Study on Olaparib Plus Abiraterone as First-line Therapy in Men with Metastatic Castration-resistant Prostate Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Feb 2019 → ongoing

Decision date (initial)

2024-03-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2024-511144-86-00

EudraCT number

2018-002011-10

ClinicalTrials.gov

NCT03732820

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To determine the efficacy of the combination of olaparib and abiraterone vs placebo and abiraterone by investigator assessment of rPFS in patients with mCRPC who have received no prior cytotoxic chemotherapy or NHA at mCRPC stage.

Secondary objectives 7

1. To determine the efficacy of the combination of olaparib and abiraterone vs placebo and abiraterone by assessment of OS, TFST, and TTPP.
2. To further evaluate the efficacy of the combination of olaparib and abiraterone vs placebo and abiraterone by assessment of time to opiate use, time to an SSRE, and PFS2.
3. To assess the effect of the combination of olaparib and abiraterone vs placebo and abiraterone on disease related symptoms and HRQoL using BPI-SF and FACT - Prostate Cancer (FACT-P).
4. To evaluate tumour and blood samples for mutations in BRCA1, BRCA2, ATM and 11 other HRR genes.
5. To determine steady-state exposure to abiraterone and its active metabolite Δ4-abiraterone in the presence and absence of olaparib.
6. To evaluate the safety and tolerability of the combination of olaparib and abiraterone vs placebo and abiraterone.
7. To determine steady-state exposure to olaparib when co-administered with abiraterone.

Conditions and MedDRA coding

Metastatic castration-resistant prostate cancer

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 fulfil 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 CT/MRI scan.
7. First-line mCRPC.
8. Ongoing androgen deprivation with gonadotropin-releasing hormone analogue or bilateral orchiectomy, with serum testosterone <50 ng/dL (<2.0 nmol/L) within 28 days before randomisation. Patients receiving 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 (see Appendix B), 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 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 HRR status subgroup analysis of the primary endpoint 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 (see Appendix I for acceptable methods) if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking olaparib and for 3 months following the last dose of olaparib

Exclusion criteria 29

1. Has a known additional malignancy that has had progression or has required active treatment in the last 5 years.
2. Patients with MDS/AML or with features suggestive of MDS/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 BP ≥160 mmHg or diastolic BP ≥95 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 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 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 CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor (eg, abiraterone, orteronel).
21. Concomitant use of known strong CYP3A 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 CYP3A inducers (eg, phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine or St John’s wort) or moderate CYP3A 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Radiological progression free survival (rPFS) defined as the time from randomisation to radiological progression, or death from any cause, whichever occurs first

Secondary endpoints 10

1. Overall survival (OS)
2. Time to first subsequent anticancer therapy or death (TFST)
3. Time to pain progression (TTPP)
4. Time to first opiate use for cancer-related pain
5. Time to first symptomatic skeletal-related event (SSRE)
6. Time to second progression or death (PFS2)
7. BPI-SF: progression in pain severity domain, change in pain interference domain
8. FACT-P total score, FACT-G total score, trial outcome index, functional well-being, physical well being, prostate cancer subscale, and FACT Advanced Prostate Symptom Index 6 (FAPSI 6)
9. HRR gene status
10. Plasma concentration data at steady state for olaparib, abiraterone, and Δ4-abiraterone in the subset of patients evaluable for PK

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

6 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 72 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications