What's going well: a qualitative analysis of positive patient and family feedback in the context of the diagnostic process.

OBJECTIVES: Accurate and timely diagnosis relies on close collaboration between patients/families and clinicians. Just as patients have unique insights into diagnostic breakdowns, positive patient feedback may also generate broader perspectives on what constitutes a "good" diagnostic process (DxP). METHODS: We evaluated patient/family feedback on "what's going well" as part of an online pre-visit survey designed to engage patients/families in the DxP. Patients/families living with chronic conditions with visits in three urban pediatric subspecialty clinics (site 1) and one rural adult primary care clinic (site 2) were invited to complete the survey between December 2020 and March 2022. We adapted the Healthcare Complaints Analysis Tool (HCAT) to conduct a qualitative analysis on a subset of patient/family responses with ≥20 words. RESULTS: In total, 7,075 surveys were completed before 18,129 visits (39 %) at site 1, and 460 surveys were completed prior to 706 (65 %) visits at site 2. Of all participants, 1,578 volunteered positive feedback, ranging from 1-79 words. Qualitative analysis of 272 comments with ≥20 words described: Relationships (60 %), Clinical Care (36 %), and Environment (4 %). Compared to primary care, subspecialty comments showed the same overall rankings. Within Relationships, patients/families most commonly noted: thorough and competent attention (46 %), clear communication and listening (41 %) and emotional support and human connection (39 %). Within Clinical Care, patients highlighted: timeliness (31 %), effective clinical management (30 %), and coordination of care (25 %). CONCLUSIONS: Patients/families valued relationships with clinicians above all else in the DxP, emphasizing the importance of supporting clinicians to nurture effective relationships and relationship-centered care in the DxP.

Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial.

PURPOSE: In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS: This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS: The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION: Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

Fast acrobatic maneuvers enable arboreal spiders to hunt dangerous prey.

Spiders, the most specious taxon of predators, have evolved an astounding range of predatory strategies, including group hunting, specialized silk traps, pheromone-loaded bolas, and aggressive mimicry. Spiders that hunt prey defended with behavioral, mechanical, or chemical means are under additional selection pressure to avoid injury and death. Ants are considered dangerous because they can harm or kill their predators, but some groups of spiders, such as the Theridiidae, have a very high diversification of ant-hunting species and strategies [J. Liu et al., Mol. Phylogenet. Evol. 94, 658-675 (2016)]. Here, we provide detailed behavioral analyses of the highly acrobatic Australian ant-slayer spider, Euryopis umbilicata (Theridiidae), that captures much larger and defended Camponotus ants on vertical tree trunks. The hunting sequence consists of ritualized steps performed within split seconds, resulting in an exceptionally high prey capture success rate.

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial.

PURPOSE: The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer. PATIENTS AND METHODS: PARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined. RESULTS: Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group. CONCLUSIONS: Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.

The global spread of misinformation on spiders.

In the internet era, the digital architecture that keeps us connected and informed may also amplify the spread of misinformation. This problem is gaining global attention, as evidence accumulates that misinformation may interfere with democratic processes and undermine collective responses to environmental and health crises1,2. In an increasingly polluted information ecosystem, understanding the factors underlying the generation and spread of misinformation is becoming a pressing scientific and societal challenge3. Here, we studied the global spread of (mis-)information on spiders using a high-resolution global database of online newspaper articles on spider-human interactions, covering stories of spider-human encounters and biting events published from 2010-20204. We found that 47% of articles contained errors and 43% were sensationalist. Moreover, we show that the flow of spider-related news occurs within a highly interconnected global network and provide evidence that sensationalism is a key factor underlying the spread of misinformation.

AnimalTraits - a curated animal trait database for body mass, metabolic rate and brain size.

Trait databases have become important resources for large-scale comparative studies in ecology and evolution. Here we introduce the AnimalTraits database, a curated database of body mass, metabolic rate and brain size, in standardised units, for terrestrial animals. The database has broad taxonomic breadth, including tetrapods, arthropods, molluscs and annelids from almost 2000 species and 1000 genera. All data recorded in the database are sourced from their original empirical publication, and the original metrics and measurements are included with each record. This allows for subsequent data transformations as required. We have included rich metadata to allow users to filter the dataset. The additional R scripts we provide will assist researchers with aggregating standardised observations into species-level trait values. Our goals are to provide this resource without restrictions, to keep the AnimalTraits database current, and to grow the number of relevant traits in the future.

An expert-curated global database of online newspaper articles on spiders and spider bites.

Mass media plays an important role in the construction and circulation of risk perception associated with animals. Widely feared groups such as spiders frequently end up in the spotlight of traditional and social media. We compiled an expert-curated global database on the online newspaper coverage of human-spider encounters over the past ten years (2010-2020). This database includes information about the location of each human-spider encounter reported in the news article and a quantitative characterisation of the content-location, presence of photographs of spiders and bites, number and type of errors, consultation of experts, and a subjective assessment of sensationalism. In total, we collected 5348 unique news articles from 81 countries in 40 languages. The database refers to 211 identified and unidentified spider species and 2644 unique human-spider encounters (1121 bites and 147 as deadly bites). To facilitate data reuse, we explain the main caveats that need to be made when analysing this database and discuss research ideas and questions that can be explored with it.

Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study.

BACKGROUND: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest. METHODS: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed. RESULTS: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05). CONCLUSIONS: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

Supporting urban ecosystem services across terrestrial, marine and freshwater realms.

The terrestrial, freshwater and marine realms all provide essential ecosystem services in urban environments. However, the services provided by each realm are often considered independently, which ignores the synergies between them and risks underestimating the benefits derived collectively. Greater research collaboration across these realms, and an integrated approach to management decisions can help to support urban developments and restoration projects in maintaining or enhancing ecosystem services. The aim of this paper is to highlight the synergies and trade-offs among ecosystem services provided by each realm and to offer suggestions on how to improve current practice. We use case studies to illustrate the flow of services across realms. In our call to better integrate research and management across realms, we present a framework that provides a 6-step process for conducting collaborative research and management with an Australian perspective. Our framework considers unifying language, sharing, and understanding of desired outcomes, conducting cost-benefit analyses to minimise trade-offs, using multiple modes of communication for stakeholders, and applying research outcomes to inform regulation. It can be applied to improve collaboration among researchers, managers and planners from all realms, leading to strategic allocation of resources, increased protection of urban natural resources and improved environmental regulation with broad public support.

Filling a gap in safety metrics: development of a patient-centred framework to identify and categorise patient-reported breakdowns related to the diagnostic process in ambulatory care.

BACKGROUND: Patients and families are important contributors to the diagnostic team, but their perspectives are not reflected in current diagnostic measures. Patients/families can identify some breakdowns in the diagnostic process beyond the clinician's view. We aimed to develop a framework with patients/families to help organisations identify and categorise patient-reported diagnostic process-related breakdowns (PRDBs) to inform organisational learning. METHOD: A multi-stakeholder advisory group including patients, families, clinicians, and experts in diagnostic error, patient engagement and safety, and user-centred design, co-developed a framework for PRDBs in ambulatory care. We tested the framework using standard qualitative analysis methods with two physicians and one patient coder, analysing 2165 patient-reported ambulatory errors in two large surveys representing 25 425 US respondents. We tested intercoder reliability of breakdown categorisation using the Gwet's AC1 and Cohen's kappa statistic. We considered agreement coefficients 0.61-0.8=good agreement and 0.81-1.00=excellent agreement. RESULTS: The framework describes 7 patient-reported breakdown categories (with 40 subcategories), 19 patient-identified contributing factors and 11 potential patient-reported impacts. Patients identified breakdowns in each step of the diagnostic process, including missing or inaccurate main concerns and symptoms; missing/outdated test results; and communication breakdowns such as not feeling heard or misalignment between patient and provider about symptoms, events, or their significance. The frequency of PRDBs was 6.4% in one dataset and 6.9% in the other. Intercoder reliability showed good-to-excellent reliability in each dataset: AC1 0.89 (95% CI 0.89 to 0.90) to 0.96 (95% CI 0.95 to 0.97); kappa 0.64 (95% CI 0.62, to 0.66) to 0.85 (95% CI 0.83 to 0.88). CONCLUSIONS: The PRDB framework, developed in partnership with patients/families, can help organisations identify and reliably categorise PRDBs, including some that are invisible to clinicians; guide interventions to engage patients and families as diagnostic partners; and inform whole organisational learning.

The World Spider Trait database: a centralized global open repository for curated data on spider traits.

Spiders are a highly diversified group of arthropods and play an important role in terrestrial ecosystems as ubiquitous predators, which makes them a suitable group to test a variety of eco-evolutionary hypotheses. For this purpose, knowledge of a diverse range of species traits is required. Until now, data on spider traits have been scattered across thousands of publications produced for over two centuries and written in diverse languages. To facilitate access to such data, we developed an online database for archiving and accessing spider traits at a global scale. The database has been designed to accommodate a great variety of traits (e.g. ecological, behavioural and morphological) measured at individual, species or higher taxonomic levels. Records are accompanied by extensive metadata (e.g. location and method). The database is curated by an expert team, regularly updated and open to any user. A future goal of the growing database is to include all published and unpublished data on spider traits provided by experts worldwide and to facilitate broad cross-taxon assays in functional ecology and comparative biology. Database URL:https://spidertraits.sci.muni.cz/.

Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up. METHODS: SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants. FINDINGS: Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2-24·9) in the olaparib group and 13·9 months (8·0-24·8) in the placebo group; median follow-up was 4·8 years (2·8-5·3) in the olaparib group and 5·0 years (2·6-5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9-not reached) with olaparib versus 13·8 months (11·1-18·2) with placebo (hazard ratio 0·33 [95% CI 0·25-0·43]). The most common grade 3-4 adverse events were anaemia (57 [22%] of 260 patients receiving olaparib vs two [2%] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period. INTERPRETATION: For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting. FUNDING: AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial.

OBJECTIVES: In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. METHODS: Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). RESULTS: Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily. CONCLUSIONS: Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients.

Cover Crop Soil Legacies Alter Phytochemistry and Resistance to Fall Armyworm (Lepidoptera: Noctuidae) in Maize.

Plant-soil feedbacks can mediate aboveground plant-herbivore interactions by impacting plant chemistry. Given that soil legacies and agricultural practices are closely tied, a better understanding of soil legacy cascades and their application in pest management are needed. We tested how cover crop legacies alter resistance to fall armyworm (Spodoptera frugiperda Smith, Lepidoptera: Noctuidae) in maize (Zea mays L., Poales: Poaceae). We compared herbivore performance and behavior of fall armyworm larvae on maize grown after four cover crop treatments: a leguminous mycorrhizal cover crop (pea: Pisum sativum L., Fabales: Fabaceae), a nonleguminous mycorrhizal cover crop (triticale: x Triticosecale Wittm. Ex A. Camus, Poales: Poaceae), a nonleguminous nonmycorrhizal cover crop (radish: Raphanus sativus L., Brassicales: Brassicaceae), and no cover crops (fallow). Soil inorganic N was highest in pea treatments and lowest in triticale treatments, while maize AMF colonization was greatest when grown after mycorrhizal cover crops compared to nonmycorrhizal or no cover crops. Cover crop legacies altered the emission of maize volatiles and fall armyworm larvae oriented toward odors emitted by maize grown after radish more frequently than triticale in olfactometer assays. Additionally, larvae performed better and consumed more leaf tissue when feeding on maize grown after radish and poorest on plants grown after triticale. When damaged by fall armyworm, maize grown after triticale expressed higher levels of lipoxygenase-3 (lox3), while plants grown after radish upregulated maize proteinase inhibitor (mpi) gene expression. Our results highlight the importance of appropriate cover crop selection and suggest that triticale could strengthen maize resistance to fall armyworm.

Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial.

BACKGROUND: In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. METHODS: SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. FINDINGS: Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. INTERPRETATION: The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. FUNDING: AstraZeneca and Merck Sharp & Dohme.

Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial.

PURPOSE: In SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed BRCA1- and/or BRCA2-mutated advanced ovarian cancer compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; median not reached v 13.8 months). We investigated PFS in SOLO1 for subgroups of patients based on preselected baseline factors. PATIENTS AND METHODS: Investigator-assessed PFS subgroup analyses of SOLO1 included clinical response after platinum-based chemotherapy (complete [CR] or partial response [PR]), surgery type (upfront or interval surgery), disease status after surgery (residual or no gross residual disease), and BRCA mutation status (BRCA1 or BRCA2). Additionally, we evaluated PFS in patients with stage III disease who underwent upfront surgery and had no gross residual disease. We also report objective response rate. RESULTS: The risk of disease progression or death was reduced with olaparib compared with placebo by 69% (HR, 0.31; 95% CI, 0.21 to 0.46) and 63% (HR, 0.37; 95% CI, 0.24 to 0.58) in patients undergoing upfront or interval surgery; 56% (HR, 0.44; 95% CI, 0.25 to 0.77) and 67% (HR, 0.33; 95% CI, 0.23 to 0.46) in patients with residual or no residual disease after surgery; 66% (HR, 0.34; 95% CI, 0.24 to 0.47) and 69% in women with clinical CR or PR at baseline (HR, 0.31; 95% CI, 0.18 to 0.52); and 59% (HR, 0.41; 95% CI, 0.30 to 0.56) and 80% (HR 0.20; 95% CI, 0.10 to 0.37) in patients with a BRCA1 or BRCA2 mutation, respectively. CONCLUSION: Patients with newly diagnosed advanced ovarian cancer achieve substantial benefit from maintenance olaparib treatment regardless of baseline surgery outcome, response to chemotherapy, or BRCA mutation type.

Author Correction: A global database for metacommunity ecology, integrating species, traits, environment and space.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.