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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 : Completed
First Posted : December 9, 2016
Results First Posted : October 12, 2020
Last Update Posted : October 6, 2023
Sponsor:
Collaborators:
Merck Sharp & Dohme LLC
Foundation Medicine, Inc.
Myriad Genetics, Inc.
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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.

Condition or disease Intervention/treatment Phase
Metastatic Castration-resistant Prostate Cancer Drug: olaparib Drug: enzalutamide Drug: abiraterone acetate Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 387 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : February 6, 2017
Actual Primary Completion Date : June 4, 2019
Actual Study Completion Date : February 15, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arms and Interventions
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Arm Intervention/treatment
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
 Drug: olaparib
300 mg (2x 150 mg tablets) twice daily
Other Name: Lynparza
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.

 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


Outcome Measures
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Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02987543


Locations
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Sponsors and Collaborators
AstraZeneca
Merck Sharp & Dohme LLC
Foundation Medicine, Inc.
Myriad Genetics, Inc.
Investigators
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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
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] March 7, 2019
Statistical Analysis Plan  [PDF] July 4, 2019

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02987543    
Other Study ID Numbers: D081DC00007
2016-000300-28 ( EudraCT Number )
First Posted: December 9, 2016    Key Record Dates
Results First Posted: October 12, 2020
Last Update Posted: October 6, 2023
Last Verified: September 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
metastatic castration-resistant prostate cancer (mCRPC)
homologous recombination repair (HRR)
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Genital Diseases
Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Olaparib
 Abiraterone Acetate
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 Enzyme Inhibitors