Clinical Trials

Date: 2017-09-11

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2017 Congress

Company: Tesaro (US - MA) ENGOT (European Network of Gynaecological Oncology Trial Groups) NSGO (Nordic Society of Gynaecological Oncology)

Product: niraparib (MK-4827)

Action mechanism:

• poly ADP ribose polymerase PARP inhibitor/PARP inhibitor. Niraparib is an orally administered poly polymerase (PARP) inhibitor, currently in late-stage development for patients with metastatic breast cancer and ovarian cancer. PARP proteins play a key survival role in DNA repair in cancer cells. By inhibiting PARP, certain defective cancer cells are not able to repair themselves, leading to cell death. A portion of men with prostate cancer have these defective cancer cells and may benefit from use of a PARP inhibitor, either alone, or in combination with other treatments.

Disease: ovarian cancer

Therapeutic area: Cancer - Oncology

Country: Austria, Belgium, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Norway, Poland, Spain, Sweden, UK, USA

Trial details:

• NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that planned to enroll 490 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. Patients were enrolled into one of two independent cohorts based on germline BRCA mutation status. One cohort enrolled patients who were germline BRCA mutation carriers (gBRCAmut), and the second cohort enrolled patients who were not germline BRCA mutation carriers (non-gBRCAmut). The non-gBRCAmut cohort included patients with HRD-positive tumors, including those with somatic BRCA mutations and other HR defects, and patients with HRD-negative tumors. Within each cohort, patients were randomized 2:1 to receive niraparib or placebo and were treated continuously with placebo or 300 milligrams of niraparib, dosed as three 100 milligram tablets once per day, until progression. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints include patient-reported outcomes, chemotherapy-free interval length, PFS2, overall survival, and other measures of safety and tolerability. (NCT01847274)

Latest news:

• • On September 11, 2017, Tesaro provided a summary of Zejula® data presented at the 2017 European Society of Medical Oncology (ESMO) Annual Meeting in Madrid. Dr. Amit M. Oza, Senior Staff Physician, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, presented quality of life data from the Phase 3 ENGOT-OV16/NOVA trial. Patient-reported outcomes (PROs) were evaluated along with individual patient-reported symptoms using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L). The most common PRO symptoms at baseline were fatigue and pain, and 20% of patients experienced nausea at baseline. No significant difference in mean patient-reported outcomes scores was observed between patients treated with niraparib versus placebo, regardless of germline BRCA mutation status. Hematologic adverse events (thrombocytopenia, neutropenia, anemia) decreased over time with dose modification and did not impact QoL. These results also suggest that patients with ovarian cancer often experience residual symptoms of their disease following the conclusion of chemotherapy.
• In a poster discussion session, safety and efficacy results from the ENGOT-OV16/NOVA trial were highlighted for a sub-group of elderly patients, aged 70 years and older. In this post-hoc analysis, the efficacy of niraparib was similar for patients aged <70 years compared to patients aged ?70 years in both the gBRCAmut and non-gBRCAmut cohorts. Grade ?3 treatment-emergent adverse events occurring in >10% of niraparib treated patients were also consistent between the two groups, and dose reductions, interruptions, and treatment discontinuations occurred with similar frequency, regardless of age. These results demonstrate that niraparib may provide clinical benefit to a broad population of patients with ovarian cancer irrespective of age.
• Niraparib exposure — response findings support dosing patients at individually adjusted maximal tolerated dose In a poster discussion session, the relationship between niraparib exposure and efficacy, as well as exposure and safety, was highlighted in patients enrolled in the ENGOT-OV16/NOVA trial. Efficacy as measured by PFS was compared in patients with high exposure (defined as greater than median exposure) versus low exposure (defined as less than or equal to median exposure). Patients experienced similar efficacy at their individual maximum tolerated dose regardless of the dose received. Reaching maximal exposure for individual patients, as was done in the ENGOT-OV16/NOVA trials via dose modifications, was likely an important factor in achieving maximal efficacy, especially for patients without a BRCA mutation. Limited exposure-efficacy association was observed among patients who were germline BRCA mutation carriers, while the exposure-efficacy association was more apparent for patients who were not germline BRCA mutation carriers. On a population level, the incidence of treatment-emergent adverse events was higher with increased dose. These findings support that patients, especially those with BRCA wild-type tumors, should be treated at their individually adjusted maximal tolerated dose to provide the optimal chance of efficacy.
• Model highlights niraparib pharmacokinetic properties, including high tissue distribution and slow elimination, and no need for dose adjustments in patients with mild-to-moderate renal or hepatic impairment In a poster display session, data from the Phase 1 dose-escalation and expansion studies (n=104) and the Phase 3 ENGOT-OV16/NOVA study (n=408) of niraparib were used to model the impact of patient variables (age, race, ethnicity, body weight), renal impairment (normal, mild, or moderate), and hepatic function (baseline serum alanine and aspartate aminotransferase, albumin, total bilirubin) on niraparib pharmacokinetic parameters. In the base model, the typical value for niraparib apparent clearance was 16.2 L/h, with inter-individual variability of 52.6%. The estimated volume of distribution was 1074 L (290 L central and 784 L peripheral compartment). None of the patient variables impacted niraparib pharmacokinetics, including mild-to-moderate renal impairment and mild hepatic impairment, and model diagnostics showed good agreement between predicted and observed individual niraparib plasma concentrations. These results demonstrate that no dose adjustments are needed for patients treated with niraparib with mild-to-moderate renal or hepatic impairment.
• • On October 8, 2016, Tesaro announced the presentation of the niraparib Phase 3 ENGOT-OV16/NOVA clinical trial results at the ESMO 2016 Congress by Dr. Mansoor Raza Mirza, M.D., Medical Director of the Nordic Society of Gynecologic Oncology (NSGO) and principal investigator on the ENGOT-OV16/NOVA trial. These data were discussed during the ESMO press briefing in Copenhagen as part of the congress, and were simultaneously published online in the New England Journal of Medicine.
• Primary Endpoint Results:Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27 (95% CI, 0.173-0.410). The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p<0.0001).
• Statistically Significant PFS Results in the non-gBRCAmut Cohort: Niraparib showed statistical significance for patients in the non-germline BRCA mutant cohort. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45 (95% CI, 0.338-0.607). The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p<0.0001).
• Statistically Significant PFS Results in non-gBRCAmut Cohort for Patients with HRD-Positive Tumors For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice® HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38 (95% CI, 0.243-0.586). The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p<0.0001).
• Secondary Endpoint Results: Secondary endpoint analyses, including chemotherapy-free interval, time to first subsequent treatment, and PFS 2 were all statistically significant and favored niraparib over control for patients in both the gBRCAmut and non-gBRCAmut cohorts. Patient-reported outcome results from validated survey tools indicated that niraparib-treated patients reported no difference from control in measures associated with quality of life. Data for overall survival are immature (HR 0.73; 95% CI, 0.480 to 1.125; p=0.1545), as fewer than 20% of events had occurred at the time of analysis.
• Safety Results: The most common treatment-emergent grade 3/4 adverse events in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) with treatment discontinuation for these events of 3.3%, 1.4% and 1.9%, respectively. Thrombocytopenia was not associated with grade 3/4 bleeding events. The majority of these hematological laboratory abnormalities occurred within the first three cycles; following dose modifications the incidence of these lab abnormalities decreased and thrombocytopenia and neutropenia were infrequent beyond cycle 3. The rates of MDS/AML in the niraparib (1.4%) and control (1.1%) arms were similar. There were no deaths among patients during study treatment.
• • On July 8, 2016, ENGOT (European Network of Gynaecological Oncology Trial Groups) announced that the Phase 3 ENGOT-OV16/NOVA trial of niraparib successfully achieved its primary endpoint of progression-free survival (PFS). This trial is led by NSGO (Nordic Society of Gynaecological Oncology) in partnership with TESARO, Inc. and is the first successful Phase 3 trial of a PARP inhibitor to be completed in ovarian cancer. More than 500 patients with recurrent disease who were in response to their most recent platinum-based chemotherapy regimen enrolled in the trial. As previously reported, this trial demonstrated that niraparib significantly prolonged PFS compared to control among patients who are germline BRCA mutation (gBRCAmut) carriers, among patients who are not germline BRCA mutation (non-gBRCAmut) carriers but who have homologous recombination deficient (HRD) tumors as determined by the Myriad myChoice®HRD test, and overall in patients who are not germline BRCA mutation carriers.
• • On June 29, 2016, Tesaro announced that the Phase 3 NOVA trial of niraparib successfully achieved its primary endpoint of progression-free survival (PFS). This trial demonstrated that niraparib significantly prolonged PFS compared to control among patients who are germline BRCA mutation (gBRCAmut) carriers, among patients who are not germline BRCA mutation (non-gBRCAmut) carriers but who have homologous recombination deficient (HRD) tumors as determined by the Myriad myChoice® HRD test, and overall in patients who are not germline BRCA mutation carriers. For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice® HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38. The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p < 0.0001). Niraparib also showed statistical significance in the overall non-germline BRCA mutant cohort, which included patients with both HRD-positive and HRD-negative tumors. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p < 0.0001).

Is general: Yes