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

Phase 3

Active, not recruiting

• Conditions: Metastatic Castration-resistant Prostate Cancer
• Interventions: Drug: olaparib; Drug: abiraterone acetate

• Registration Number: NCT05171816
• Lead Sponsor: AstraZeneca

Brief Summary

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

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.

Study Timeline

• Study Start: 2021-06-24
• Study First Submitted: 2021-12-20
• Study First Submitted QC: 2021-12-28
• Study First Posted: 2021-12-29
• Primary Completion: 2024-01-22
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-02
• Last Update Posted: 2025-01-03
• Study Completion: 2026-04-28

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 108

Inclusion Criteria

1. 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.

2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.

3. 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.

4. 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.

5. Histologically or cytologically confirmed prostate adenocarcinoma.

6. 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.

7. First-line metastatic castration-resistant prostate cancer (mCRPC).

8. 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.

9. Candidate for abiraterone therapy with documented evidence of progressive disease.

10. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment.

11. Eastern Cooperative Oncology Group (ECOG) performance status 0-1, with no deterioration over the previous 2 weeks.

12. The participant has, in the opinion of the investigator, a life expectancy of at least 6 months.

13. 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.

14. 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

1. Has a known additional malignancy that has had progression or has required active treatment in the last 5 years.
2. Patients with myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) or with features suggestive of yelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML).
3. 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.
4. Planned or scheduled cardiac surgery or percutaneous coronary intervention procedure.
5. Prior revascularisation procedure (significant coronary, carotid, or peripheral artery stenosis).
6. Uncontrolled hypertension (systolic blood pressure (BP) ≥160 millimeters of mercury (mmHg) or diastolic blood pressure (BP) ≥95 millimeters of mercury (mmHg)).
7. History of uncontrolled pituitary or adrenal dysfunction.
8. Active infection or other medical condition that would make prednisone/prednisolone use contraindicated.
9. Any chronic medical condition requiring a systemic dose of corticosteroid >10 milligrams (mg) prednisone/prednisolone per day.
10. Patients who are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
11. Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAEs] grade >2) caused by previous cancer therapy, excluding alopecia.
12. Patients with brain metastases. A scan to confirm the absence of brain metastases is not required.
13. 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.
14. Patients who are unevaluable for both bone and soft tissue progression
15. Patients who are unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
16. Immunocompromised patients
17. Patients with known active hepatitis infection (ie, hepatitis B or C).
18. Any previous treatment with Polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase (PARP) inhibitor, including olaparib.
19. 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.
20. Any previous exposure to a Cytochrome P450 (CYP) 17 (17α-hydroxylase/C17,20-lyase) inhibitor (eg, abiraterone, orteronel).
21. 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.
22. 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.
23. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
24. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
25. Participation in another clinical study with an investigational product or investigational medical devices within 1 month of randomisation.
26. 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.
27. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and Merck staff and/or staff at the study site).
28. 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.
29. Previous randomisation in the present study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
olaparib plus abiraterone	abiraterone acetate	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.
olaparib plus abiraterone	olaparib	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.
placebo plus abiraterone	abiraterone acetate	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.

Primary Outcome Measures

Name	Time	Method
Radiological progression free survival (rPFS)	From date of randomization to study completion (up to 4 years)	Radiological progression free survival (rPFS) - defined as the time from randomisation to; 1. 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; 2. death from any cause, whichever occurs first

Secondary Outcome Measures

Name	Time	Method
Time to first subsequent anticancer therapy or death (TFST)	From date of randomization to study completion (up to 4 years)	Time from randomisation to the earlier of the first subsequent anticancer therapy start date following study treatment discontinuation or death from any cause
Time to pain progression (TTPP)	From date of randomization to study completion (up to 4 years)	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)
Time to opiate use	From date of randomization to study completion (up to 4 years)	Time from randomisation to the first opiate use for cancer-related pain
Time to a Symptomatic Skeletal-Related Event (SSRE)	From date of randomization to study completion (up to 4 years)	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.
Time to second progression or death (PFS2)	From date of randomization to study completion (up to 4 years)	Time from randomisation to second progression or clinical progression or death, whichever occurs earlier
Brief Pain Inventory-Short Form (BPI-SF)	From date of randomization to study completion (up to 4 years)	To assess progression in pain severity domain, change in pain interference domain, and pain palliation
Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P)	From date of randomization to study completion (up to 4 years)	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)
Homologous Recombination Repair (HRR) gene status	At baseline	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.
Number of adverse events	From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days)	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
Vital signs-blood pressure	From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days)	To assess systolic and diastolic blood pressure as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone
Overall survival (OS)	From date of randomization to study completion (up to 4 years)	Time from randomisation to death from any cause
Change in Magnesium (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Magnesium recorded in the eCRF will be listed and summarized by treatment group and visit.
Vital signs-pulse rate	From the time of signature of informed consent throughout the treatment period (up to 4 years)	To assess pulse rate as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone
Vital signs-body temperature	From the time of signature of informed consent throughout the treatment period (up to 4 years)	To assess body temperature as variable of safety and tolerability of the combination of olaparib and arbiraterone vs placebo and arbiraterone
ECG	From the time of signature of informed consent throughout the treatment period (up to 4 years)	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.
Change in Albumin (g/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Albumin recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Alkaline phosphatase (U/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Alkaline phosphatase recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Aspartate aminotransferase (U/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Aspartate aminotrasnferase recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Amylase (U/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Amylase recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Alanine aminotransferase (U/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Alanine aminotransferase recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Total bilirubin (μmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Total bilirubin recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Direct bilirubin	At scheduled visits from screening to 30 days after last dose of study medication	Data for Direct bilirubin recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Calcium (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Calcium recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Chloride (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Chloride recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Creatinine (μmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Creatinine recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Gamma glutamyltransferase (U/L)	At screening only	Data for Gamma glutamyltransferase recorded in the eCRF will be listed and summarized by treatment group.
Change in Fasting gucose (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Fasting glucose recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Lactate dehydrogenase (U/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Lactate dehydrogenase recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Potassium (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Potassium recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Phosphorus ((mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Phosphorus will be recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Sodium (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Sodium recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Carbon dioxide (mEq/L )	At scheduled visits from screening to 30 days after last dose of study medication	Data for Carbon dioxide recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Total protein (g/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for protein recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Urea or blood urea nitrogen, depending on the local practice (mmol/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for urea or urea nitrogen recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in absolute neutrophil count (/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for absolute neutrophil recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in absolute lymphocyte count (/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for absolute lymphocyte recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in haemoglobin (g/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for haemoglobin recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in platelet count with differential (/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for platelet count with differential recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in total white blood cell count with differential(/L)	At scheduled visits from screening to 30 days after last dose of study medication	Data for WBC count recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in red blood cell count (/l)	At scheduled visits from screening to 30 days after last dose of study medication	Data for RBC count recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Haematocrit (%)	At scheduled visits from screening to 30 days after last dose of study medication	Data for Haematocrit recorded in the eCRF will be listed and summarized by treatment group and visit.
Change in Mean Cell Volume (fL)	At scheduled visits from screening to 30 days after last dose of study medication	Data for MCV count recorded in the eCRF will be listed and summarized by treatment group and visit.
Urinalysis:change in blood	At scheduled visits from screening to 30 days after last dose of study medication	Data for blood testing recorded in the eCRF will be listed and summarized by treatment group and visit.
Urinalysis: Change in protein	At scheduled visits from screening to 30 days after last dose of study medication	Data for urine protein recorded in the eCRF will be listed and summarized by treatment group and visit.
Urinalysis: change in glucose	At scheduled visits from screening to 30 days after last dose of study medication	Data for urine glucose recorded in the eCRF will be listed and summarized by treatment group and visit.

Trial Locations

Locations (1)

Research Site; 🇨🇳 Zhejiang, China