BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.

A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity.This article is highlighted in the In This Issue feature, p. 151.

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer.

PURPOSE: Evidence suggests that endothelin (ET)-1 and its primary receptor, the ET(A) receptor, may contribute to the progression of prostate and other cancers. Atrasentan (ABT-627) is a highly potent, selective ET(A) receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokinetics (PK) in patients with refractory adenocarcinomas, primarily prostate cancer. EXPERIMENTAL DESIGN: This 28-day, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5-95 mg) given daily (except day 2) to eligible patients >/==" BORDER="0">18 years old with an adenocarcinoma proven resistant to standard therapy. Priority was given to patients with hormone-refractory prostate cancer. After 28 days, patients without objective signs of tumor progression were eligible to continue atrasentan in an extension study. RESULTS: Thirty-nine patients (30 of whom had prostate cancer) were treated in cohorts of three patients each with escalating atrasentan doses (2.5, 5, 10, 20, 30, 45, 60, 75, and 95 mg). The most common adverse events were rhinitis, headache, and peripheral edema. Anemia consistent with a reversible hemodilution effect was observed. No maximum tolerated dose was found in the dose range studied. Atrasentan PK were characterized by rapid absorption (mean T(max) = 0.9 h), mean +/- SD oral clearance of 24 +/- 15 liters/h, and volume distribution of 726 +/- 477 liters. PK were approximately dose-proportional and time independent across doses. CONCLUSIONS: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 95 mg. Adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing.

Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy.

The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a 'dropouts as censored' analysis, plasma HIV RNA < or = 400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline lopinavir mutation score of 0-5, 6-7 and > or = 8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to lopinavir/ritonavir.

Clinical observation of liver chemistry abnormalities in asthmatics.

OBJECTIVES: Describe the population characteristics of liver chemistries, the incidence and patterns of liver chemistry abnormalities, and the longitudinal behavior of alanine aminotransferase in mild-to-moderate asthmatic patients. METHODS: We undertook a retrospective analysis of comparator arm data from a long-term safety surveillance study of a leukotriene inhibitor. RESULTS: Several liver chemistry elevations relative to the upper limit of normal were observed. We identified three other types of outliers: liver chemistry elevations relative to screening values, persistent liver chemistry elevations, and unusually variable alanine aminotranferase. CONCLUSIONS: In the absence of any common drug therapy, there are considerable within-population differences of liver chemistry profiles including substantial outliers. This ordinary variability should be taken into account in the design of clinical trials and analysis of drug-induced liver injury therein.

A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS: This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS: Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (>/=50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS: Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.