Shefali Agarwal

Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial

BACKGROUNDnQuality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.nnnMETHODSnThe ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274.nnnFINDINGSnBetween Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0-25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects.nnnINTERPRETATIONnThese PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.nnnFUNDINGnTESARO.

Abstract C53: Homologous recombination deficiency (HRD) of high grade serous ovarian tumors from the NOVA Phase III clinical study

Background: Genome-wide analysis was conducted on tumors obtained from patients enrolled in the NOVA study, a Phase 3 clinical trial evaluating the PARP inhibitor niraparib as a maintenance treatment in patients with platinum-sensitive ovarian cancer. Homologous recombination deficiency (HRD) and mutations in DNA damage repair genes were evaluated. Material and methods: DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue and used to create libraries that were hybridized to a custom Agilent SureSelect capture array carrying probes for 54,091 single nucleotide polymorphism sites distributed across the human genome, as well as probes targeting 43 genes involved in DNA repair, including BRCA1 and BRCA2. The captured and enriched DNA was sequenced on an Illumina HiSeq 2500 sequencer. Sequences covering SNP positions were used to generate allelic imbalance profiles. Measures of genomic instability, including determination of an HRD score (integer value of 0-100), were calculated using allelic imbalance profiles and determination of loss of heterozygosity (LOH) by allele-specific copy number (ASCN). A previously identified HRD threshold score of 42 was used to define HRD positivity in the absence of a BRCA mutation. Results: The NOVA study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of niraparib as maintenance therapy in ovarian cancer patients who have either gBRCAmut or a tumor with high-grade serous histology and who have responded to their most recent chemotherapy containing a platinum agent. Tumor BRCA mutational status, HRD score and genomic sequencing of 43 DNA repair genes were obtained from tumor samples from both gBRCAmut and non-gBRCAmut cohorts. In the gBRCAmut cohort, HRD analysis of the tumor confirmed the presence of a deleterious or suspected deleterious mutation in all cases. In addition, an HRD score ≥ 42 and the presence of a deleterious mutation in TP53 with loss of heterozygosity (LOH) were observed in nearly all tumors. In the non-gBRCA cohort, somatic BRCA mutations were observed in approximately 13% of tumors, and approximately half of tumors with no evidence of a BRCA mutation had a high HRD score. In both cohorts, the use of three scoring algorithms (LOH, telomeric allelic imbalance [TAI], large-scale state transitions [LST]), was more predictive of BRCA mutational status than LOH alone. Additional genomic sequencing identified deleterious mutations with LOH in DNA repair genes, such as BRIP1, CDK12, RAD51C, PTEN, and RAD51D, with many tumors exhibiting multiple deleterious mutations. Conclusions: High grade serous ovarian cancer is characterized by a high degree of genomic instability. Genomic analysis in the clinical setting is able to identify patients with both germline and somatic BRCA mutations, in addition to BRCAwt tumors with other genetic defects that may be sensitive to agents exploiting deficiencies in HR. Citation Format: Keith Wilcoxen, Christopher Neff, Victor Abkevich, Joshua Timothy Jones, Kathryn Kolquist, Michael Mirza, Jerry Lanchbury, Keith Mikule, Shefali Agarwal, Anne-Renee Hartman, Alexander Gutin, Kirsten Timms. Homologous recombination deficiency (HRD) of high grade serous ovarian tumors from the NOVA Phase III clinical study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C53.

941TiPENGOT-OV16/NOVA: A PHASE 3 RANDOMIZED DOUBLE-BLIND TRIAL OF MAINTENANCE WITH PARP-INHIBITOR NIRAPARIB VERSUS PLACEBO IN PATIENTS WITH PLATINUM-SENSITIVE OVARIAN CANCER

ABSTRACT Background: Niraparib is an oral PARP-1/2 inhibitor with efficacy in both germline BRCA mutated (gBRCA) ovarian cancer (OvCa) and high grade serous OvCa (HGSC) patients (pts) who are non-gBRCA. Phase I data established a RP2D of 300u2003mg. At the recommended dose, 75% platinum sensitive patients achieved RECIST response in phase 1. Trial design: ENGOT-OV16/NOVA study (n = 360) is a double-blind, 2:1 randomized, placebo controlled phase III study of oral niraparib versus placebo in pts with platinum (plat) sensitive recurrent OvCa. Primary objective is to evaluate efficacy of niraparib as maintenance therapy assessed by the prolongation of progression free survival (PFS). PFS will be independently evaluated in a cohort of gBRCA pts and in HGSC pts who are non-gBRCA. Secondary objectives: overall survival in each cohort; bridge the centralized BRCA mutation test method to the candidate companion diagnostic test; patient-reported outcomes; PFS2; chemotherapy free interval; safety/tolerability; QTc in a subset of niraparib-treated pts. Study eligibility includes: histologically confirmed OvCa, HGSC histology or known gBRCA, plat sensitive recurrence, at least 2 prior courses of plat-containing therapy with no/minimal radiological residual disease, and normal CA125 or decrease by 90% after last plat, PS 0-1, and normal organ function. The study is powered to assess PFS and OS in both cohorts (gBRCA & non-gBRCA). The trial is being conducted in 126 sites in collaboration with European Network of Gynaecological Oncological Trials Groups (NSGO Denmark-Norway-Sweden, AGO Austria, AGO Germany, BGOG Belgium, ISGO Israel, GEICO Spain, GINECO France, MaNGO Italy, MITO Italy, NCRI UK), US, Canada, Hungary & Poland. The pt. enrolment is according to the timelines. ClinicalTrials.gov Identifier: NCT01847274 Disclosure: S. Agarwal: Medical Officer, Tesaro Bio Inc. (sponsor of the trial); R.E. Martell: Chief Medical Officer, Tesaro Bio Inc. (Sponsor of the trial). All other authors have declared no conflicts of interest.