebo + abiraterone: TFST

Olaparib + abiraterone versus placebo + abiraterone: TSST

TFST

TSST

Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST)

Part B: Median Overall Survival (OS)

Part B: Median Time to Second Progression or Death (PFS2)

Patients received olaparib 200 milligrams (mg) twice daily (bid) and abiraterone 1000 mg once daily. Patients were assessed at Weeks 1, 2 and 4, then every 4 weeks up to Week 52, and every 12 weeks thereafter.

Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Spots Global Cancer Trial Database for prior docetaxel chemotherapy