Clinical trial NCT05171816: Study on Olaparib Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (China Cohort)
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: metastatic castration-resistant prostate cancer (mCRPC)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-12-29
Enrollment: 108
Sex: MALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Radiological progression free survival (rPFS)
timeFrame: From date of randomization to study completion (up to 4 years)
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Time to first subsequent anticancer therapy or death (TFST)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Time to pain progression (TTPP)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Time to opiate use
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Time to a Symptomatic Skeletal-Related Event (SSRE)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Time to second progression or death (PFS2)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Brief Pain Inventory-Short Form (BPI-SF)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P)
timeFrame: From date of randomization to study completion (up to 4 years)
measure: Homologous Recombination Repair (HRR) gene status
timeFrame: At baseline
measure: Number of adverse events
timeFrame: From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days)
measure: Vital signs-blood pressure
timeFrame: From the time of signature of informed consent throughout the treatment period (up to 4 years plus 30 days)
measure: Vital signs-pulse rate
timeFrame: From the time of signature of informed consent throughout the treatment period (up to 4 years)
measure: Vital signs-body temperature
timeFrame: From the time of signature of informed consent throughout the treatment period (up to 4 years)
measure: ECG
timeFrame: From the time of signature of informed consent throughout the treatment period (up to 4 years)
measure: Change in Albumin (g/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Alkaline phosphatase (U/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Aspartate aminotransferase (U/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Amylase (U/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Alanine aminotransferase (U/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Total bilirubin (μmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Direct bilirubin
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Calcium (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Chloride (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Creatinine (μmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Gamma glutamyltransferase (U/L)
timeFrame: At screening only
measure: Change in Fasting gucose (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Lactate dehydrogenase (U/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Magnesium (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Potassium (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Phosphorus ((mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Sodium (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Carbon dioxide (mEq/L )
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Total protein (g/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Urea or blood urea nitrogen, depending on the local practice (mmol/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in absolute neutrophil count (/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in absolute lymphocyte count (/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in haemoglobin (g/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in platelet count with differential (/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in total white blood cell count with differential(/L)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in red blood cell count (/l)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Haematocrit (%)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Change in Mean Cell Volume (fL)
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Urinalysis:change in blood
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Urinalysis: Change in protein
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
measure: Urinalysis: change in glucose
timeFrame: At scheduled visits from screening to 30 days after last dose of study medication
Other outcomes:
Locations:
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Guizhou
country: China
facility: Research Site
city: Henan
country: China
facility: Research Site
city: Hubei
country: China
facility: Research Site
city: Hunan
country: China
facility: Research Site
city: Hunan
country: China
facility: Research Site
city: Jilin
country: China
facility: Research Site
city: Jilin
country: China
facility: Research Site
city: Liaoning
country: China
facility: Research Site
city: Nanchang
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Ningbo
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Sichuan
country: China
facility: Research Site
city: Sichuan
country: China
facility: Research Site
city: Xian
country: China
facility: Research Site
city: Zhejiang
country: China
facility: Research Site
city: Zhejiang
country: China
facility: Research Site
Study officials:
affiliation: Christie Hospital Foundation Trust
name: Noel Clarke, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Montreal Hospital Center
name: Fred Saad, MD
role: PRINCIPAL_INVESTIGATOR
References: