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

Phase 3

Completed

Conditions: Non-Germline BRCA Mutated Ovarian Cancer

Interventions: Drug: Olaparib

Registration Number: NCT03402841

Lead Sponsor: AstraZeneca

Brief Summary: 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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 279

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Olaparib	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.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to maximum of 32 months	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.

Secondary Outcome Measures

Name	Time	Method
PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status	Up to maximum of 32 months	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.
Chemotherapy-free Interval (CT-FI)	Up to a maximum of 43 months	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.
Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period	Baseline up to a maximum of 32 months	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.
Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period	Baseline up to a maximum of 32 months	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.
Overall Survival (OS)	Up to a maximum of 43 months	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.
Time to First Subsequent Therapy or Death (TFST)	Up to a maximum of 43 months	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.
Time to Treatment Discontinuation or Death (TDT)	Up to a maximum of 43 months	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.