Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer.

BACKGROUND: OCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC). AIMS: The main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC). METHODS: In total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power). RESULTS: The majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm. DISCUSSION: OCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option. TRIAL REGISTRATION: ISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018 .

Comparative gene co-expression networks show enrichment of brassinosteroid and vitamin B processes in a seagrass under simulated ocean warming and extreme climatic events.

Introduction: Ocean warming combined with extreme climatic events, such as marine heatwaves and flash flooding events, threaten seagrasses globally. How seagrasses cope with these challenges is uncertain, particularly for range-edge populations of species such as Posidonia australis in Shark Bay, Western Australia. Analyzing gene expression while manipulating multiple stressors provides insight into the genetic response and resilience of seagrasses to climate change. We conducted a gene expression study on a polyploid clone of P. australis during an 18-week mesocosm experiment to assess the responses to single and combined future climate change-associated stressors. Methods: Plants were exposed to (1) future ocean warming temperature (baseline +1.5°C) followed by a simulated marine heat wave (baseline +5.5°C), (2) light deprivation simulating observed marine heatwave driven turbidity (95% shade) at baseline temperatures, or (3) both stressors simultaneously. Basal leaf meristems were sampled for gene expression analysis using RNA-seq at four time points during the experiment. Weighted gene co-expression network analysis, GO term enrichment, and KEGG pathway enrichment analyses were used to identify stress responses. Results: Shaded plants showed specific gene enrichment for shade avoidance (programmed cell death) after three weeks of stress, and before any heated tanks showed a specific heat response. Shaded plants were positively correlated with programmed cell death and stress-related processes at the end of the experiment. Once ocean warming temperatures (+1.5°C) were in effect, gene enrichment for heat stress (e.g., ROS scavenging and polyamine metabolism) was present. Vitamin B processes, RNA polymerase II processes. and light-related meristematic phase changes were expressed with the addition of simulated MHW. Heated plants showed meristematic growth signatures as well as trehalose and salicylic acid metabolism. Brassinosteroid-related processes were significantly enriched in all stressor treatments at all time points, except for the isolated heat-stressed plants three weeks after stressor initiation. Discussion: Gene expression responses to the interaction between heat waves and turbidity-induced light reduction support the observed geographical scale mortality in seagrasses observed for P. australis in Shark Bay, suggesting that even this giant polyploid clone will be negatively impacted by more extreme climate change projections.