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)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 110
- 试验地点
- 26
- 主要终点
- Radiological Progression Free Survival (rPFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
olaparib plus abiraterone
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.
干预措施: olaparib (Drug)
olaparib plus abiraterone
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.
干预措施: abiraterone acetate (Drug)
placebo plus abiraterone
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.
干预措施: abiraterone acetate (Drug)
结局指标
主要结局
Radiological Progression Free Survival (rPFS)
时间窗: Tumour imaging CT/MRI and bone scan were assessed every 8 weeks from randomisation to week 24 and then every 12 weeks until RECIST progression. Patients were followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum
Radiological progression free survival is defined as the time from randomisation until the earlier date of radiological progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomised therapy or receives another anticancer therapy prior to progression. Per RECIST v1.1, progression is defined as the sum of TLs has a 20% and absolute ≥ 5mm increase from nadir, and/or unequivocal progression in any non target lesions, and/or any new lesion identified. Per PCWG3, progression on a bone scan is defined as 2 or more new lesions observed from the first visit after baseline compared to baseline, or from all other visits compared to first visit after baseline. A confirmatory scan is required.
次要结局
- Overall Survival (OS)(Assessed every 12 weeks from randomisation until death or data cut-off. The endpoint was followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Time to First Subsequent Anticancer Therapy or Death (TFST)(Assessed from from randomization on 30 day follow-up after last dose of study medication and every 12 weeks after that until DCO. The endpoint was followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Time to Pain Progression (TTPP)(The BPI-SF and AQA were assessed on screening, day 1, day 15, day 29, day 43, day 57, day 71, and every 4 weeks after week 13 until DCO. The endpoint was followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Time to Opiate Use(Assessed on screening, days 1, 29, and 57, every 4 weeks after week 13, treatment discontinuation, and 30-day follow-up after last dose of study medication. Followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Time to a Symptomatic Skeletal-Related Event (SSRE)(Assessed at every visit from randomisation up to and including treatment discontinuation visit. The endpoint was followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Time to Second Progression or Death (PFS2)(Assessed from randomization every 12 weeks following the progression event used for PFS and the start of the next-line anticancer therapy. The endpoint was followed up for 479 days (approx 16 months) at minimum and 913 days (approx 30 months) at maximum.)
- Change From Baseline in BPI-SF Pain Severity and Pain Interference(Assessed from date of first subject randomised: 23Jul2021 to data cut off (China DCO): 22Jan2024 (913 days). BPI-SF were completed by patients daily for 7 consecutive days every 4 weeks. Change from baseline is reported every 4 weeks until week 49.)
- Change From Baseline in Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P)(Assessed from date of first subject randomised: 23Jul2021 to data cut off (China DCO): 22Jan2024 (913 days). FACT-P were assessed every 4 weeks from Day 1 until Week 52. Change from baseline is reported every 4 weeks until week 49.)