OBJECTIVE:To characterize the occurrence, duration, and outcomes of the most common non-hematological (nausea, vomiting, fatigue/asthenia) and hematological (anemia, neutropenia) adverse events experienced by patients receiving olaparib in the phase III SOLO2 trial. METHODS:SOLO2 (NCT01874353) is a randomized, double-blind, placebo-controlled trial. Eligible patients had histologically confirmed relapsed high-grade serous ovarian cancer or high-grade endometrioid cancer with a BRCA mutation and were in response after platinum-based chemotherapy. Patients were randomized 2:1 to olaparib tablets 300 mg twice daily (N = 196) or placebo (N = 99). Safety outcomes were analyzed in all randomized patients who received ≥1 dose of study drug (olaparib, n = 195; placebo, n = 99). RESULTS:The most common adverse events of interest (nausea, vomiting, fatigue/asthenia, anemia, and neutropenia) were generally reported early, within the first 1 to 3 months of olaparib treatment, and were mostly grade 1/2. For all adverse events of interest, the risk of experiencing an event was statistically significantly higher with olaparib than with placebo (nausea hazard ratio [HR] 3.38, p <.001; vomiting HR 1.86, p =.016; fatigue/asthenia HR 2.11, p <.001; anemia HR 5.80, p <.001; and neutropenia HR 2.66, p =.027). Of these adverse events, only nausea had a statistically significantly higher risk of experiencing a second event with olaparib than with placebo (HR 3.62, p <.001). The prevalence of nausea, fatigue/asthenia, and anemia was higher with olaparib than with placebo across all time points. The median time to resolution of the first adverse event for olaparib versus placebo was 1.7 versus 0.4 months (nausea), 2 versus 2 days (vomiting), 6.4 versus 2.3 months (fatigue/asthenia), 3.2 versus 2.9 months (anemia), and 29 versus 14 days (neutropenia). Fatigue/asthenia was the slowest adverse event to resolve. CONCLUSION:These data confirm that the use of olaparib as long-term maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer is tolerable. Adverse events occurred early, were manageable, and few occurred with late onset.

Objective Therapeutic interventions for epithelial ovarian cancer (EOC) have increased greatly over the last decade but improvements outside of biomarker selected therapies have been limited. There remains a pressing need for more effective treatment options that can prolong survival and enhance the quality of life of patients with EOC. In contrast to the significant benefits of immunotherapy with immune checkpoint inhibitors (CPI) seen in many solid tumors, initial experience in EOC suggests limited efficacy of CPIs monotherapy. Methods A systematic review of phase III studies testing the role of CPIs in ovarian cancer was performed. Results Seven randomized trials testing CPIs in newly diagnosed (n = 3) and recurrent (n = 4) EOC are evaluated. Overall, those trials included data of 5671 patients. Single-agent PD-L1 inhibitor trials have not shown significant efficacy in newly diagnosed ovarian cancer. Triplet maintenance with bevacizumab plus olaparib and durvalumab is associated with longer progression-free survival than maintenance with bevacizumab alone in patients without tumor BRCA mutations. CPIs were not effective in platinum-sensitive (n = 1031) and platinum-resistant (n = 1420) EOC. Conclusions The value of adding CPI to standard treatment including poly (ADP-ribose) polymerase (PARP) inhibitors with or without bevacizumab remains unclear and is being addressed in ongoing clinical trials. The combination of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors may enhance the efficacy of immunotherapy in EOC and studies are underway to investigate the combination of CPI with other emerging treatment modalities.PROSPERO registration ID: CRD42024536017.

(Abstracted from Lancet 2024;404:1525–1535) Cervical cancer is the cause of 350,000 global deaths annually as of 2022, and prevalence remains around 660,000 new cases a year. High-income countries have decreased incidence due to the implementation of screening and vaccinations, but cervical cancer remains the most common cancer in 23 countries and the leading cancer to cause death in 36 countries.

More than half of all gynecological cancers are classified as rare (annual incidence <6 per 100,000), and present significant challenges in diagnosis, management, and research. Rare cancers collectively comprise more than 20% of new cancer diagnoses and exceed the burden of individual common cancers. Their rarity complicates evidence-based guideline development, clinical trial design, and drug access, and is exacerbated by variations in epidemiology, histology, and biological behavior. Key controversies include the need for centralized pathological reviews and harmonized diagnostic criteria. Recent World Health Organization classification updates, such as the redefinition of ovarian and fallopian tube cancers, illustrate the impact of evolving guidelines on epidemiology and patient management. Variations in the classification among pathologists and limited access to molecular diagnostics further hinder effective management. Multidisciplinary care in expert centers improves outcomes; however, significant geographic and resource disparities persist. National and international collaborations including European Reference Network for rare adult solid tumors, Gynecologic Cancer Intergroup, Gynecologic Oncology Group, Asia-Pacific Gynecologic Oncology Trials Group, and European Network for Gynaecological Oncology Trials have made strides in standardizing care and advancing research. Novel trial designs, such as basket and umbrella trials, alongside synthetic control arms, are essential for addressing the small sample sizes typical of rare tumors. Emerging consortia, such as International Ovarian Tumor Tissue Analysis Consortium and International Consortium for Low-grade Serous Ovarian Cancer, provide robust platforms for translational research and biomarker validation. However, challenges remain in fostering cross-border collaboration, streamlining regulatory pathways, and ensuring equitable access to trials and therapy. To optimize outcomes, a comprehensive approach that integrates centralized care, innovative trial designs, and international networks is imperative. This paradigm fosters the harmonization of care, accelerates translational research, and bridges the gap between scientific innovation and patient benefits.

This systematic review and meta-analysis investigates the association of first-line poly(adenosine diphosphate-ribose) polymerase inhibitor (PARP inhibitor) maintenance therapy with efficacy and safety outcomes among patients with advanced-stage epithelial ovarian cancer. QuestionWhat is the association of first-line poly(adenosine diphosphate-ribose) polymerase inhibitor (PARP inhibitor) maintenance therapy with survival outcomes in epithelial ovarian cancer, and how do outcomes vary across regimens and subgroups?FindingsIn this meta-analysis of 7 randomized clinical trials among 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy, progression-free survival improved in most subgroups but not in homologous recombination-proficient tumors, and no subgroup demonstrated a statistically significant overall survival benefit. Efficacy and toxic effects varied across agents.MeaningThis study found that first-line PARP inhibitor maintenance therapy was associated with a progression-free survival benefit in many patient populations; however, the lack of overall survival benefit, increased toxic effects, and variability across subgroups and regimens, suggest that treatment should be individualized. ImportanceFirst-line maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) after platinum-based chemotherapy improves progression-free survival (PFS) in advanced epithelial ovarian cancer (EOC), particularly in patients with BRCA-variant or homologous recombination-deficient tumors. However, overall survival (OS) benefits remain uncertain, and toxic effect profiles emphasize the need for optimized patient and agent selection.ObjectiveTo evaluate the efficacy and safety of first-line PARP inhibitor maintenance therapy compared with chemotherapy alone in advanced-stage EOC, with subgroup analyses by BRCA and HRD status, up-front or interval surgery, chemotherapy response, and residual disease.Data sourcesMedline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to August 19, 2024.Study SelectionRandomized clinical trials and prospective 2-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage EOC responding to first-line platinum-based chemotherapy were included.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed in reporting this study. Data were independently extracted by 2 reviewers. Random-effects models were used for meta-analysis. Risk of bias was assessed with Cochrane risk of bias and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.Main Outcomes and MeasuresPrimary outcomes were PFS and OS; secondary outcomes included high-grade adverse events.ResultsA total of 7 randomized clinical trials with 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy were included. PARP inhibitor maintenance was associated with improved PFS in the overall population (hazard ratio [HR], 0.57; 95% CI, 0.46-0.70; high certainty) and in all molecular subgroups except the homologous recombination proficient group (BRCA variant: HR, 0.40; 95% CI, 0.35-0.45; BRCA wild type: HR, 0.62; 95% CI, 0.44-0.86; homologous recombination deficient: HR, 0.44; 95% CI, 0.39-0.50; all high certainty). PFS benefits were consistent across surgical timing, chemotherapy responses, and residual disease; for example, surgical timing had HRs of 0.51 (95% CI, 0.31-0.84) for neoadjuvant chemotherapy and 0.54 (95% CI, 0.36-0.81) for primary cytoreductive surgery (all high certainty). No molecular subgroup showed a statistically significant OS improvement (high to low certainty). High-grade adverse events were more common in the PARP inhibitor group (HR, 2.40; 95% CI, 1.16-4.93; high certainty). Observed treatment efficacy and toxic effects varied across PARP inhibitor regimens; for example, the risk ratio for any recurrence or death in the overall study group ranged from 0.53 (95% CI, 0.40-0.70) for senaparib to 0.83 (95% CI, 0.68-1.00) for olaparib, while the risk ratio for high-grade adverse events ranged from 1.15 (95% CI, 0.64-2.06) for veliparib to 4.73 (95% CI, 2.77-8.07) for niraparib.Conclusions and RelevanceIn this study, no subgroup showed an association between first-line PARP inhibitor maintenance therapy in advanced-stage EOC and improved OS, and findings suggest that the consistency of associated PFS benefits may vary, particularly in homologous recombination proficient and BRCA wild type tumors. Variability in efficacy and toxic effects across subgroups and PARP inhibitor regimens underscores the importance of individualized treatment decisions.

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have significantly improved the treatment of advanced ovarian cancer, however, there are still many aspects of their use that require further understanding. The optimal duration, timing and dosage of these agents and how to manage (oligo) progression occurring both during and following PARPi therapy are discussed. The evidence supporting their rechallenge, and how to overcome resistance are addressed. The long-term impacts of PARPi and monitoring patients during therapy are all important research themes to expand on.

OBJECTIVE:To evaluate secondary efficacy endpoints and safety for the ENGOT-OV16/NOVA (NCT01847274) trial of niraparib maintenance therapy after extended follow-up and vital-status-data retrieval. Previously reported analyses (data cutoff, October 1, 2020) indicated benefit of niraparib maintenance therapy beyond first progression, but overall survival (OS) analyses were limited by missing data. METHODS:Patients were randomized 2:1 to niraparib (300 mg once daily) or placebo. A vital status check was extended to retrieve last-known-alive status for patients with missing survival data. Prespecified secondary efficacy outcomes (OS, chemotherapy-free interval [CFI], time to first subsequent therapy [TFST], PFS2, time to second subsequent therapy [TSST]) and safety are reported based on the extended data cutoff (March 31, 2021). RESULTS:Survival status was available for 97.6% (540/553) of randomized patients (germline BRCA [gBRCA]-mutated, 203; non-gBRCA-mutated, 350). Median OS with niraparib and placebo was 40.9 and 38.1 months, respectively, in the gBRCA-mutated cohort (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.20) and 31.0 and 34.8 months, respectively, in the non-gBRCA-mutated cohort (HR, 1.06; 95% CI, 0.81-1.37). Medians for CFI, TFST, PFS2, and TSST numerically favored niraparib in both cohorts. No new safety signals were detected. CONCLUSIONS:OS did not significantly differ between treatment arms. Prespecified secondary efficacy endpoints numerically favored niraparib. Long-term safety remained consistent with the established niraparib safety profile. Taken together with the significant improvements in PFS observed in the primary analysis, these data support a favorable overall benefit-risk profile for niraparib in the recurrent OC maintenance setting.

Importance:First-line maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) after platinum-based chemotherapy improves progression-free survival (PFS) in advanced epithelial ovarian cancer (EOC), particularly in patients with BRCA-variant or homologous recombination-deficient tumors. However, overall survival (OS) benefits remain uncertain, and toxic effect profiles emphasize the need for optimized patient and agent selection. Objective:To evaluate the efficacy and safety of first-line PARP inhibitor maintenance therapy compared with chemotherapy alone in advanced-stage EOC, with subgroup analyses by BRCA and HRD status, up-front or interval surgery, chemotherapy response, and residual disease. Data sources:Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to August 19, 2024. Study Selection:Randomized clinical trials and prospective 2-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage EOC responding to first-line platinum-based chemotherapy were included. Data Extraction and Synthesis:The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed in reporting this study. Data were independently extracted by 2 reviewers. Random-effects models were used for meta-analysis. Risk of bias was assessed with Cochrane risk of bias and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Main Outcomes and Measures:Primary outcomes were PFS and OS; secondary outcomes included high-grade adverse events. Results:A total of 7 randomized clinical trials with 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy were included. PARP inhibitor maintenance was associated with improved PFS in the overall population (hazard ratio [HR], 0.57; 95% CI, 0.46-0.70; high certainty) and in all molecular subgroups except the homologous recombination proficient group (BRCA variant: HR, 0.40; 95% CI, 0.35-0.45; BRCA wild type: HR, 0.62; 95% CI, 0.44-0.86; homologous recombination deficient: HR, 0.44; 95% CI, 0.39-0.50; all high certainty). PFS benefits were consistent across surgical timing, chemotherapy responses, and residual disease; for example, surgical timing had HRs of 0.51 (95% CI, 0.31-0.84) for neoadjuvant chemotherapy and 0.54 (95% CI, 0.36-0.81) for primary cytoreductive surgery (all high certainty). No molecular subgroup showed a statistically significant OS improvement (high to low certainty). High-grade adverse events were more common in the PARP inhibitor group (HR, 2.40; 95% CI, 1.16-4.93; high certainty). Observed treatment efficacy and toxic effects varied across PARP inhibitor regimens; for example, the risk ratio for any recurrence or death in the overall study group ranged from 0.53 (95% CI, 0.40-0.70) for senaparib to 0.83 (95% CI, 0.68-1.00) for olaparib, while the risk ratio for high-grade adverse events ranged from 1.15 (95% CI, 0.64-2.06) for veliparib to 4.73 (95% CI, 2.77-8.07) for niraparib. Conclusions and Relevance:In this study, no subgroup showed an association between first-line PARP inhibitor maintenance therapy in advanced-stage EOC and improved OS, and findings suggest that the consistency of associated PFS benefits may vary, particularly in homologous recombination proficient and BRCA wild type tumors. Variability in efficacy and toxic effects across subgroups and PARP inhibitor regimens underscores the importance of individualized treatment decisions.

OBJECTIVE:Maintenance olaparib demonstrated clinical activity for progression-free survival in patients without a germline BRCA1 and/or BRCA2 mutation (non-gBRCAm) who had platinum-sensitive relapsed ovarian cancer in the phase IIIb, open-label, single-arm, non-comparator, international OPINION trial (NCT03402841). We report final overall survival (OS; secondary endpoint), prespecified secondary endpoint updates and ad hoc OS analysis by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. METHODS:Patients with non-gBRCAm platinum-sensitive relapsed ovarian cancer, ≥2 prior lines of platinum-based chemotherapy, and in response following their last platinum-based chemotherapy received 300 mg olaparib tablets twice daily until disease progression or unacceptable toxicity. RESULTS:279 patients were enrolled and treated. With a median follow-up in patients censored for OS of 33.1 months (data cut-off September 17, 2021), median OS was 32.7 months (95 % CI 29.5-35.3); the 24-month OS rate was 65.8 %. In ad hoc subgroup analyses, OS rates tended to be higher in patients with HRD-positive tumors; 24-month OS rates were 81.5 %, 74.2 %, 72.0 % and 55.8 % in the sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative subgroups, respectively. Grade ≥ 3 treatment-emergent adverse events were reported in 82 patients (29.4 %), most commonly anemia (13.6 %). Overall, two cases of myelodysplastic syndrome were reported (no new cases since the primary analysis). CONCLUSION:These data provide additional evidence of olaparib as maintenance therapy in patients with non-gBRCAm platinum-sensitive relapsed ovarian cancer, with longer OS observed in those with HRD-positive tumors. The safety profile was consistent with the primary analysis and known safety profile of olaparib, with no new safety findings.

ObjectiveUnderrepresentation of elderly ovarian cancer patients in clinical trials has led to lack of clarity regarding optimal first-line chemotherapy in this cohort. The Elderly Women with Ovarian Cancer (EWOC)-1 trial demonstrated that 3-weekly carboplatin (3wC) resulted in worse survival and feasibility compared with standard 3-weekly carboplatin-paclitaxel (3wCP) in frail, elderly ovarian cancer patients. Our retrospective study compares feasibility, safety, and efficacy of first-line 3wCP and 3wC in a frail ovarian cancer cohort.MethodsClinical data were retrospectively analyzed for newly-diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV, ≥70-year-old epithelial ovarian cancer patients, treated by clinician choice with 3wC or 3wCP at two London cancer centers over a 2 year period. Charlson Comorbidity Index (CCI) and Eastern Cooperative Oncology Group (ECOG) performance status provided surrogate markers of frailty. Common Terminology Criteria for Adverse Events v5.0 graded toxicity.ResultsA total of 107 patients were treated with 3wC (n=30) and 3wCP (n=77). Age, performance status, and CCI were significantly different between cohorts, with 3wC patients older (84 vs 75 years, p<0.001), with more comorbidities (median CCI 4 vs 3, p<0.001) and worse performance status (47% vs 17% PS ≥2, p=0.015). Surgical outcomes differed significantly between cohorts, with 20 (67%) 3wC patients not undergoing surgery, compared with 22 (29%) 3wCP patients (p<0.001). Median follow-up was 45.8 months (IQR 38.7–56.3 months). While we observed improved progression-free (HR 0.55, 95% CI 0.33 to 0.90, p=0.017) and overall survival (HR 0.44, 95% CI 0.27 to 0.73, p=0.001, log-rank test) in a univariate cox proportional hazards comparison between 3wCP and 3wC, this was not significant on multivariate analysis. Completion of six planned chemotherapy cycles was achieved by the majority, with similar discontinuation rates between groups (13% 3wC vs 8% 3wCP, p>0.05). Overall grade ≥3 hematological toxicity rates were similar between regimens (33% 3wC vs 44% 3wCP, p=0.37) with grade ≥3 neutropenia (p=0.019) and grade ≥3 thrombocytopenia (p=0.006) more common with 3wCP and 3wC, respectively. No treatment-related deaths occurred.ConclusionOur data demonstrates that standard 3wCP is a well-tolerated, feasible first-line treatment for frail, elderly ovarian cancer patients. Improved survival with 3wCP was not significant when corrected for established clinical prognostic factors.

BACKGROUND:In ARIEL3, rucaparib maintenance significantly improved progression-free survival (PFS; primary endpoint) and long-term follow-up (LTFU) outcomes (including PFS2: time to disease progression on subsequent therapy or death) versus placebo in patients with recurrent, platinum-sensitive ovarian cancer. Here we report the final analysis of overall survival (OS; key secondary endpoint), LTFU outcomes, and safety. METHODS:OS and updated LTFU efficacy outcomes were analyzed (data cutoff date: April 4, 2022) across three nested populations (BRCA-mutated, homologous recombination deficient [HRD], and intention to treat [ITT]). RESULTS:Patients were randomized 2:1 to rucaparib (600 mg BID; n = 375) or placebo (n = 189). Median follow-up was 77.0 months. 168 patients in the placebo arm received subsequent treatment; of these, 77 (46 %) received a poly(ADP-ribose) polymerase inhibitor-containing treatment. Median OS from randomization post chemotherapy for rucaparib vs placebo was 45.9 vs 47.8 months (HR 0.83, 95 % CI 0.58-1.19) for the BRCA-mutated population; no OS benefit was found with rucaparib in the HRD and ITT populations. Median PFS2 for rucaparib vs placebo was 26.1 vs 18.4 months (HR 0.67, 95 % CI 0.48-0.94) for the BRCA-mutated population. Rucaparib numerically improved PFS2 and other LTFU outcomes versus placebo in the HRD and ITT populations. Safety was consistent with prior reports; myelodysplastic syndrome and/or acute myeloid leukemia occurred in 4 % and 3 % of patients in the rucaparib and placebo arms, respectively. CONCLUSIONS:OS was similar between treatment arms. PFS benefit with rucaparib was maintained through the subsequent therapy line. These data support rucaparib as maintenance treatment for recurrent ovarian carcinoma.

OBJECTIVE:To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS). METHODS:We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially‑platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS. RESULTS:The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001). CONCLUSION:Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control.

Background Immunotherapy directed at 5T4 tumor antigen may delay the need for further chemotherapy. An attenuated modified vaccinia Ankara virus containing the gene encoding for 5T4 (MVA-5T4) was studied in asymptomatic relapsed ovarian cancer.Objective To assess the effectiveness and safety of MVA-5T4 as treatment for asymptomatic relapsed ovarian cancer.Methods TRIOC was a phase II randomized (1:1), placebo-controlled, double-blind multicenter study. The primary aim was to assess the effectiveness and safety of MVA-5T4 as a treatment for asymptomatic patients with relapsed ovarian cancer. Eligible patients had International Federation of Gynecology and Obstetrics (FIGO) stage IC1-III or IVA epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, Eastern Cooperative Oncology Group (ECOG) 0-1, with relapse defined by a rise in CA-125 to twice the upper limit of normal or low-volume disease on CT scan. The primary endpoint was disease progression (including deaths from ovarian cancer) at 25 weeks. Following a brief suspension, the trial restarted as a single-arm study. The revised single-arm design required 45 evaluable patients treated with MVA-5T4 to detect a 25-week progression rate of 50%, assuming an expected 70% rate without MVA-5T4; 85% power with one-sided 5% significance.Results A total of 94 eligible patients were recruited, median age was 65 years (range 42-82), median follow-up 34 months (range 2-46). Overall, 59 patients received MVA-5T4 and 35 patients received placebo. The median number of MVA-5T4 injections received was 7 (range 0-9), compared with a median of 6 (range 1-12) for patients receiving placebo. Median progression-free survival was the same in both arms (3.0 months). The 25-week progression rate was similar in both arms: 80.0% for patients treated with MVA-5T4 and 85.7% for those receiving placebo (risk difference -5.7%, 95% CI -21.4% to 10.0%). Median time to clinical intervention was improved with MVA-5T4: 7.6 months (range 6.7-9.5) vs 5.6 (range 4.9-7.6),Conclusion MVA-5T4 vaccination in patients with asymptomatic relapse was well-tolerated but did not improve the progression rate at 25 weeks. The majority of patients who received MVA-5T4 had clinical intervention later than those assigned to placebo.Trial registration number NCT01556841.

Introduction/Background We compared outcomes between patients with stage IIIC ovarian cancer and different patterns of metastases in stage IV disease following cytoreductive surgery. Methodology We conducted a single-centre retrospective cohort study of all patients diagnosed with FIGO stage IIIC, IVA, IVBi (extra-abdominal lymphatic metastases) and IVBii (parenchymal metastases), who underwent Primary Cytoreductive Surgery (PCS) or Interval Cytoreductive Surgery (ICS) at University College London Hospital between 2006–2019. Patients with low grade or non-epithelial histologies were excluded. Disease stage, timing of surgery, cytoreduction completeness, age, Charlson Comorbidity Index and modified-Aletti surgical complexity score were investigated in multivariable analyses. Results 415 patients were identified for inclusion, 245 (59.0%) had stage IIIC disease, 66 (15.9%) IVA, 56 (13.5%) IVBi and 48 (11.6%) IVBii. The majority (92.0%) had high grade serous histology. Overall, 283 (68.2%) underwent ICS and 132 (31.8%) PCS; complete cytoreduction was achieved in 287 (69.3%) patients. After 7.0 years median follow-up, median recurrence-free survival (RFS) was 12.0 months (95%CI:10.8–13.1) and median overall survival (OS) was 42.0 months (95%CI:38.0–45.9). Overall, there was no evidence of an association between disease stage and RFS (p=0.40) nor OS (p=0.20). PCS was independently associated with longer RFS (HR=0.48, 95%CI:0.37–0.62, p<0.001) and OS (HR=0.55, 95%CI:0.41–0.73, p<0.001). Patients with optimal and suboptimal resection had shorter RFS [HR=1.60 (95%CI:1.20–2.13, p<0.01] and HR=1.37 (95%CI:1.00–1.87, p=0.05) respectively) and OS [HR=1.56 (95%CI:1.17–2.09, p<0.01) and HR=1.38 (95%CI:0.99–1.92, p=0.06) respectively], compared to those with complete cytoreduction. Patients with higher surgical complexity score had shorter RFS (HR=1.07, 95%CI:1.02–1.12, p<0.01) and OS (HR=1.09, 95%CI:1.04–1.14, p<0.001). Conclusion Similar RFS and OS were observed in stages IIIC, IVA and IVB epithelial tubo-ovarian cancer. However, timing of surgery, surgical complexity and completeness of cytoreduction were independently associated with outcomes. These data suggest that primary cytoreductive surgery should be considered for stage IV disease where complete intra-abdominal cytoreduction can be achieved. Disclosures COI form submitted for two authors.

Abstract Background The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability. Patients and methods Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors. Results BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29–58]) and non-HRRm (n = 1005; median 32 [IQR 20–55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41–58]), RAD51C (median 58 [IQR 48–66]), RAD51D (median 62 [IQR 54–69]), and PALB2 (median 64 [IQR 58–74]), and non-HRR genes NF1 (median 49 [IQR 25–60]) and RB1 (median 55 [IQR 30–71]). CCNE1-amplified and PIK3CA-mutated tumors had low GIS (CCNE1-amplified: median 24 [IQR 18–29]; PIK3CA-mutated: median 32 [IQR 14–52]) and were predominantly non-BRCAm. Conclusions These analyses provide valuable insight into patterns of genomic instability and potential drivers of HRD, besides BRCAm, in ovarian cancer and will help guide future research into the potential clinical effectiveness of anti-cancer treatments in ovarian cancer, including PARP inhibitors as well as other precision oncology agents. Trial registration The SOLO1 trial was registered at ClinicalTrials.gov (NCT01844986) on April 30, 2013; the PAOLA-1 trial was registered at ClinicalTrials.gov (NCT02477644) on June 18, 2015 (retrospectively registered); Study 19 was registered at ClinicalTrials.gov (NCT00753545) on September 12, 2008 (retrospectively registered); the SOLO2 trial was registered at ClinicalTrials.gov (NCT01874353) on June 7, 2013; the OPINION trial was registered at ClinicalTrials.gov (NCT03402841) on January 3, 2018; the LIGHT trial was registered at ClinicalTrials.gov (NCT02983799) on November 4, 2016.