Study on Olaparib Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer
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| ClinicalTrials.gov Identifier: NCT03732820 |
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Recruitment Status :
Active, not recruiting
First Posted : November 7, 2018
Results First Posted : June 15, 2023
Last Update Posted : February 28, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Metastatic Castration-resistant Prostate Cancer | Drug: olaparib Drug: abiraterone acetate | Phase 3 |
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.
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 895 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | 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) |
| Actual Study Start Date : | October 31, 2018 |
| Actual Primary Completion Date : | July 30, 2021 |
| Estimated Study Completion Date : | April 28, 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 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. |
Drug: olaparib
300 mg (2 x 150 milligrams (mg) tablets) twice daily
Other Name: Lynparza Drug: abiraterone acetate 1000 milligrams (mg) once daily
Other Name: Zytiga |
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Placebo Comparator: 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. |
Drug: abiraterone acetate
1000 milligrams (mg) once daily
Other Name: Zytiga |
- Number of Participants With Radiological Progression Free Survival (rPFS) Event by Investigator Assessment [ Time Frame: Assessed from date of randomisation to data cut off (DCO1): 30Jul2021 (Approx. 2 years 9 months) ]
An rPFS event is defined as progression determined by Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1] and/or Prostate Cancer Working Group 3 [PCWG-3] 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.
- Number of Participants With Overall Survival (OS) Event [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months). DCO3 is the final data cut-off for the OS analysis and therefore no further updates will be made. ]An OS event is defined as death by any cause, regardless of whether the patient withdraws from randomised therapy or receives another anticancer therapy.
- Number of Participants With Time to First Subsequent Anticancer Therapy or Death (TFST) Event [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]A TFST (excluding radiotherapy) event is defined as the start of the first subsequent anticancer therapy after discontinuation of randomised treatment or death from any cause.
- Number of Participants With Time to Pain Progression (TTPP) Event [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]A TTPP event is defined as pain progression based on the Brief Pain Inventory-Short Form (BPI-SF) Item 3 (range 0-10, a higher score indicates worse pain) and opiate analgesic use (Analgesic quantification algorithm [AQA] score, range 0-7, a higher score indicates increased opioid use). For patients who are asymptomatic at baseline (average worst pain score of 0 and not taking opioids): A ≥2 point change from baseline in average (4-7 days) worst pain score observed at 2 consecutive visits or initiation of opioid use; For patients who are symptomatic at baseline (average worst pain score >0 and/or receiving opioids): A ≥2 point change from baseline in average (4-7 days) worst pain score observed at 2 consecutive visits and an average worst pain score ≥4, and no decrease in average opioid use (≥1-point decrease in AQA score from a starting value of ≥2), or increase in opioid use (≥1-point increase, or ≥2-point increase if the starting value is 0) at 2 consecutive follow-up visits.
- Number of Participants With Opiate Use [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]An event for opiate use is defined as the first opiate use for cancer related pain.
- Number of Participants With First Symptomatic Skeletal Related Event (SSRE) [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]
An SSRE event is defined as the first sympomatic skeletal-related event defined by
- Use of radiation therapy to prevent or relieve skeletal symptoms.
- Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral).
- Number of Participants With Second Progression or Death (PFS2) Event [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]An event for PFS2 is defined as the second progression on next-line anticancer therapy or death, whichever occurs earlier.
- Brief Pain Inventory-Short Form (BPI-SF) [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]The BPI-SF is a validated, 15-item domain-specific instrument designed to assess the severity of pain and the impact/interference of pain on daily functions. BPI-SF worst pain, pain severity and pain interference score changes can be a minimum of -10 and a maximum of 10. A negative change from baseline value indicates improvement.
- Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P) [ Time Frame: Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months) ]
Functional Assessment of Cancer Therapy-Prostate Cancer (FACT-P) total score and Functional Assessment of Cancer Therapy-General (FACT-G) total score.
Total FACT-P score is the sum of Physical Well-being (PWB), Social Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) and Prostate cancer subscale (PCS). FACT-P total score change from baseline values can be a minimum of -156 and a maximum of 156. A positive value indicates improvement.
FACT-G total score is the sum of PWB, SWB, EWB and FWB. FACT-G Total score change from baseline values can be a minimum of -108 and a maximum of 108. A positive value indicates improvement.
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| Ages Eligible for Study: | 18 Years to 99 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
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.
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03732820
Show 132 study locations
| Principal Investigator: | Fred Saad, MD | University of Montreal Hospital Center | |
| Principal Investigator: | Noel Clarke, M.D. | Christie Hospital Foundation Trust |
Documents provided by AstraZeneca:
| Responsible Party: | AstraZeneca |
| ClinicalTrials.gov Identifier: | NCT03732820 |
| Other Study ID Numbers: |
D081SC00001 2018-002011-10 ( EudraCT Number ) |
| First Posted: | November 7, 2018 Key Record Dates |
| Results First Posted: | June 15, 2023 |
| Last Update Posted: | February 28, 2024 |
| Last Verified: | February 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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metastatic castration-resistant prostate cancer (mCRPC) |
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Prostatic Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Neoplasms Genital Diseases, Male Genital Diseases Urogenital Diseases Prostatic Diseases Male Urogenital Diseases Olaparib |
Abiraterone Acetate Poly(ADP-ribose) Polymerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Cytochrome P-450 Enzyme Inhibitors |