Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients (OPINION)

A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non-Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy

The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer who do not have known deleterious or suspected deleterious germline BRCA mutations (non-gBRCAm) and who had responded following platinum based chemotherapy

Study Overview

• Status: Completed
• Conditions: Non-Germline BRCA Mutated Ovarian Cancer
• Intervention / Treatment: Drug: Olaparib

Detailed Description

Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose [Poly (ADP-ribose)] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.

Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens.

While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Research Site
  • Innsbruck, Austria, 6020
    • Research Site
  • Wein, Austria, 1130
    • Research Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Research Site
  • Loverval, Belgium, 6280
    • Research Site
  • Wilrijk, Belgium, 2610
    • Research Site
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • Research Site
  • Plovdiv, Bulgaria, 4004
    • Research Site
  • Sofia, Bulgaria, 1330
    • Research Site
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Research Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Research Site
    • Toronto, Ontario, Canada, M5G2M9
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Research Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Research Site
• Czechia
  • Brno, Czechia, 625 00
    • Research Site
  • Olomouc, Czechia, 775 20
    • Research Site
  • Ostrava, Czechia, 708 52
    • Research Site
  • Praha 2, Czechia, 128 08
    • Research Site
• Denmark
  • Ålborg, Denmark, 9100
    • Research Site
• Finland
  • Kuopio, Finland, 70210
    • Research Site
  • Oulu, Finland, 90029
    • Research Site
  • Tampere, Finland, 33520
    • Research Site
• Israel
  • Beer Sheva, Israel
    • Research Site
  • Haifa, Israel, 91096
    • Research Site
  • Jerusalem, Israel, 91031
    • Research Site
  • Kfar Saba, Israel, 4428164
    • Research Site
  • Ramat Gan, Israel, 52621
    • Research Site
• Italy
  • Ancona, Italy, 60020
    • Research Site
  • Brescia, Italy, 25123
    • Research Site
  • Lecco, Italy, 23900
    • Research Site
  • Milano, Italy, 20141
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Torino, Italy, 10126
    • Research Site
  • Torino, Italy, 10128
    • Research Site
• Netherlands
  • Breda, Netherlands, 4818 CK
    • Research Site
  • Tilburg, Netherlands, 5022 GC
    • Research Site
• Norway
  • Bergen, Norway, 5053
    • Research Site
  • Oslo, Norway, 424
    • Research Site
• Poland
  • Gdynia, Poland, 81-519
    • Research Site
  • Kraków, Poland, 31-501
    • Research Site
  • Olsztyn, Poland, 10-513
    • Research Site
  • Poznań, Poland, 60-569
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
• Portugal
  • Lisboa, Portugal, 1400-048
    • Research Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Research Site
• Spain
  • Badalona, Spain, 08916
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 8035
    • Research Site
  • Barcelona, Spain, 08041
    • Research Site
  • Córdoba, Spain, 14004
    • Research Site
  • Girona, Spain, 17007
    • Research Site
  • Hospitalet deLlobregat, Spain, 08907
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Madrid, Spain, 28027
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
  • Valencia, Spain, 46009
    • Research Site
• Sweden
  • Linköping, Sweden, 581 85
    • Research Site
  • Lund, Sweden, 221 85
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bellinzona, Switzerland, 6500
    • Research Site
  • Frauenfeld, Switzerland, 8501
    • Research Site
  • Genève 14, Switzerland, 1205
    • Research Site
  • Zürich, Switzerland, 8091
    • Research Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Research Site
  • Exeter, United Kingdom, EX2 5DW
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • London, United Kingdom, WC1N 3BG
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Northampton, United Kingdom, NN1 5BD
    • Research Site
  • Scarborough, United Kingdom, YO12 6QL
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Key Inclusion Criteria:

• Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
• Documented gBRCA1/2 mutation status
• Patients must have completed at least 2 previous courses of platinum containing therapy
• Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment
• ECOG performance status 0-1 (see Appendix E)
• Patients must have a life expectancy ≥16 weeks
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1
• At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment OR No evidence of disease following a complete response to chemotherapy
• An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status

Exclusion Criteria:

• Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
• Any previous treatment with PARP inhibitor, including olaparib
• Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function)
• Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.
• Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A inducers
• Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
• Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
• Patients with symptomatic uncontrolled brain metastases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olaparib; Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib. Patients will be administered olaparib orally twice daily (bid) at 300 mg.	Drug: Olaparib; 300 mg twice daily - oral; Other Names: Lynparza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS is defined as the time from date of first dose until the date of objective radiological disease progression. Assessed according to modified Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. Confidence intervals (CI) for median PFS was derived based on Brookmeyer-Crowley method.	Up to maximum of 32 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Subsequent Therapy or Death (TFST)	TFST is defined as the time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment. Calculated using the Kaplan-Meier technique. CI for median TFST was derived based on Brookmeyer-Crowley method.	Up to a maximum of 43 months
Time to Treatment Discontinuation or Death (TDT)	TDT is defined as the time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation. Calculated using the Kaplan-Meier technique. CI for median TDT was derived based on Brookmeyer-Crowley method.	Up to a maximum of 43 months
PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status	HRD/BRCAm status was based on the central blood and tumour assessments. Assessed according to modified RECIST 1.1 or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. CI for median PFS was derived based on Brookmeyer-Crowley method.	Up to maximum of 32 months
Chemotherapy-free Interval (CT-FI)	CT-FI is defined as the time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of initiation of the next anticancer therapy. Calculated using the Kaplan-Meier technique. CI for median CT-FI was derived based on Brookmeyer-Crowley method.	Up to a maximum of 43 months
Overall Survival (OS)	OS is defined as the time from the date of first dose of olaparib to the date of death from any cause. Calculated using the Kaplan-Meier technique. CI for median OS was derived based on Brookmeyer-Crowley method.	Up to a maximum of 43 months
Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period	Improvement was defined as a functional assessment of cancer therapy - ovarian (FACT-O) TOI response of "any improvement" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better health related quality of life (HRQoL). An increase in score from baseline indicates an improvement in HRQoL.	Baseline up to a maximum of 32 months
Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period	10-point deterioration was defined as a FACT-O TOI response of "10-point deterioration" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better HRQoL. A decrease in score of at least 10 points from baseline was defined as a clinically meaningful deterioration.	Baseline up to a maximum of 32 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel; Covance; Iqvia Pty Ltd; Theradex; Myriad Genetics, Inc.
• Investigators: Study Director: Chris Wilks, AstraZeneca

Publications and helpful links

General Publications

• Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123-34. doi: 10.1056/NEJMoa0900212. Epub 2009 Jun 24.
• Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25. Erratum In: Lancet Oncol. 2017 Sep;18(9):e510.
• Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7.
• Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29.
• Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. doi: 10.1158/0008-5472.CAN-12-2753.
• Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011 Aug;5(4):387-93. doi: 10.1016/j.molonc.2011.07.001. Epub 2011 Jul 22.
• Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009 May 1;69(9):3850-5. doi: 10.1158/0008-5472.CAN-08-2388. Epub 2009 Apr 21.
• Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.
• Poveda A, Lheureux S, Colombo N, Cibula D, Lindemann K, Weberpals J, Bjurberg M, Oaknin A, Sikorska M, Gonzalez-Martin A, Madry R, Perez MJR, Ledermann J, Davidson R, Blakeley C, Bennett J, Barnicle A, Skof E. Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis. Gynecol Oncol. 2022 Mar;164(3):498-504. doi: 10.1016/j.ygyno.2021.12.025. Epub 2022 Jan 19.
• Poveda AM, Davidson R, Blakeley C, Milner A. Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Future Oncol. 2019 Nov;15(32):3651-3663. doi: 10.2217/fon-2019-0343. Epub 2019 Sep 25.

Helpful Links

• D0816C00020 CSP-v-3_Final Draft_13Sep21_Redacted
• D0816C00020-sap-v-2_Final_Draft_13Sep21_Redacted
• D0816C00020-study-synopsis-pa_Final draft_13Sep21_Redacted.pdf
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Actual): October 2, 2020
• Study Completion (Actual): March 10, 2022

Study Registration Dates

• First Submitted: January 3, 2018
• First Submitted That Met QC Criteria: January 17, 2018
• First Posted (Actual): January 18, 2018

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Ovarian cancer; Platinum; Chemotherapy; non-gBRCA
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: D0816C00020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No