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Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study)

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ClinicalTrials.gov Identifier: NCT02987543
Recruitment Status : Active, not recruiting
First Posted : December 9, 2016
Results First Posted : October 12, 2020
Last Update Posted : February 25, 2021
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Foundation Medicine, Inc.
Myriad Genetics, Inc.
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE November 15, 2016
First Posted Date  ICMJE December 9, 2016
Results First Submitted Date  ICMJE June 3, 2020
Results First Posted Date  ICMJE October 12, 2020
Last Update Posted Date February 25, 2021
Actual Study Start Date  ICMJE February 6, 2017
Actual Primary Completion Date June 4, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 7, 2020)
Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A Only [ Time Frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). ]
The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a >=20% increase in the sum of diameters of target lesions and an absolute increase of >=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as >= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, >=6 weeks later, must show >=2 more new bone lesions (for a total of >=4 new bone lesions since baseline).
Original Primary Outcome Measures  ICMJE
 (submitted: December 6, 2016)
Change in radiographic progression free survival (rPFS) [ Time Frame: During study period (up to 3 years) ]
rPFS in subjects with BRCA1, BRCA2, or ATM qualifying gene mutations defined as the time from randomization to radiographic progression by blinded independent central reader (BICR) using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria or death.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2020)
  • Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) - Cohort A Only [ Time Frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). ]
    ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = >=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.
  • Radiological Progression Free Survival (rPFS) by Blinded Independent Central Review (BICR) - Cohort A+B [ Time Frame: Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). ]
    The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
  • Time to Pain Progression - Cohort A Only [ Time Frame: Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively). ]
    Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain [Item 3] and Analgesic Quantification Algorithm [AQA] score.
  • Overall Survival (OS) - Cohort A Only [ Time Frame: Approximately 35 months after the first patient was randomised. ]
    Number of Participants with Overall Survival (OS) - Cohort A only.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2016)
  • Confirmed Objective Response Rate (ORR) by BICR [ Time Frame: During study period (up to 3 years) ]
    Confirmed ORR by BICR in subjects with measurable disease using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria
  • Time to Pain progression [ Time Frame: To be completed by subject daily for 7 consecutive days before each respective 4-week visit/assessment date with Day 1 as the baseline visit date (not required to be at site) ]
    Time to pain progression defined as the time from randomization to increase in pain based on brief pain inventory (short form) question #3 and opioid analgesic usage
  • Overall Survival (OS) [ Time Frame: During study period (up to 4 years) ]
    OS defined as time from randomization to death due to any cause
  • rPFS [ Time Frame: During study period (up to 3 years) ]
    rPFS in subjects with HRR qualifying mutations defined as the time from randomization to radiographic progression by blinded independent central reader (BICR) using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria or death
  • AEs/SAEs and Collection of clinical chemistry/hematology parameters [ Time Frame: From the time of signature of informed consent throughout the treatment period up to and including the 30-day follow-up period. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study)
Official Title  ICMJE A Phase III, Open Label, Randomized Study to Assess the Efficacy and Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment With a New Hormonal Agent and Have Homologous Recombination Repair Gene Mutations (PROfound)
Brief Summary The purpose of this study is to evaluate the efficacy and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations.
Detailed Description

This is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status.

Approximately 340 subjects will be randomized 2:1 (olaparib : investigator choice of enzalutamide or abiraterone acetate) into the trial.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castration-resistant Prostate Cancer
Intervention  ICMJE
  • Drug: olaparib
    300 mg (2x 150 mg tablets) twice daily
    Other Name: Lynparza
  • Drug: enzalutamide
    160 mg (4 x 40 mg capsules) once daily
    Other Name: XTANDI
  • Drug: abiraterone acetate
    1,000 mg (4 x 250 mg tablets) once daily
    Other Name: ZYTIGA
  • Drug: abiraterone acetate
    1,000 mg (2 x 500 mg tablets) once daily
    Other Name: ZYTIGA
  • Drug: enzalutamide
    160 mg (4 x 40 mg tablets) once daily
    Other Name: XTANDI
Study Arms  ICMJE
  • Experimental: Olaparib
    Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. Subjects will be administered study treatment orally at a dose of 300 mg twice daily (bid). The planned dose of 300 mg bid will be made up of two x 150 mg tablets twice daily, with 100 mg tablets used to manage dose reductions
    Intervention: Drug: olaparib
  • Active Comparator: Enzalutamide OR abiraterone acetate

    Enzalutamide:

    Enzalutamide is available as capsules or tablets containing 40 mg of enzalutamide. Subjects will be administered study treatment orally at a dose of 160 mg once daily.

    Abiraterone acetate with prednisone: Abiraterone acetate is available as tablets containing 250 mg or 500 mg of abiraterone acetate. Subjects will be administered study treatment orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg administered twice daily orally. Prednisolone is permitted for use instead of prednisone if necessary.

    Interventions:
    • Drug: enzalutamide
    • Drug: abiraterone acetate
    • Drug: abiraterone acetate
    • Drug: enzalutamide
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 7, 2020)
387
Original Estimated Enrollment  ICMJE
 (submitted: December 6, 2016)
340
Estimated Study Completion Date  ICMJE December 31, 2021
Actual Primary Completion Date June 4, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  1. Histologically confirmed diagnosis of prostate cancer.
  2. Documented evidence of metastatic castration resistant prostate cancer (mCRPC).
  3. Subjects must have progressed on prior new hormonal agent (e.g. abiraterone acetate and/or enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC .
  4. Ongoing therapy with LHRH analog or bilateral orchiectomy.
  5. Radiographic progression at study entry while on androgen deprivation therapy (or after bilateral orchiectomy).
  6. Qualifying HRR mutation in tumor tissue.

Exclusion criteria

  1. Any previous treatment with PARP inhibitor, including olaparib.
  2. Subjects who have any previous treatment with DNA-damaging cytotoxic chemotherapy, except if for non-prostate cancer indication and last dose > 5 years prior to randomization.
  3. Other malignancy (including MDS and MGUS) within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥5 years.
  4. Subjects with known brain metastases.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Brazil,   Canada,   China,   Denmark,   France,   Germany,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Norway,   Spain,   Sweden,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02987543
Other Study ID Numbers  ICMJE D081DC00007
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • Foundation Medicine, Inc.
  • Myriad Genetics, Inc.
Investigators  ICMJE
Principal Investigator: Johann de Bono, M.D., Ph.D. The Institute of Cancer Research, United Kingdom
Principal Investigator: Maha Hussain, M.D., FACP, FASCO Northwestern University, United States of America
PRS Account AstraZeneca
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP