Study on Olaparib Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (China Cohort)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety (including evaluating side effects) of combination of olaparib and abiraterone versus placebo and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have received no prior cytotoxic chemotherapy or new hormonal agents (NHAs) at metastatic castration-resistant prostate cancer (mCRPC) stage.

Detailed Description
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PROpel is a phase III study evaluating the efficacy, safety, and tolerability of olaparib versus placebo when given in addition to abiraterone to patients with metastatic castration-resistant prostate cancer (mCRPC) who have not received prior chemotherapy or new hormonal agents (NHAs) for metastatic castration-resistant prostate cancer (mCRPC) (first-line setting). Approximately 720 patients globally were planned to be randomized in PROpel in a 1:1 ratio to treatment with either olaparib and abiraterone or placebo and abiraterone. Enrolment had completed with a total of 796 patients randomised. Following the completion of global enrolment, the China cohort will randomise approximately 108 additional patients at sites in China, also in a 1:1 ratio. This cohort will enable standalone safety and efficacy analyses to support Chinese regulatory requirements. Patients from China will not be included in the Full Analysis Set for the global study analysis. In addition, all of the statistical analyses defined in this SAP will be performed using all patients randomised at sites in Asian countries (South Korea and Japan) excluding China, to be designated the Asian subgroup analysis. Patients will receive oral treatment with olaparib 300 mg twice daily + abiraterone 1000 mg once daily or placebo twice daily + abiraterone 1000 mg once daily. Patients in both treatment groups will also receive either prednisone or prednisolone 5 mg twice daily.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (PROpel Study)

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: olaparib
* Drug: abiraterone acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the study protocol. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfill the following criteria: Provision of informed consent for genetic research prior to collection of sample. Provision of informed consent for biomarker research prior to collection of sample. If a patient declines to participate in the optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study. Patients must be ≥18 years of age (or ≥19 years of age in South Korea) at the time of signing the informed consent form. For patients enrolled in Japan who are <20 years of age, written informed consent should be obtained from the patient and from his legally acceptable representative. Histologically or cytologically confirmed prostate adenocarcinoma. Metastatic status defined as at least 1 documented metastatic lesion on either a bone scan or a computed tomography(CT)/ magnetic resonance imaging (MRI) scan. First-line metastatic castration-resistant prostate cancer (mCRPC). Ongoing androgen deprivation with gonadotropin-releasing hormone analogue or bilateral orchiectomy, with serum testosterone <50 nanograms per decilitre (ng/dL) (<2.0 nanomoles per litre (nmol/L)) within 28 days before randomisation. Patients receiving androgen deprivation therapy (ADT) at study entry should continue to do so throughout the study. Candidate for abiraterone therapy with documented evidence of progressive disease. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment. Eastern Cooperative Oncology Group (ECOG) performance status 0-1, with no deterioration over the previous 2 weeks. The participant has, in the opinion of the investigator, a life expectancy of at least 6 months. Prior to randomisation, sites must confirm availability of either an archival formalin fixed, paraffin embedded (FFPE) tumour tissue sample, or a new biopsy taken during the screening window, which meets the minimum pathology and sample requirements in order to enable homologous recombination repair (HRR) status subgroup analysis of the primary endpoint radiographic progression-free survival (rPFS). If there is not written confirmation of the availability of tumour tissue prior to randomisation, the patient is not eligible for the study. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib+abiraterone when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Exclusion Criteria: Has a known additional malignancy that has had progression or has required active treatment in the last 5 years. Patients with myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) or with features suggestive of yelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML). Clinically significant cardiovascular disease Association Class II-IV heart failure or cardiac ejection fraction measurement of <50% during screening as assessed by echocardiography or multigated acquisition scan. Planned or scheduled cardiac surgery or percutaneous coronary intervention procedure. Prior revascularisation procedure (significant coronary, carotid, or peripheral artery stenosis). Uncontrolled hypertension (systolic blood pressure (BP) ≥160 millimeters of mercury (mmHg) or diastolic blood pressure (BP) ≥95 millimeters of mercury (mmHg)). History of uncontrolled pituitary or adrenal dysfunction. Active infection or other medical condition that would make prednisone/prednisolone use contraindicated. Any chronic medical condition requiring a systemic dose of corticosteroid >10 milligrams (mg) prednisone/prednisolone per day. Patients who are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAEs] grade >2) caused by previous cancer therapy, excluding alopecia. Patients with brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with spinal cord compression are excluded unless they are considered to have received definitive treatment for this and have evidence of clinically stable disease for 4 weeks. Patients who are unevaluable for both bone and soft tissue progression Patients who are unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Immunocompromised patients Patients with known active hepatitis infection (ie, hepatitis B or C). Any previous treatment with Polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase (PARP) inhibitor, including olaparib. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment. Patients who receive palliative radiotherapy need to stop radiotherapy 1 week before randomisation. Any previous exposure to a Cytochrome P450 (CYP) 17 (17α-hydroxylase/C17,20-lyase) inhibitor (eg, abiraterone, orteronel). Concomitant use of known strong Cytochrome P450 (CYP) 3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong Cytochrome P450 (CYP) 3A inducers (eg, phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine or St John's wort) or moderate Cytochrome P450 (CYP) 3A inducers (eg, bosentan, efavirenz or modafinil). The required period prior to starting study treatment is 5 weeks for phenobarbital and enzalutamide and 3 weeks for other agents. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). Participation in another clinical study with an investigational product or investigational medical devices within 1 month of randomisation. History of hypersensitivity to olaparib or abiraterone, any of the excipients of olaparib or abiraterone, or drugs with a similar chemical structure or class to olaparib or abiraterone. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and Merck staff and/or staff at the study site). Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. Previous randomisation in the present study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: olaparib plus abiraterone<br>Olaparib is available as a film-coated tablet containing 100 milligrams (mg) or 150 milligrams (mg) of olaparib. Subjects will be administered olaparib orally at a dose of 300 milligrams (mg) twice daily (bid). The initial dosage of 300 milligrams (mg) twice daily will be composed of 2 x 150 milligrams (mg) tablets per dose. The 100 milligrams (mg) and 150 milligrams (mg) tablets will be used to manage dose reductions during the study. Abiraterone acetate with prednisone or prednisolone will be sourced locally as commercially available materials. Subjects will be administered abiraterone orally at a dose of 1000 milligrams (mg) once daily, in combination with prednisone or prednisolone 5 milligrams (mg) administered orally twice daily. | Drug: olaparib<br>* 300 mg (2 x 150 milligrams (mg) tablets) twice daily<br>* Other names: Lynparza;Drug: abiraterone acetate<br>* 1000 milligrams (mg) once daily<br>* Other names: Zytiga;|
| Placebo Comparator: placebo plus abiraterone<br>Placebo to match olaparib is available as a film-coated tablet in 100 milligrams (mg) or 150 milligrams (mg). Subjects will be administered placebo orally at a dose of 300 milligrams (mg) twice daily (bid). The initial dosage of 300 milligrams (mg) twice daily will be composed of 2 x 150 milligrams (mg) tablets per dose. The 100 milligrams (mg) and 150 milligrams (mg) tablets will be used to manage dose reductions during the study. Abiraterone acetate with prednisone or prednisolone will be sourced locally as commercially available materials. Subjects will be administered abiraterone orally at a dose of 1000 milligrams (mg) once daily, in combination with prednisone or prednisolone 5 milligrams (mg) administered orally twice daily. | Drug: abiraterone acetate<br>* 1000 milligrams (mg) once daily<br>* Other names: Zytiga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological progression free survival (rPFS) | Radiological progression free survival (rPFS) - defined as the time from randomisation to radiological progression, assessed by investigator per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone), or death from any cause, whichever occurs first | From date of randomization to study completion (up to 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Time from randomisation to death from any cause | From date of randomization to study completion (up to 4 years) | 
| Time to first subsequent anticancer therapy or death (TFST) | Time from randomisation to the earlier of the first subsequent anticancer therapy start date following study treatment discontinuation or death from any cause | From date of randomization to study completion (up to 4 years) | 
| Time to pain progression (TTPP) | Time to pain progression (TTPP) is defined as the time from randomisation to pain progression based on the Brief Pain Inventory-Short Form (BPI-SF) Item 3 worst pain in 24 hours and opiate analgesic use (analgesic quantification algorithm [AQA] score) | From date of randomization to study completion (up to 4 years) | 
| Time to opiate use | Time from randomisation to the first opiate use for cancer-related pain | From date of randomization to study completion (up to 4 years) | 
| Time to a Symptomatic Skeletal-Related Event (SSRE) | A Symptomatic Skeletal-Related Event (SSRE) is defined as use of radiation therapy to bone in order to prevent or relieve skeletal complications, occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral, resulting from minimal or no trauma), occurrence of radiologically confirmed spinal cord compression or a tumour-related orthopaedic surgical intervention. | From date of randomization to study completion (up to 4 years) | 
| Time to second progression or death (PFS2) | Time from randomisation to second progression or clinical progression or death, whichever occurs earlier | From date of randomization to study completion (up to 4 years) | 
| Brief Pain Inventory-Short Form (BPI-SF) | To assess progression in pain severity domain, change in pain interference domain, and pain palliation | From date of randomization to study completion (up to 4 years) | 
| Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P) | Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P) total score, Functional Assessment of Cancer Therapy- General (FACT-G) total score, trial outcome index, functional well-being, physical well-being, prostate cancer subscale, and Functional Assessment of Cancer Therapy (FACT) Advanced Prostate Symptom Index-6 (FAPSI-6) | From date of randomization to study completion (up to 4 years) | 
| Homologous Recombination Repair (HRR) gene status | Tumour samples for mutations in Breast Cancer 1 gene (BRCA1), or Breast Cancer 2 gene (BRCA2), Ataxia-telangiectasia mutated (ATM) and 12 other Homologous Recombination Repair (HRR) genes will be evaluated. | At baseline | 
| Number of adverse events | Percentage of patients with any adverse event (AE), adverse event (AE) leading to study drug discontinuation, adverse event (AE) leading to death, serious adverse event (SAE), adverse event (AE) related to study drug, serious adverse event (SAE) related to study drug | From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days) | 
| Vital signs-blood pressure | To assess systolic and diastolic blood pressure as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone | From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days) | 
| Vital signs-pulse rate | To assess pulse rate as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone | From the time of signature of informed consent throughout the treatment period (up to 4 years) | 
| Vital signs-body temperature | To assess body temperature as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone | From the time of signature of informed consent throughout the treatment period (up to 4 years) | 
| ECG | To assess 12 lead resting ECG as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone. According to Clinical Study Protocol all ECGs should be assessed by the investigator as to whether they are clinically significantly abnormal / not clinically significantly abnormal. | From the time of signature of informed consent throughout the treatment period (up to 4 years) | 
| Change in Albumin (g/L) | Data for Albumin recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Alkaline phosphatase (U/L) | Data for Alkaline phosphatase recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Aspartate aminotransferase (U/L) | Data for Aspartate aminotrasnferase recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Amylase (U/L) | Data for Amylase recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Alanine aminotransferase (U/L) | Data for Alanine aminotransferase recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Total bilirubin (μmol/L) | Data for Total bilirubin recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Direct bilirubin | Data for Direct bilirubin recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Calcium (mmol/L) | Data for Calcium recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Chloride (mmol/L) | Data for Chloride recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Creatinine (μmol/L) | Data for Creatinine recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Gamma glutamyltransferase (U/L) | Data for Gamma glutamyltransferase recorded in the eCRF will be listed and summarized by treatment group. | At screening only | 
| Change in Fasting gucose (mmol/L) | Data for Fasting glucose recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Lactate dehydrogenase (U/L) | Data for Lactate dehydrogenase recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Magnesium (mmol/L) | Data for Magnesium recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Potassium (mmol/L) | Data for Potassium recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Phosphorus ((mmol/L) | Data for Phosphorus will be recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Sodium (mmol/L) | Data for Sodium recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Carbon dioxide (mEq/L ) | Data for Carbon dioxide recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Total protein (g/L) | Data for protein recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Urea or blood urea nitrogen, depending on the local practice (mmol/L) | Data for urea or urea nitrogen recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in absolute neutrophil count (/L) | Data for absolute neutrophil recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in absolute lymphocyte count (/L) | Data for absolute lymphocyte recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in haemoglobin (g/L) | Data for haemoglobin recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in platelet count with differential (/L) | Data for platelet count with differential recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in total white blood cell count with differential(/L) | Data for WBC count recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in red blood cell count (/l) | Data for RBC count recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Haematocrit (%) | Data for Haematocrit recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Change in Mean Cell Volume (fL) | Data for MCV count recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Urinalysis:change in blood | Data for blood testing recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Urinalysis: Change in protein | Data for urine protein recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 
| Urinalysis: change in glucose | Data for urine glucose recorded in the eCRF will be listed and summarized by treatment group and visit. | At scheduled visits from screening to 30 days after last dose of study medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic castration-resistant prostate cancer (mCRPC)