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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.

BackgroundLittle is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC).MethodsWe 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.ResultsLandscapes 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.ConclusionThese 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.

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: 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]

Purpose: There is a paucity of data analyzing the anatomic locations and dose volume metrics achieved for surgically transposed ovaries in patients desiring fertility or hormonal preservation receiving pelvic radiation therapy (RT), which were examined herein., Methods and Materials: This is a retrospective study including women who underwent ovarian transposition before pelvic RT between 2010 to 2020. The craniocaudal (CC) distance of the ovary centroid to the (1) plane of the sacral promontory, (2) iliac crest, and (3) the nearest distance between the ovary edge and RT planning target volume (PTV) were measured (cm). The area under the receiver operating characteristic curve and cut-point analysis estimating ovary location outside the PTV was performed., Results: Thirty-one ovaries were analyzed from 18 patients. Thirteen (72.2%) were treated with intensity modulated RT, and 5 (27.8%) were treated with 3-dimensional conformal radiation therapy. Most ovaries were located above the sacral promontory (64.5%, n = 20), below the iliac crest (96.8%, n = 30), and outside the PTV (64.5%, n = 20). The median distance from the ovaries to the sacral promontory, iliac crest, and PTV was 0.8 cm (interquartile range [IQR], -0.83 to 1.59 cm), -3.22 cm (IQR, -5.12 to -1.84 cm), and 0.9 cm (IQR, -1.0 to 1.9 cm), respectively. The area under the receiver operating characteristic curve and cut-point analysis demonstrated that distance from the iliac crest predicted an ovary to be outside the PTV with an optimal cut-point of -3.0 cm (C-index = 0.82). The median mean and maximum (Dmax) ovary doses were 15.5 Gy (IQR, 9.6-20.2 Gy) and 32.2 Gy (IQR 24.8-46.5 Gy), respectively., Conclusions: Despite most transposed ovaries being located outside the PTV, nearly all remained below the iliac crest and received RT doses associated with a high risk of ovarian failure. These findings deepen our understanding of the spatial relationship between transposed ovaries and dose to inform surgical and pre-RT planning and suggest that more aggressive ovary-sparing strategies are warranted., (© 2021 The Authors.)