Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer.

NCT01972217 | Completed Phase 2 Results

• 3 other identifiers: D081DC00008UVA979342013-003520-37
• Study Type: interventional
• Target: 158
• Locations: 11 countries
• Sites: 41

Brief Summary

This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and pharmacokinetics (PK) of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo given in addition to abiraterone. Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg twice daily (bid) will be administered with the abiraterone in this study.

Conditions

Metastatic Castration-resistant Prostate Cancer

Keywords

Olaparib; castration-resistant, metastatic prostate cancer; Prior Docetaxel Chemotherapy

Outcome Measures

Primary Outcomes (4)

• Part A: Percentage of Patients Experiencing Adverse Events (AEs)

  The safety and tolerability of olaparib in combination with abiraterone was assessed during Part A of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented. Severity of AEs was assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) v4.0. AEs were assigned to a Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. 'c-r' = causally related 'discont' = discontinuation.

  Cohort 1 and 2: From baseline in Part A (Day 1 for each cohort) up to 30 days following last dose of study treatment.

• Part A: Number of Patients With Dose Limiting Toxicities (DLTs)

  DLTs were assessed by a Safety Review Committee (SRC) after a minimum of 3 patients had received at least 14 days of treatment in Part A. A DLT was defined as any toxicity which was not a recognised AE of abiraterone or prednisolone, and was not attributable to the disease or disease-related processes under investigation, which occurred during a minimum period of 14 days treatment and which included: 1. haematological toxicity CTCAE v4.0 Grade 4 or higher present for more than 4 days (except anaemia); 2. non-haematological toxicity CTCAE v4.0 Grade 3 or higher including infection, corrected QT interval prolongation; 3. any other toxicity that was greater than that at baseline, was clinically significant and/or unacceptable, did not respond to supportive care, resulted in a disruption of dosing schedule of 7 days or more, or was judged to be a DLT by the SRC. A DLT excluded alopecia and isolated laboratory changes of any grade without clinical sequelae or clinical significance.

  From Day 1 for Cohort 1 and from Day 4 for Cohort 2 up to 14 days treatment with olaparib + abiraterone for 3 patients.

• Part B: Median Radiological Progression-Free Survival (rPFS) Time

  The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (for soft tissue disease) and Prostate Cancer Working Group 2 (PCWG-2) (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit).

  From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.

• Part B: Percentage of Patients With Progression Events or Death (rPFS)

  The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using RECIST version 1.1 (for soft tissue disease) and PCWG-2 (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit). The percentage of patients with progression events is presented overall and according to RECIST 1.1 and/or PCWG-2 criteria, or death.

  From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.

Secondary Outcomes (16)

• Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

  PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone.

• Part A PK: Abiraterone Cmax,ss

  PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone.

• Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss)

  PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone.

• Part A PK: Abiraterone Tmax,ss

  PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone.

• Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

  PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone.

Study Arms (2)

Olaparib

ACTIVE COMPARATOR

200 mg or 300 mg bid

Drug: Olaparib; Drug: Abiraterone; Drug: Prednisone or prednisolone

Placebo

PLACEBO COMPARATOR

placebo to match olaparib bid

Drug: Placebo; Drug: Abiraterone; Drug: Prednisone or prednisolone

Interventions

Olaparib DRUG

Olaparib bid

Also known as: PARP inhibition

Olaparib

Placebo DRUG

Placebo bid

Also known as: Placebo to PARP inhibition

Placebo

Abiraterone DRUG

Abiraterone 1000 mg

Olaparib; Placebo

Prednisone or prednisolone DRUG

Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.

Olaparib; Placebo

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated written informed consent prior to any study specific procedures.
• Male aged 18 years and older.
• Histologically or cytologically proven diagnosis of prostate cancer.
• Candidate for abiraterone therapy with documented evidence of metastatic castration-resistant prostate cancer. Metastatic status is defined as at least one documented metastatic lesion on either bone scan or CT/MRI scan. Castration resistant prostate cancer is defined as rising PSA or other signs of disease progression despite treatment with androgen deprivation therapy and the presence of a castrate level of testosterone (≤50 ng/dL).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 with no deterioration over the previous 2 weeks.
• Patients must have a life expectancy ≥12 weeks.
• Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations, and completing PRO instruments.
• Patients must be on a stable concomitant medication regimen, defined as no changes in medication or in dose within 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4 weeks prior to start of olaparib dosing.
• For the randomised phase only, patients must have received chemotherapy in the form of docetaxel treatment for metastatic castration-resistant prostate cancer. Note: patients who discontinued docetaxel for toxicity reasons and without completing the full course will still be eligible to enter this study provided they received at least 2 cycles of chemotherapy.
• Provide informed consent for the pharmacogenetic sampling and analyses.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents and/or staff at the study site).
• Previous treatment in the present study.
• Treatment with any of the following:
• Previous exposure to any 2nd generation anti-hormonal including abiraterone and enzalutamide
• More than 2 prior courses of chemotherapy for metastatic prostate cancer
• Previous use of immunotherapy or radium-223 for the treatment of metastatic prostate cancer
• Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment;
• Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor;
• Substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine);
• Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort).
• Any previous treatment with a PARP inhibitor, including olaparib.
• With the exception of alopecia or toxicities related to the use of gonadotropinreleasing hormone agonists, any unresolved toxicities from prior therapy greater than CTCAE Grade 2 at the time of starting study treatment.
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• Any of the following cardiac criteria:

Sponsors & Collaborators

• AstraZeneca: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (41)

Research Site

San Diego, California, 92123, United States

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Lake Success, New York, 11041, United States

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Edegem, 2650, Belgium

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Liège, 4000, Belgium

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Wilrijk, 2610, Belgium

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London, Ontario, N6A 4G5, Canada

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Greenfield Park, Quebec, J4V 2H1, Canada

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Montreal, Quebec, H2L 4M1, Canada

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Brno, 656 53, Czechia

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Brno, 656 91, Czechia

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Liberec, 460 63, Czechia

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Angers, 49933, France

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Dijon, 21079, France

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Lyon, 69373, France

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Lecce, 73100, Italy

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Mirano, 30035, Italy

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Napoli, 80131, Italy

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Parma, 43100, Italy

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Pisa, 56126, Italy

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Arnhem, 6815 AD, Netherlands

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Maastricht, 6202 AZ, Netherlands

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Nijmegen, 6532 SZ, Netherlands

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Gdansk, 80-214, Poland

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Warsaw, 02-781, Poland

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Ivanovo, 153040, Russia

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Moscow, 115478, Russia

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Moscow, 125284, Russia

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Saint Petersburg, 197022, Russia

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Badalona, 08916, Spain

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Córdoba, 14004, Spain

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Girona, 17007, Spain

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L'Hospitalet de Llobregat, 08908, Spain

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Madrid, 28050, Spain

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Palma de Mallorca, 7014, Spain

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Valencia, 46010, Spain

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Cardiff, CF14 2TL, United Kingdom

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Exeter, EX2 5DW, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Plymouth, PL6 8DH, United Kingdom

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Torquay, TQ2 7AA, United Kingdom

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Westcliff-on-Sea, SS0 0RY, United Kingdom

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Related Publications (2)

• Clarke N, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, Chiuri VE, Jassem J, Flechon A, Redfern C, Goessl C, Burgents J, Kozarski R, Hodgson D, Learoyd M, Saad F. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):975-986. doi: 10.1016/S1470-2045(18)30365-6. Epub 2018 Jun 4.

  PMID: 29880291 BACKGROUND

• Saad F, Thiery-Vuillemin A, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, Chiuri VE, Jassem J, Flechon A, Redfern C, Kang J, Burgents J, Gresty C, Degboe A, Clarke NW. Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2022 Oct;23(10):1297-1307. doi: 10.1016/S1470-2045(22)00498-3. Epub 2022 Sep 2.

  PMID: 36063830 DERIVED

Related Links

• Redacted SAP
• Redacted CSR synopsis

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

olaparib; abiraterone; Prednisone; Prednisolone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols

Results Point of Contact

• Title: Medical Director
• Organization: AstraZeneca

ClinicalTrialTransparency@astrazeneca.com

+13028851180

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2013
• First Posted: October 30, 2013
• Study Start: April 1, 2014
• Primary Completion: September 22, 2017
• Study Completion: August 24, 2023
• Last Updated: November 14, 2023
• Results First Posted: October 2, 2018

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

IT (5); US (2); CZ (3); RU (4); ES (7); FR (3); PL (2); CA (3); GB (6); NL (3); BE (3)