2 Minute Medicine Rewind August 20, 2018

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation

Breast cancer cells with BRCA1 and BRCA2 mutations are deficient in the DNA double-strand break repair mechanism, and therefore, are dependent on single-strand DNA repairs regulated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors cause the accumulation of DNA damage and trap PARP at sites of DNA damage, ultimately leading to cancer cell death. Talazoparib, a PARP inhibitor, has shown clinical efficacy in phase 1 and 2 trials for patients with advanced breast cancer and a germline BRCA1/2 mutation. In this phase 3 randomized controlled trial, 431 patients were assigned to receive either talazoparib or standard single-agent therapy in a 2:1 ratio to study the impact on progression-free survival. Researchers found that patients in the talazoparib group experienced a longer median progression-free survival (8.6 months) than those in the standard-therapy group (5.6 months) (HR 0.54, 95% CI 0.41 to 0.71, p<0.001). In addition, more patients in the talazoparib group (37%) evaded disease progression or death at 1 year compared to the standard-therapy group (20%) (HR 0.54, 95% CI 0.42 to 0.69). The objective response rate was also significantly higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%, OR 5.0, 95% CI 2.9 to 8.8, p<0.001). Finally, there was a significant improvement in the estimated overall mean change from baseline in the global health status-quality-of-life scale in the talazoparib group, as compared with a significant worsening in the standard-therapy group (3.0 points vs. -5.4 points on the scale, p<0.001). This study therefore shows that talazoparib may provide substantial clinical benefit to patients with advanced breast cancer and germline BRCA1/2 mutations.

Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1

Patients with multidrug-resistant (MDR) HIV-1 are highly vulnerable to treatment failure and poor clinical outcomes. This underlines the need for new and safe antiretroviral agents without drug cross-resistance. Ibalizumab, a humanized IgG4 monoclonal antibody, binds CD4 on T cells, thereby preventing conformational changes in the CD4-HIV envelope glycoprotein 120 complex that allow for viral entry. It does not appear to interfere with CD4-dependent immunity nor is it confined to specific HIV-1 isolates. In this single-drug, phase 3 trial, 40 patients with MDR HIV-1 received at least the loading dose of ibalizumab after a 7-day control period in which patients continued their current therapy. All patients then received further doses of ibalizumab for up to 25 weeks. The primary endpoint was the proportion of patients who had a decrease in viral load of at least 0.5 log10 copies per milliliter (mL) from baseline to day 14. Researchers found that 83% of patients had a decrease in viral load of at least 0.5 log10 copies per mL from baseline (p<0.001 for comparison with the control period). Furthermore, at week 25, 43% of patients had a viral load of less than 50 copies per mL, and 50% had a viral load of less than 200 copies per mL. The mean CD4 count increased from 150 per mL at baseline to 240 per mL at week 25, with a mean increase of 62 per Ll. There was one serious adverse event related to ibalizumab that resulted in discontinuation of the drug (progressive multifocal leukoencephalopathy with associated immune reconstitution inflammatory syndrome (IRIS). Nine out of ten patients who experienced virologic failure or rebound by week 25 were found to have a lower degree of susceptibility to ibalizumab than at baseline. Overall, this study suggests that ibalizumab may possess significant antiviral activity in patients with MDR HIV-1 who have exhausted other therapeutic options.

Fixed Low-Dose Triple Combination Antihypertensive Medication vs Usual Care for Blood Pressure Control in Patients With Mild to Moderate Hypertension in Sri Lanka: A Randomized Clinical Trial

Hypertension is the leading cause of mortality and cardiovascular disease worldwide, with low- and middle-income countries, in particular, carrying the highest disease burden. Only one-third of patients with hypertension in these countries receive treatment, and most of those receiving treatment use monotherapy, which has been shown to have modest clinical efficacy. A combination of inexpensive blood pressure (BP)-lowering drugs could address cost and availability barriers while improving blood pressure control. In this randomized controlled trial, 700 patients in Sri Lanka with mild to moderate hypertension were randomized to receive a once-daily fixed-dose triple combination pill (telmisartan, amlodipine, and chlorthalidone) or usual care to determine the proportion of patients achieving a target BP of <140 mmHg systolic and <90 mmHg diastolic at 6 months. Researchers found that at 6 months, more patients in the combination pill group achieved their BP target (69.5%) compared with the usual care group (55.3%) (RR 1.23, 95% CI 1.09 to 1.39, p<0.001). In addition, the mean BP of the combination pill group (125 mmHg systolic, 76mm Hg diastolic) was less than that of the usual care group (134 mmHg systolic, 81 mmHg diastolic) (adjusted difference systolic BP -9.8 mmHg, 95% CI -7.9 mmHg to -11.6 mmHg; diastolic BP -5.0 mmHg, 95% CI -3.9 mmHg to -6.1 mmHg; p<0.001 for both comparisons). This study was limited by its open-label design, and the fact that both study arm medications were distributed free of charge, which may limit generalizability. Overall, results from this trial support the use of a combination pill with three antihypertensive medications in patients with mild to moderate hypertension.

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21A Randomized Clinical Trial

Cell-free DNA (cfDNA) testing is being increasingly used to screen for trisomy 21 in high-risk pregnancies in place of invasive fetal karyotyping procedures, such as amniocentesis or chorionic villus sampling. It is thought that cfDNA testing is safer than invasive testing, however, this has not yet been assessed in practice. Moreover, cfdNA testing may overlook other common aneuploidies and structural chromosomal anomalies. In this randomized controlled trial, 2111 women with high-risk pregnancies (as established through first-trimester combined screening) were assigned to receive either cfDNA testing followed by invasive testing only when cfDNA results were positive, or to receive immediate invasive testing. The primary outcome was the number of miscarriages before 24 weeks gestation. Researchers found that there was no significant difference in miscarriage rates between the cfDNA and invasive testing groups (risk difference -0.03%, one-sided 95% CI -0.68% to ∞, p=0.47). The sensitivity of cfDNA testing for trisomy 21 was 100% (95% CI 87.2% to 100%) and the false-positive rate was 5.6% (95% CI 4.2% to 7.2%). There was 1 (0.1%) non-trisomy 21 chromosomal abnormality identified by cfDNA, and 11 (1.5%) identified by invasive testing (risk difference -1.02%, 95% CI -1.71% to -0.34%, p=0.003). While cfDNA testing was only performed for trisomy 21 in this study, the ability of the test to rule out other chromosomal abnormalities is likely to improve. Overall, this study suggests that, in high-risk pregnancies, performing invasive testing only if cfDNA testing is positive does not reduce the miscarriage rates. However, this study may have been underpowered to detect a clinically significant difference.

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial

Obesity is associated with a number of clinical complications, from diabetes to depression. Studies have shown that body mass reduction in turn reduces obesity-related complications and improves quality of life. However, clinically significant weight loss is often difficult to achieve with lifestyle interventions alone. Five compounds are currently approved for weight management in the United States, including liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, and semaglutide, a recently approved longer-acting GLP-1 analog. The efficacy and safety of semaglutide have not yet been compared with liraglutide. In this randomized controlled trial, 957 individuals with a body mass index (BMI) of 30 kg/m2 or more were assigned in a 6:1 ratio to each active treatment group (varying doses of semaglutide or liraglutide) or the matching placebo group to study the relative percentage change in body weight from baseline to week 52. Researchers found that the estimated mean weight loss was greater in all semaglutide groups (-6.0% (0.05 mg), -8.6% (0.1 mg), -11.6% (0.2 mg), -11.2% (0.3 mg), -13.8% (0.4 mg) than in the placebo group (-2.3%) (all comparisons p0.001). Moreover, mean body weight reductions in patients receiving 0.2 mg or more of semaglutide were significantly greater than in those using liraglutide (-7.8%). Significantly more patients receiving semaglutide (0.1 mg or more) achieved an estimated weight loss of at least 10% than those receiving placebo (37%-65% vs. 10%, p<0.0001). Limitations of this study included the lack of systematic exercise activity evaluation and the absence of dose-masking. These findings support a role for semaglutide for weight management in obese individuals.

Image: PD

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