Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Association of Multiple High-Risk Factors on Observed Outcomes in Real-World Patients With Advanced Ovarian Cancer Treated With First-Line Therapy.

PURPOSE: To identify risk factors for disease progression or death and assess outcomes by risk categories in real-world patients with advanced ovarian cancer. METHODS: This retrospective study included adult patients from a nationwide electronic health record-derived deidentified database with stage III/IV ovarian cancer who received first-line therapy and had ≥12 weeks of follow-up after index date (end of first-line therapy). Factors predictive of time to next treatment and overall survival (OS) were assessed. Patients were grouped according to the cumulative number of high-risk factors present (stage IV disease, no debulking surgery or neoadjuvant therapy and interval debulking surgery, visible residual disease after surgery, and breast cancer gene [BRCA] wild-type disease/unknown BRCA status), and time to next treatment and OS were assessed. RESULTS: Region of residence, disease stage, histology, BRCA status, surgery modality, and visible residual disease were significant predictors of time to next treatment; age, Eastern Cooperative Oncology Group performance status, disease stage, BRCA status, surgery modality, visible residual disease, and platelet levels were significant predictors of OS (N = 1,920). Overall, 96.4%, 74.1%, and 40.3% of patients had at least 1, 2, or 3 high-risk factors, respectively; 15.7% of patients had all four high-risk factors. Observed median time to next treatment was 26.4 months (95% CI, 17.1 to 49.2) in patients with no high-risk factors and 4.6 months (95% CI, 4.1 to 5.7) in patients with four high-risk factors. Observed median OS was shorter among patients with more high-risk factors. CONCLUSION: These results underscore the complexity of risk assessment and demonstrate the importance of assessing a patient's cumulative risk profile rather than the impact of individual high-risk factors. They also highlight the potential for bias in cross-trial comparisons of median progression-free survival because of differences in risk-factor distribution among patient populations.

Real-World Outcomes Following First-Line Treatment in Patients with Advanced Ovarian Cancer with Multiple Risk Factors for Disease Progression who Received Maintenance Therapy or Active Surveillance.

INTRODUCTION: We evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) treatment. METHODS: This retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stage III/IV OC from January 1, 2011 to February 28, 2021, who received 1L therapy and had ≥ 12 weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stage IV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had BRCA wild-type disease/unknown BRCA status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan-Meier method. RESULTS: Among 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3 months (95% CI 11.7-15.8) and 39.1 months (95% CI 32.5-48.6) in the MT cohort, respectively, and 8.6 months (95% CI 8.0-9.5) and 38.4 months (95% CI 36.4-41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1 RF, 19.3 months, 95% CI 13.5-37.8; 2 RF, 17.2 months, 95% CI 12.8-20.2; 3 RF, 11.0 months, 95% CI 8.2-13.8; 4 RF, 7.0 months, 95% CI 6.2-8.8; AS: 1 RF, 17.7 months, 95% CI 13.5-22.3; 2 RF, 10.2 months, 95% CI 9.1-11.5; 3 RF, 6.5 months, 95% CI 5.8-7.4; 4 RF, 4.1 months, 95% CI 3.5-4.5). CONCLUSION: Regardless of RF number, MT was associated with longer TTNT in real-world patients with AOC.

Real-world treatment patterns of maintenance therapy in platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: The clinical utility of maintenance therapy (MT) for patients with platinum-sensitive recurrent ovarian cancer has been validated in several clinical trials. We assessed "real-world" treatment patterns using an electronic health record (EHR) database. METHODS: A retrospective study of patients diagnosed with ovarian cancer between January 1, 2011 and July 31, 2019 was conducted using the US nationwide Flatiron Health (EHR)-derived de-identified database. Patients were included if they received second- or third-line (2 L or 3 L) platinum-based chemotherapy (PBCT). Information regarding biomarker status was obtained. RESULTS: 2292 patients with ovarian cancer received at least two lines of therapy. 222 patients completed PBCT on or after March 1, 2017 and had ≥2 months of active surveillance or received MT with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) or bevacizumab. 46 (20%) had BRCA mutations (BRCAm), 132 (59%) had a wildtype BRCA (BRCAwt) gene, and 47 (21%) were unknown. Of patients with BRCAm, 63% received a PARPi, 17% received bevacizumab, and 20% underwent active surveillance. Of patients with BRCAwt, 40% received a PARPi, 23% received bevacizumab, and 36% underwent active surveillance. MT was more common in those with younger age and a BRCA mutation. PARPi use increased on average by 1.3% every 3 months (p = .02) with no statistically significant change in use of bevacizumab. CONCLUSIONS: In this real-world population, MT is becoming progressively more common following 2 L or 3 L PBCT regardless of biomarker status. The results provide insight into the shifting treatment patterns for patients with recurrent ovarian cancer.

Gastrointestinal symptoms and diagnosis preceding ovarian cancer diagnosis: Effects on treatment allocation and potential diagnostic delay.

OBJECTIVE: To determine whether gastrointestinal (GI) disorder insurance claims in the year preceding a diagnosis of ovarian cancer (OC) lead to differing treatment allocations. The hypothesis is that GI disorders may be indicative of advanced OC. METHODS: This retrospective study identified patients with newly diagnosed OC from January 2015 to January 2019 in the IBM® MarketScan® US commercial insurance and Medicare databases. Analysis was limited to patients with primary or interval debulking surgery or chemotherapy, with or without GI claims in the year prior to diagnosis, with commercial or Medicare coverage for ≥12 months prior and ≥1 month after the index date. Patients were compared in terms of the odds of treatment with neoadjuvant chemotherapy (NCT) or primary debulking surgery (PDS) (logistic regression analysis). Median treatment-free interval in the subset of patients with antineoplastic treatment was compared (Kaplan-Meier analysis). RESULTS: Of the 6286 patients, 22% had a diagnosis of ≥1 GI disorder before their OC diagnosis. Of these patients, 39% were diagnosed with a GI disorder between 6 and 12 months before OC diagnosis and 61% were diagnosed <6 months prior. Women with a GI diagnosis were more likely to undergo NCT than PDS (odds ratio [OR], 1.37; P < 0.0001); this remained significant even when controlling for age, region, insurance plan type, and index year (OR, 1.24; P = 0.001). CONCLUSIONS: In this database, ≈25% of women with OC had a GI claim within the past year and were more likely treated with NCT, an indicator of more advanced disease with a worse prognosis. This suggests that OC should be considered in the differential diagnosis among women with GI complaints, which could alter treatment allocation.

E-selectin genotypes and risk of type 2 diabetes in women.

Endothelial dysfunction increases risk for type 2 diabetes. We examined whether variation in the gene for E-selectin (SELE), a biomarker of endothelial dysfunction, was associated with levels of E-selectin or diabetes quantitative traits (including fasting levels of insulin and hemoglobin A(1c)) in 719 nondiabetic participants of the Nurses' Health Study or with risk of diabetes in 602 incident (over 10 years of follow-up) cases and 655 control women matched for age, race, and fasting status. Variation in three single nucleotide polymorphisms previously associated with cardiovascular disease risk and having effects on E-selectin function, S128R, G98T, and L554F, was not significantly (p > 0.05) associated with levels of E-selectin or diabetes quantitative traits, or with risk of incident diabetes in the primary analysis. Among women with low levels of subclinical inflammation (C-reactive protein levels below the population median), S128R R allele carriers had a diabetes risk factor-adjusted relative risk of incident diabetes of 1.71 (95% confidence interval, 1.04 to 2.81) relative to those with the SS genotype. Apart from an association in this subgroup, we conclude that the E-selectin variants we examined are not important genetic risk factors for type 2 diabetes in women.

Using metabolic syndrome traits for efficient detection of impaired glucose tolerance.

OBJECTIVE: Efficient detection of impaired glucose tolerance (IGT) is needed to implement type 2 diabetes prevention interventions. RESEARCH DESIGN AND METHODS: We assessed the capacity of the metabolic syndrome (MetS) to identify IGT in a cross-sectional analysis of 3,326 Caucasian Framingham Offspring Study (FOS), 1,168 Caucasian and 1,812 Mexican-American San Antonio Heart Study (SAHS), 1,983 Mexico City Diabetes Study (MCDS), and 452 Caucasian, 407 Mexican-American, and 290 African-American Insulin Resistance Atherosclerosis Study (IRAS) men and women aged 30-79 years who had a clinical examination and an oral glucose tolerance test (OGTT) during 1987-1996. Those with diabetes treatment or fasting plasma glucose > or =7.0 mmol/l were excluded (MetS was defined by Third Report of the National Cholesterol Education Program's Adult Treatment Panel criteria and IGT as 2-h postchallenge glucose [2hPG] > or =7.8 mmol/l). We calculated positive (PPV) and negative predictive values (NPV), population attributable risk percentages (PAR%), age- and sex-adjusted odds ratios (ORs), and areas under the receiver operating characteristic curve (AROCs) associated with MetS traits. RESULTS: Among FOS, SAHS, and MCDS subjects, 24-43% had MetS and 15-23% had IGT (including 2-5% with 2hPG > or =11.1 mmol/l). Among those with MetS, OR for IGT were 3-4, PPV were 0.24-0.41, NPV were 0.84-0.91, and PAR% were 30-40%. Among subjects with MetS defined by impaired fasting glucose (IFG) and any two other traits, OR for IGT were 9-24, PPV were 0.62-0.89, NPV were 0.78-0.87, and PAR% were 3-12%. Among IRAS subjects, 24-34% had MetS and 37-41% had IGT. Among those with MetS, ORs for IGT were 3-6, PPVs were 0.57-0.73, and NPVs were 0.67-0.72. In logistic regression models, IFG, large waist, and high triglycerides were independently associated with IGT (AROC 0.71-0.83) in all study populations. CONCLUSIONS: The MetS, especially defined by IFG, large waist, and high triglycerides, efficiently identifies subjects likely to have IGT on OGTT and thus be eligible for diabetes prevention interventions.