(searched for: PARP Inhibitor for Ovarian Cancer Therapy)
Published: 14 October 2012
Journal: Clinical Cancer Research
Clinical Cancer Research, Volume 18, pp 5806-5815; https://doi.org/10.1158/1078-0432.ccr-12-0857
Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design: We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions: Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 5806–15. ©2012 AACR.
Published: 20 May 2017
Journal: Journal of Clinical Oncology
Journal of Clinical Oncology, Volume 35, pp 5534-5534; https://doi.org/10.1200/jco.2017.35.15_suppl.5534
5534 Background: Current therapies for recurrent OC include chemotherapy (C) or bevacizumab (B) in combination with C followed by continuous B, which showed improved progression-free survival (PFS) compared with C followed by placebo (P) over 3.4 months (GOG-0213) or 4.0 months (OCEANS). Potential impact of B on effectiveness of subsequent therapies has not been described. Niraparib (N) is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies, N concentrates in the tumor; N showed significantly longer PFS vs P in patients (pts) with recurrent OC following complete/partial response (CR/PR) to platinum based chemotherapy (Plat) in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. We report the long term effect of treatment with N and its impact on subsequent therapy. Methods: Eligibility for NOVA included recurrent OC, fallopian tube or peritoneal cancer, no prior PARPi use, and completion of ≥2 prior courses of Plat, with a CR or PR following the most recent Plat. Pts were enrolled into g BRCAmut or non-g BRCAmut cohorts based on BRCA mutation test results and randomized 2:1 to receive N 300 mg qd or P until progression of disease or death (PD). Tumors were tested for homologous recombination deficiency (HRD). Estimated probability of PD in each cohort at 12, 18 and 24 months post randomization, representing ~18, 24 and 30 months post chemotherapy initiation, was determined; the difference between PFS2 and PFS (PFS2-PFS) was evaluated in all randomized pts. Results: 203 pts were randomized in the g BRCAmut cohort. Of 350 pts randomized in the non-g BRCAmut cohort, 162 had HRD+ and 134 HRD− tumors. Estimated probability (product-limit method) of PFS at 12, 18 and 24 months was greater in the niraparib arm than in the placebo arm in each cohort and subgroup at each time interval. Probabilities (95% CI) at 24 months for niraparib vs control were 0.42 (0.30, 0.55) vs 0.16 (0.07, 0.28) (gBRCAmut) and 0.27 (0.19, 0.35) vs 0.12 (0.06, 0.21) (non-gBRCAmut). PFS2-PFS was similar in the 2 treatment arms in the combined cohorts (HR 1.02, 95% CI 0.765, 1.349). Conclusions: Niraparib provided long term benefit in pts with recurrent OC irrespective of g BRCAmut or HRD status, and no decrement in the benefit of subsequent therapy was observed. Clinical trial information: NCT01847274.
Published: 20 May 2017
Journal: Journal of Clinical Oncology
Journal of Clinical Oncology, Volume 35, pp 5560-5560; https://doi.org/10.1200/jco.2017.35.15_suppl.5560
5560 Background: Niraparib is a highly selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor (PARPi); in preclinical studies, it concentrates in the tumor relative to plasma to deliver durable, near complete PARP inhibition and persistent antitumor effects.Niraparib demonstrated significantly longer progression free survival (PFS) vs placebo in patients (pts) with recurrent OC who were randomized following a complete response (CR) or partial response (PR) to platinum based chemotherapy in the controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. To more fully characterize the NOVA trial population, we assessed platinum resistance status, defined as a duration of response to platinum < 6 months to the most recent (ultimate) platinum regimen. Analysis was limited to pts in the placebo arm, as inclusion of pts receiving active treatment (niraparib) would have confounded the ability to determine duration of response to platinum alone. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of platinum based chemotherapy, and CR or PR to the most recent platinum based chemotherapy were eligible. Pts were assigned to one of two cohorts based on g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or placebo qd until progressive disease (PD). Randomization occurred up to 8 weeks following the last dose of the most recent platinum based chemotherapy. PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Estimated probability of pts having disease progression in each cohort and pooled across cohorts 6 months after the last dose of their most recent platinum therapy was calculated using the Kaplan-Meier methodology. Results: 181 pts were randomized to placebo (65 g BRCAmut and 116 non-g BRCAmut). Platinum resistance rate estimates for the g BRCAmut, non-g BRCAmut, and pooled cohorts were 42%, 53%, and 49%, respectively. Conclusions: Approximately half of the pts in the NOVA study, where niraparib treatment met its primary endpoint of prolonging PFS following a response to platinum, had developed platinum resistance to their last line of chemotherapy. Clinical trial information: NCT01847274.