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Introduction: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. Methods: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011–30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan–Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). Results: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60–72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7–25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0–53.9 days). Median TTD was 9.3 months (95% CI 6.1–11.3 months). Median TTNT was 12.9 months (95% CI 11.5–19.0 months). Conclusions: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC. [ABSTRACT FROM AUTHOR]

Purpose: This paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer. Methods: This was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel. Results: A total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91‐2.3] p =.935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43–1.14] p =.064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response. Conclusion: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity. Randomized study of cediranib compared with olaparib and the combination for advanced or recurrent endometrial cancer demonstrated progression‐free survival of 3.8, 2.0, and 5.5 months respectively. The treatment toxicities were manageable but the study did not meet its primary end point. [ABSTRACT FROM AUTHOR]

Background: In the United States, inequities in preventive health behaviors such as cervical cancer screening have been documented. Sexual orientation, gender identity, and race/ethnicity all individually contribute to such disparities. However, little work has investigated their joint impact on screening behavior. Methods: Using sampling weighted data from the 2016 and 2018 Behavioral Risk Factor Surveillance System, we assessed differences in two metrics via chi-square statistics: 1) lifetime uptake, and 2) up-to-date cervical cancer screening by sexual orientation and gender identity, within and across racial/ethnic classifications. Results: Within all races, individuals who identify as members of sexual and gender minority (SGM) communities reported higher rates of never being screened (except for Black transgender men) than straight or cisgender individuals (p < 0.0001). [*START* Across all races, the Asian/Pacific Islander transgender population (32.4%; weighted n (w.n.) = 1,313) had the lowest proportion of lifetime screening, followed by the Asian/Pacific Islander gay/lesbian (53.0%, w.n. = 21,771), Hispanic transgender (58.7%; w.n. = 24,780), Asian/Pacific Islander bisexual (61.8%, w.n. = 54,524), and Hispanic gay/lesbian (69.6%, w.n. = 125,781) populations. *END*] Straight or cisgender Non-Hispanic White (w.n. = 40,664,476) individuals had the highest proportion of lifetime screening (97.7% and 97.5%, respectively). However, among individuals who had been screened at least once in their lifetime, identifying as SGM was not associated with a decreased proportion of up-to-date screening within or between races. Conclusions: Due to small sample sizes, especially among Asian/Pacific Islander and Hispanic populations, confidence intervals were wide. Heterogeneity in screening participation by SGM status within and across racial/ethnic groups were observed. Impact: These screening disparities reveal the need to disaggregate data to account for intersecting identities and for studies with larger sample sizes to increase estimate reliability. [ABSTRACT FROM AUTHOR]

In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in the United States, yet significant portions of the US population remain under screened or unscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high‐quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research is needed to produce improvements in cervical cancer survival within the United States. Mortality from cervical cancer is a direct reflection of resource distribution. Future research to decrease mortality must account for systemic failures to eradicate inequities in addition to the development of novel agents against this disease. [ABSTRACT FROM AUTHOR]

Background: Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). Methods: We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results: Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. Conclusion: These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC. [ABSTRACT FROM AUTHOR]

Background: Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). Methods: We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results: Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. Conclusion: These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods: Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3–6 and as maintenance monotherapy in cycles 7–34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results: An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions: The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: As a class, PARPis work by disrupting DNA repair; however, they are metabolized by different pathways. Niraparib is metabolized by carboxylesterase-catalyzed amide hydrolysis, whereas olaparib and rucaparib are metabolized by the cytochrome P450 (CYP) system. Drugdrug interactions (DDIs) with other medications may change PARPi efficacy or safety in patients with aOC. Objective: This US-based, real-world study aimed to quantify and characterize patients with aOC who received CYP-inhibiting/inducing (CYP-i/i) medications when they initiated treatment or were eligible to receive PARPi first-line maintenance therapy (1LMT), to better understand the potential for DDIs with PARPis and other CYP-metabolized medications. Methods: This retrospective cohort study used data from Optum's de-identified Market Clarity Data with Optum® Enriched Oncology, which deterministically links medical and pharmacy claims with electronic health record data from providers across the continuum of care. Eligible patients were diagnosed with aOC between January 1, 2015, and March 31, 2021; were aged ≥18 years at end of first-line platinum-based chemotherapy (index date); had confirmed CYP-i/i medication use (≥1 claim between 90 days before to 120 days after index date); and had received or were eligible to receive PARPi 1LMT. Strong/moderate CYP-i/i medications were defined based on estimates of how much they increased/decreased drug exposure over time (area under the plasma concentration--time curve ratio). Patients in the PARPi-treated group received PARPi monotherapy for 1LMT (olaparib/rucaparib/niraparib). Patients in the PARPi-eligible group did not receive 1LMT within 120 days or start second-line treatment within 60 days of the index date. Descriptive statistics were used for patient characteristics. Results: The analysis included 1411 patients (PARPi treated, n=158; PARPi eligible, n=1253). Median age was 63 years for PARPi-treated patients and 64 years for PARPi-eligible patients. Among PARPi-treated patients, 46% (n=73) used niraparib, and 54% (n=85) used other PARPis metabolized by the CYP system (olaparib, 49% [n=77]; rucaparib, 5% [n=8]). The percentage of patients taking a strong/ moderate CYP-i/i medication was 38% (n=60) for the overall PARPi-treated group, 42% (n=36) for PARPi-treated patients who received olaparib or rucaparib, and 33% (n=414) for the PARPi-eligible group. For each group, the most common strong/moderate CYP-i/i medications were antiemetics and fluoroquinolone antibiotics (overall PARPi treated, 48% [n=29] and 28% [n=17], respectively; PARPi-treated olaparib/rucaparib, 50% [n=18] and 25% [n=9], respectively; and PARPi eligible, 41% [n=169] and 37% [n=154], respectively). Other common strong/moderate CYP-i/i medications were imidazole-related antifungals, calcium channel--blocking blood pressure medications, and topical antifungals. Conclusions: Patients with aOC may be treated with PARPi 1LMT to delay or prevent recurrence. Multiple PARPi options exist, including niraparib, which is metabolized by carboxylesterase-catalyzed amide hydrolysis, and olaparib and rucaparib, which are metabolized by the CYP system. In this analysis, 38% of PARPi-treated and 33% of PARPi-eligible patients with aOC also received medications that were strong/moderate CYP-i/i. Cotreatment with CYP-metabolized PARPis and CYP-i/i medications could potentially lead to DDIs that could alter the efficacy and tolerability of the PARPis. Additional studies are needed to understand this important issue. Funding: Funding for this study was provided by GSK. [ABSTRACT FROM AUTHOR]

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results. [ABSTRACT FROM AUTHOR]