PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers.

BACKGROUND: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). METHODS: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. RESULTS: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. CONCLUSIONS: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03101280).

A phase-II study of atezolizumab in combination with obinutuzumab or rituximab for relapsed or refractory mantle cell or marginal zone lymphoma or Waldenström's macroglobulinemia.

We report efficacy, safety and biomarker data from a phase-II study evaluating atezolizumab (eight 21-day cycle as induction therapy) in combination with obinutuzumab in patients with relapsed/refractory mantle cell lymphoma (MCL, n = 30) or Waldenström's macroglobulinemia (WM, n = 4), and in combination with rituximab in patients with marginal zone lymphoma (MZL, n = 21). All patients received atezolizumab monotherapy as maintenance for ≤10 cycles. Objective response rates at end of induction were 16.7% (MCL) and 42.9% (MZL), with no responses in WM. Median duration of response was 6.8 months (range 5.7-not estimable) for MCL and not reached for MZL. Treatment-emergent adverse events (TEAEs) occurred in 93.3%, 95.2% and 100% of MCL, MZL and WM patients, respectively. One fatal TEAE (pneumonia) occurred in each of the MCL and MZL groups. Biomarker analysis highlighted the importance of characterizing the immune environment to optimize efficacy of immunotherapy regimens.Trial registration details: EudraCT: 2016-003579-22.

Comparative Safety Profile of the Fixed-Dose Combination Corticosteroid and Long-acting ß2-Agonist Fluticasone Propionate/Formoterol Fumarate: A 36-Month Longitudinal Cohort Study in UK Primary Care.

OBJECTIVE: The inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) fluticasone propionate/formoterol fumarate (FP/FORM; Flutiform®) has been available as fixed-dose combination (FDC) therapy for asthma patients aged ≥ 12 years in the UK since 2012. This post-authorisation safety study examined adverse outcomes and prescribing practices for FP/FORM and other FDC ICS/LABA therapies in a real-life clinical setting over 36 months. METHODS: Historical, longitudinal cohort database study using UK primary care data from the Clinical Practice Research Datalink (CPRD) database, for patients initiated on or switched to an FDC ICS/LABA (ENCePP study number: EUPAS12330). The main cohort was adults aged ≥ 18 years with asthma. The primary outcome was incidence of new adverse outcomes after initiation of ICS/LABA; hazard ratios (HRs) and 95% confidence intervals were estimated for FP/FORM versus other FDC ICS/LABAs using Cox regression models. RESULTS: A total of 241,007 patients with an FDC ICS/LABA prescription were identified. In the adult asthma cohort (N = 41,609), the incidence rate of new adverse outcomes [in 100 patient-years (py)] was significantly lower for FP/FORM (24.75) versus fluticasone/salmeterol metered-dose inhaler [8.86; HR 1.14 (1.04, 1.25)], fluticasone/salmeterol dry powder inhaler [31.19; HR 1.18 (1.08, 1.29)], budesonide/formoterol [25.16; HR: 1.13 (1.03, 1.25)] and beclometasone/formoterol [25.47; HR 1.14 (1.04, 1.25)]. The overall prescribing rate was lower for FP/FORM (13.85 per 1000/py) than licensed FDC ICS/LABA comparators (20.30-28.13 per 1000/py). Of those prescribed FP/FORM, 80.8% were adults with asthma and < 7% were prescribed FP/FORM "off-label". CONCLUSIONS: The results suggest that FP/FORM was associated with an overall lower adverse outcome rate than the licensed comparators.

Prevalence and Incidence Trends for Diagnosed Prescription Opioid Use Disorders in the United Kingdom.

INTRODUCTION: The prevalence of prescription opioid use disorders in the US has increased markedly in parallel with increases in opioid prescribing. Whilst an increase in opioid prescribing has also occurred in the UK, it remains unknown if there have been concurrent increases in opioid use disorders. The aim of this study was to examine national trends in the prevalence and incidence of physician-diagnosed opioid use disorders in the UK. METHODS: In a retrospective electronic health care database analysis using data from the UK Clinical Practice Research Datalink (CPRD), we identified persons receiving a first opioid prescription between January 1, 2008 and December 31, 2012. Persons with an opioid use disorder were identified by Read codes assigned by patients' physicians within 6 months following an opioid prescription. We calculated prevalence and incidence rates by dividing the analysis population by the total number of patients exposed (prevalence) or the total patient-years of exposure (incidence) using the 'exact' Clopper-Pearson Binomial method. RESULTS: Our analysis included 714,699 person-years of prescription opioid exposure. The 5-year period prevalence of opioid use disorders was 4.61 (95% CI 4.28-4.96) per 10,000 individuals, or 0.05%. The incidence rate of opioid use disorders was of 6.51 (95% CI 5.93-7.13) patients per 10,000 patient-years exposed. When examined by study year, there was no clear suggestion of a changing trend over time. When stratified by opioid drug, trends in the incidence rate during the study were either stable (i.e., codeine and tramadol), increasing (i.e., morphine) or decreasing (i.e., dihydrocodeine). CONCLUSIONS: Our study demonstrates that despite the marked increase in overall opioid prescribing in the UK in the past decade, there has not been an increase in the incidence of physician-diagnosed opioid use disorders.

The unique role of transdermal buprenorphine in the global chronic pain epidemic.

Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes.