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.

Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.

Effect of antibiotics on urine leakage in women with refractory detrusor overactivity: A phase IIb randomized trial.

AIM: Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. METHODS: In a multicenter phase IIb double-blinded randomized placebo-controlled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24-h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3-day bladder diary and quality of life measures. Microbiological data were collected at all visits. RESULTS: Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24-h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. CONCLUSION: Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6-month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment.