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ObjectiveIn the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status.MethodsWomen with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status.Results1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n=586) versus Q3W (n=546) paclitaxel (ITT: 20.5 vs 15.7months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8months, HR 0.64; BRCAwt: 18.0 vs 12.9months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n=211) and gBRCAwt (n=902) subgroups.ConclusionsDD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.

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5531 Background: The International Federation of Obstetrics and Gynecology staging system for cervical cancer (FIGO 2008) was revised in 2018 to incorporate lymph node involvement (FIGO 2018). OUTBACK is an international, randomized phase 3 trial of adjuvant chemotherapy versus observation after standard of care treatment with chemoradiation for women with locally advanced cervical cancer. OUTBACK found no benefit from the addition of adjuvant chemotherapy. We evaluated the effects of classifying participants with these 2 staging systems in the OUTBACK trial population. Methods: OUTBACK recruited April 2011 to June 2017 and staged participants according to FIGO 2008. Lymph node status, smoking status, age, race and histological subtype were documented at trial entry as important prognostic factors. We assessed the effects of stage grouping into stage I, II, and III/IVa with FIGO 2008 versus FIGO 2018, on progression-free survival (PFS) and overall survival (OS) at 5 years using Kaplan-Meier estimates, and in univariable proportional-hazards regression analyses, and in multivariable analyses adjusting for important prognostic factors and randomly allocated treatment. Results: All 919 study participants had complete data for staging according to the 2 staging systems and most prognostic factors for adjustment. Among all participants, the 5-year outcomes were PFS = 62% and OS = 72%. Classification according to FIGO 2018 rather than FIGO 2008 yielded higher 5-year PFS and OS in each stage group (see table for numbers of participants, PFS and OS for each stage group). Predictors of PFS in multivariable analysis included squamous vs non-squamous histology (HR 0.71 for FIGO 2008 and 0.74 for FIGO 2018), but not nodal involvement when FIGO 2018 was used. Both staging systems were the only independently significant prognostic factors in both univariable and multivariable analyses (all p < 0.0001) for both PFS and OS. Conclusions: Compared to FIGO 2008, reclassifying pts by FIGO 2018 staging resulted in more pts being classified as stage 3 due to the incorporation of nodal status. Staging locally advanced cervical cancer using FIGO 2018 rather than FIGO 2008 resulted in higher PFS and OS in each stage grouping that reflected stage migration, not a true improvement in outcomes. FIGO stage remains the strongest predictor of overall survival after CRT but survival outcomes by stage in trials using the old vs new staging system are not comparable. Clinical trial information: ACTRN12610000732088. [Table: see text]

Item does not contain fulltext This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Objective: The VELIA study evaluated progression-free survival (PFS) with veliparib added to carboplatin and paclitaxel with and without veliparib maintenance in newly diagnosed high-grade serous ovarian carcinoma (HGSC) patients. As anticipated, few patients experienced PFS events during carboplatin and paclitaxel, and we evaluated other parameters to explore the impact of veliparib during carboplatin and paclitaxel.Method: Patients with previously untreated stage III–IV HGSC received 6 cycles (21-day interval) of carboplatin and paclitaxel following primary cytoreduction or as neoadjuvant chemotherapy (NACT) with interval cytoreduction. Randomization was 1:1:1: veliparib-throughout, carboplatin and paclitaxel + veliparib then veliparib maintenance; veliparib-combo-only, carboplatin and paclitaxel + veliparib then placebo maintenance; and control, carboplatin and paclitaxel + placebo then placebo maintenance. These exploratory analyses evaluated responses during the combination phase, as assessed by CA-125 levels (response defined as ≥90% reduction from baseline or normalization) or Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: A total of 1,140 patients were enrolled, and 67% underwent primary cytoreduction (stratified prior to randomization). At baseline, the distribution of CA-125 levels was similar across each arm. By cycle 3, more patients receiving veliparib achieved a CA-125 response compared to control (Figure 1); a similar trend was seen among patients undergoing NACT. Among patients with measurable disease after primary surgery (n = 197), more patients in the veliparib-containing arms had complete response (CR) than those in the control arm.Conclusion: Veliparib added to frontline carboplatin and paclitaxel during induction resulted in a modest increase in CA-125 responses and CRs in women with newly diagnosed HGSC. These exploratory analyses suggest that veliparib added to carboplatin and paclitaxel during combination phase may provide antitumor activity above carboplatin and paclitaxel alone. Oral Abstract. LBA 9 – Late Breaking Abstract Session. Webinar #2: Paradigm Changes in Front Line Ovarian Cancer