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

Metastatic Castration-resistant Prostate Cancer Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03732820
• Other study ID #: D081SC00001
• Secondary ID: 2018-002011-10
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 31, 2018
• Est. completion date: April 28, 2026

Study information

• Verified date: February 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 895
• Est. completion date: April 28, 2026
• Est. primary completion date: July 30, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 99 Years

Eligibility

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 (17a-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.

Related Conditions & MeSH terms

• Metastatic Castration-resistant Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• olaparib
300 mg (2 x 150 milligrams (mg) tablets) twice daily
• abiraterone acetate
1000 milligrams (mg) once daily

Locations

Country	Name	City	State
Australia	Research Site	Box Hill
Australia	Research Site	Darlinghurst
Australia	Research Site	Greenslopes
Australia	Research Site	Herston
Australia	Research Site	Kingswood
Australia	Research Site	Kurralta Park
Australia	Research Site	St Albans
Australia	Research Site	Waratah
Belgium	Research Site	Gent
Brazil	Research Site	Belo Horizonte
Brazil	Research Site	Curitiba
Brazil	Research Site	Fortaleza
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	São José do Rio Preto
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Kelowna	British Columbia
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Temuco
Chile	Research Site	Viña del Mar
Czechia	Research Site	Brno
Czechia	Research Site	Praha
Czechia	Research Site	Praha
Czechia	Research Site	Praha 5
France	Research Site	Angers Cedex 01
France	Research Site	BESANCON Cedex
France	Research Site	Caen Cedex 05
France	Research Site	Pierre Benite
France	Research Site	Quimper Cedex
France	Research Site	Vandoeuvre les Nancy
Germany	Research Site	Bergisch Gladbach
Germany	Research Site	Bremen
Germany	Research Site	Duisburg
Germany	Research Site	Freiburg im Breisgau
Germany	Research Site	Heinsberg
Germany	Research Site	Köln
Germany	Research Site	Mettmann
Germany	Research Site	Nürnberg
Germany	Research Site	Nürtingen
Germany	Research Site	Ulm
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Orbassano
Italy	Research Site	Pavia
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Hirakata-shi
Japan	Research Site	Kanazawa-shi
Japan	Research Site	Kashihara-shi
Japan	Research Site	Kawagoe-shi
Japan	Research Site	Kita-gun
Japan	Research Site	Kyoto-shi
Japan	Research Site	Maebashi-shi
Japan	Research Site	Miyazaki-city
Japan	Research Site	Nagoya-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osakasayama-shi
Japan	Research Site	Sagamihara-shi
Japan	Research Site	Sakura-shi
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Toon-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Hilversum
Netherlands	Research Site	Nijmegen
Netherlands	Research Site	Tilburg
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Presov
Slovakia	Research Site	Sala
Slovakia	Research Site	Trencín
Spain	Research Site	Barcelona
Spain	Research Site	Gerona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Malaga
Spain	Research Site	Sevilla
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Karsiyaka
United Kingdom	Research Site	Guildford
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Southampton
United Kingdom	Research Site	Swansea
United States	Research Site	Anchorage	Alaska
United States	Research Site	Birmingham	Alabama
United States	Research Site	Bozeman	Montana
United States	Research Site	Brooklyn	New York
United States	Research Site	Charleston	South Carolina
United States	Research Site	Clovis	California
United States	Research Site	Denver	Colorado
United States	Research Site	Detroit	Michigan
United States	Research Site	Durham	North Carolina
United States	Research Site	Grand Rapids	Michigan
United States	Research Site	Jeffersonville	Indiana
United States	Research Site	Lisle	Illinois
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Myrtle Beach	South Carolina
United States	Research Site	New Hyde Park	New York
United States	Research Site	New Orleans	Louisiana
United States	Research Site	Omaha	Nebraska
United States	Research Site	Paramus	New Jersey
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Rochester	New York
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Diego	California
United States	Research Site	Syracuse	New York
United States	Research Site	Tucson	Arizona
United States	Research Site	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Chile,  Czechia,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Slovakia,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Radiological Progression Free Survival (rPFS) Event by Investigator Assessment	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.	Assessed from date of randomisation to data cut off (DCO1): 30Jul2021 (Approx. 2 years 9 months)
Secondary	Number of Participants With Overall Survival (OS) Event	An OS event is defined as death by any cause, regardless of whether the patient withdraws from randomised therapy or receives another anticancer therapy.	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.
Secondary	Number of Participants With Time to First Subsequent Anticancer Therapy or Death (TFST) Event	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.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Number of Participants With Time to Pain Progression (TTPP) Event	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.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Number of Participants With Opiate Use	An event for opiate use is defined as the first opiate use for cancer related pain.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Number of Participants With First Symptomatic Skeletal Related Event (SSRE)	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).	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Number of Participants With Second Progression or Death (PFS2) Event	An event for PFS2 is defined as the second progression on next-line anticancer therapy or death, whichever occurs earlier.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Brief Pain Inventory-Short Form (BPI-SF)	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.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)
Secondary	Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P)	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.	Assessed from date of randomisation to data cut off (DCO3): 12Oct2022 (Approx. 3 years 11 months)

External Links

•   csp_final_compressed
•   CSR Addendum 1
•   CSR addendum 2 - synopsis
•   Redacted CSR synopsis
•   Redacted SAP