| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration-resistant prostate cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the efficacy of the combination of olaparib and abiraterone vs placebo and abiraterone as assessed by time to start of first subsequent anticancer therapy or death (TFST), time to pain progression (TTPP), and OS
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, CTC conversion, and PFS2
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 Functional Assessment of Cancer Therapy (FACT) - Prostate Cancer (FACT-P)
To evaluate tumour and blood samples for mutations in BRCA1, BRCA2, ATM and 12 other HRR genes.
To determine steady-state exposure to abiraterone and its active metabolite Δ4-abiraterone in the presence and absence of olaparib.
To evaluate the safety and tolerability of the combination of olaparib and abiraterone vs placebo
and abiraterone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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. |
|
| E.4 | Principal 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 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Radiological progression free survival (rPFS) - defined as the time from randomisation to
1) radiographic progression, assessed by investigator per RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone), or
2) death from any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At baseline and every 8 weeks (± 7 days) until week 24 and every 12 weeks (± 7 days) thereafter, relative to the date of randomisation, until objective radiological disease progression is confirmed by the investigator. |
|
| E.5.2 | Secondary end point(s) |
1. Time to first subsequent anticancer therapy or death (TFST)
2. Time to pain progression (TTPP)
3. Overall survival (OS)
4. Time to opiate use
5. Time to an SSRE
6. Proportion of patients who achieve a decline in the number of CTCs from ≥5 cells/7.5 mL at baseline to <5 cells/7.5 mL at any time post baseline in whole blood (CTC conversion rate).
7. PFS2
8. BPI-SF: progression in pain severity domain, change in pain interference domain, and pain palliation.
9. 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).
10. HRR gene status
11. Plasma concentration data at steady state for olaparib, abiraterone, and Δ4-abiraterone in the subset of patients evaluable for PK. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time from randomisation to the earlier of the first subsequent anticancer therapy start date following study treatment discontinuation or death from any cause.
2. Time from randomisation to pain progression
3. Time from randomisation to death from any cause.
4. Time from randomisation to the first opiate use for cancer-related pain.
5. Time from randomisation to the first SSRE.
6. From baseline to at any time post baseline.
7. Time from randomisation to second progression or clinical progression or death.
8. Subjects will complete the BPI-SF daily on the ePRO device for 7 days just prior to day 1 baseline visit and every 4 weeks.
9. Every 4 weeks (starting on Day 1) in the first year and every 8 weeks thereafter.
10. At baseline
11. Visit 4 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Czech Republic |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Slovakia |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as ‘the last visit of the last patient undergoing the study’. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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