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

• 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: AstraZeneca
• Collaborators: Merck Sharp & Dohme LLC; Foundation Medicine, Inc.; Myriad Genetics, Inc.
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 15, 2016
• First Posted Date: December 9, 2016
• Results First Submitted Date: June 3, 2020
• Results First Posted Date: October 12, 2020
• Last Update Posted Date: October 6, 2023
• Actual Study Start Date: February 6, 2017
• Actual Primary Completion Date: June 4, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study)
• 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)
• 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Castration-resistant Prostate Cancer

Intervention

• 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

• 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 *

• Roubaud G, Ozguroglu M, Penel N, Matsubara N, Mehra N, Kolinsky MP, Procopio G, Feyerabend S, Joung JY, Gravis G, Nishimura K, Gedye C, Padua C, Shore N, Thiery-Vuillemin A, Saad F, van Alphen R, Carducci MA, Desai C, Brickel N, Poehlein C, Del Rosario P, Fizazi K. Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: Further analyses from the PROfound study. Eur J Cancer. 2022 Jul;170:73-84. doi: 10.1016/j.ejca.2022.04.016. Epub 2022 May 19.
• Matsubara N, Nishimura K, Kawakami S, Joung JY, Uemura H, Goto T, Kwon TG, Sugimoto M, Kato M, Wang SS, Pang ST, Chen CH, Fujita T, Nii M, Shen L, Dujka M, Hussain M, de Bono J. Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis. Jpn J Clin Oncol. 2022 May 5;52(5):441-448. doi: 10.1093/jjco/hyac015.
• Thiery-Vuillemin A, de Bono J, Hussain M, Roubaud G, Procopio G, Shore N, Fizazi K, Dos Anjos G, Gravis G, Joung JY, Matsubara N, Castellano D, Degboe A, Gresty C, Kang J, Allen A, Poehlein C, Saad F. Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Mar;23(3):393-405. doi: 10.1016/S1470-2045(22)00017-1. Epub 2022 Feb 11. Erratum In: Lancet Oncol. 2022 Apr;23(4):e161.
• Hussain M, Corcoran C, Sibilla C, Fizazi K, Saad F, Shore N, Sandhu S, Mateo J, Olmos D, Mehra N, Kolinsky MP, Roubaud G, Ozguroglu M, Matsubara N, Gedye C, Choi YD, Padua C, Kohlmann A, Huisden R, Elvin JA, Kang J, Adelman CA, Allen A, Poehlein C, de Bono J. Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib). Clin Cancer Res. 2022 Apr 14;28(8):1518-1530. doi: 10.1158/1078-0432.CCR-21-3940.
• Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Ozguroglu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357. doi: 10.1056/NEJMoa2022485. Epub 2020 Sep 20.
• de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. doi: 10.1056/NEJMoa1911440. Epub 2020 Apr 28.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 7, 2020): 387
• Original Estimated Enrollment (submitted: December 6, 2016): 340
• Actual Study Completion Date: February 15, 2023
• Actual Primary Completion Date: June 4, 2019 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Brazil, Canada, Denmark, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, Norway, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: China

Administrative Information

• NCT Number: NCT02987543
• Other Study ID Numbers: D081DC00007; 2016-000300-28 ( EudraCT Number )
• 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: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current

Collaborators

• Merck Sharp & Dohme LLC
• Foundation Medicine, Inc.
• Myriad Genetics, Inc.

Investigators

• 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: September 2023