Search

BackgroundRucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.MethodsIn this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.FindingsBetween April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p

Lavanya Mariappan,1 Xue Yan Jiang,1 Josie Jackson,2 Yvette Drew2 1Northern Centre for Cancer Care, Freeman Hospital, 2Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK Abstract: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting class of anticancer drugs, which have revolutionized the management of BRCA mutant/homologous recombination-deficient recurrent high-grade serous ovarian cancer (HGSOC). With three PARPi now approved by the US Food and Drug Administration, olaparib (Lynparza™), niraparib (Zejula™), and rucaparib (Rubraca™) in 2014 (and 2017 for the tablet formulation), 2016, and 2017, respectively, these drugs have now entered routine clinical practice. The marked single-agent efficacy of PARPi either as maintenance following response to platinum-based chemotherapy or as up-front treatment in these indications is based on the well-known concept of synthetic lethality. PARPi themselves work by blocking the repair of single-strand DNA breaks by the base excision/single-strand break repair pathway and can also be directly cytotoxic by the mechanism of PARP trapping. The greatest benefit in terms of progression-free survival, in all three PARPi maintenance registration studies, was seen in women with platinum-sensitive BRCA mutation-associated HGSOC. However, it is clear that non-BRCA HGSOC can benefit from PARPi and the ongoing challenge of biomarker driven studies is how best to define these patients. PARPi are well tolerated, but more information is needed to assess the longer-term/later onset toxicities as these agents are investigated in the first-line setting. The future direction and challenges for PARPi will be to continue to expand beyond BRCA and ovarian cancer by identifying molecular or functional signatures of response; to see if the durable responses in ovarian cancer can be improved and efficacy can be achieved in other cancer sub-types by combining with novel targeted agents. This review summarizes the development of PARPi as a class in ovarian cancer with particular focus on the PARPi rucaparib. Keywords: ovarian cancer, BRCA, PARP inhibitors, rucaparib

Dr. Madeleine Leininger--founder and mother of transcultural nursing (TCN)--worked tirelessly with nurses from around the world to expand its body of knowledge. Leininger's Sunrise Model is based on culture care bridging generic folk care and professional care and uses three action modes to provide culturally congruent care. Other proponents of TCN and followers of Dr. Leininger developed theories and models and further added to the body of expanding knowledge in TCN. This article includes some exemplars of theories and models developed by Andrews and Boyle, Campinha-Bacote, Choi, Giger and Davidhizar, Jeffreys, Purnell, and Spector to further integrate TCN in nursing education, practice, administration, and research. The authors gathered some application of these theories and models in nursing education, practice, administration, and research. Research agenda for the future and gaps in knowledge focusing on increasing diversity of nursing workforce, preventing health disparities, and adding to TCN body of knowledge are likewise included. [ABSTRACT FROM AUTHOR]

Olaparib, the first-in-class poly ADP-ribose polymerase (PARP) inhibitor, is approved for first line maintenance treatment in platinum-sensitive FIGO stage 3 and 4 high grade serous ovarian cancer (HGSOC) associated with a deleterious BRCA mutation. We report a case involving a 70-year-old female who experienced significant CTCAE Grade 4 hepatocellular injury after initiating first line maintenance Olaparib for Stage 3C HGSOC. Her liver injury resolved upon discontinuation of Olaparib but promptly recurred upon rechallenge. Extensive investigations, including abdominal ultrasound, computed tomography, and assessments for infectious, metabolic, and autoimmune aetiologies of liver injury, were unremarkable. Her liver enzymes returned to baseline after discontinuing Olaparib once again. Subsequently, the patient was started on Niraparib for maintenance therapy, which she tolerated well. This case represents the first instance of positive rechallenge following Olaparib-induced liver injury and highlights the absence of cross-reactive hepatotoxicity between PARP inhibitors., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YD has received institutional research funding and honorarium for advisory boards, scientific symposia and educational events from GSK. YD has received honorarium for advisory boards, scientific symposia and educational events from AstraZeneca. KZ and SJ have no conflict of interest to declare., (© 2024 The Authors. Published by Elsevier Inc.)

Purpose: Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities., Experimental Design: sWGS and targeted panel sequencing was performed on formalin-fixed, paraffin-embedded p53abn endometrial cancers. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed., Results: In 187 p53abn endometrial cancers, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. Twenty-two percent of potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with a high ploidy state, and CCNE1, ERBB2, and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. Twenty-eight percent of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. Thirty-four percent of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on IHC, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations., Conclusions: sWGS and targeted sequencing identified therapeutic opportunities in 75% of patients with p53abn endometrial cancer. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn endometrial cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)