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Objective: ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib., Methods: Patients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes., Results: Rucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C, and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit., Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma., Competing Interests: Declaration of Competing Interest DMO reports personal fees from consulting and/or advisory board participation from Clovis Oncology, AbbVie, Agenus, Ambry, Amgen, Arquer Diagnostics, AstraZeneca, Celsion Corp, Corcept Therapeutics, Eisai, Elevar, Genelux, Genentech/Roche, GOG Foundation, Immunogen, Inxmed, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Merck, Mersana, Myriad Genetics, Novartis, Novocure, Regeneron, Roche Diagnostics MSA, Rubis, SeaGen, SDP Oncology (BBI), Takeda, and Tesaro/GlaxoSmithKline, Toray; research funding (all funding to institution) from Clovis Oncology, AbbVie, Agenus, Ajinomoto, Amgen, Array Biopharma, AstraZeneca, Bristol Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed, Genentech/Roche, GenMab, GOG Foundation, Immunogen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Ludwig Institute for Cancer Research, Merck, National Cancer Institute, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron, SeaGen, Serono, Stemcentrx, Tesaro/GlaxoSmithKline, Tracon Pharmaceuticals, VentiRx, and Yale University; and has given a presentation on ovarian cancer at the National Comprehensive Cancer Network. AMO reports grants to his institution from AstraZeneca; has served on steering committees for Clovis Oncology, AstraZeneca (uncompensated), and Tesaro (uncompensated); has served in an advisory role for AstraZeneca and GlaxoSmithKline (uncompensated); and has acted as a principal investigator on investigator-initiated trials with agents from Clovis Oncology, AstraZeneca, and GlaxoSmithKline. DL reports institutional research funding from Clovis Oncology, AstraZeneca, Corcept Therapeutics, GlaxoSmithKline, Genmab, ImmunoGen, Merck Sharp & Dohme, Novartis, PharmaMar, Roche, and Seagen; consulting fees from Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and PharmaMar; payment or honoraria for lectures from Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and Seagen; support for attending meetings and/or travel from AstraZeneca, PharmaMar, and Roche; participation on a data safety monitoring board or advisory board for Clovis Oncology, Agenus, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche; and serves on the board of directors for GCIG and as chair of GCA for ENGOT. CA has served on a steering committee for AbbVie and Genentech; has served as a principle investigator for studies by Clovis Oncology, AbbVie, AstraZeneca, and Genentech; served on advisory boards for AbbVie, AstraZeneca/Merck, Blueprint Medicine, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech; and serves on the board of directors (unpaid) for GOG Foundation and NRG Oncology. AO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Clovis Oncology, AstraZeneca Farmaceutica Spain, AstraZeneca, Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, F. Hoffmann-La Roche, GlaxoSmithKline, Got It Consulting, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, PharmaMar, prIME Oncology, Roche Farma, Shattuck Labs, Sutro Biopharma, Tesaro Bio GmbH, Tesaro Bio Spain, and Tesaro; and support for attending meetings and/or travel from AstraZeneca, Roche, and PharmaMar. AD has served in a consulting or advisory role for Precision Oncology Australia, Shire Pharmaceuticals, and Specialised Therapeutics Australia; and sits on the scientific advisory board for A2A Pharmaceuticals. NC reports institutional research funding from Clovis Oncology; serving in a consulting or advisory role for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Novartis, Nuvation Bio, Oncxerna, Pfizer, PharmaMar, Roche, and Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; and support for attending meetings and/or travel from AstraZeneca. JIW has received research support from AstraZeneca. ARC reports consulting fees for advisory boards for AstraZeneca; payment or honoraria for speakers bureaus for Clovis Oncology and Merck Sharp & Dohme; support for attending meetings and/or travel from Tesaro; and institutional research funding from Clovis Oncology and AstraZeneca. GS reports royalties or licenses from Merck Sharp & Dohme Italia; consulting fees from Tesaro Bio Italy and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Clovis Oncology Italy. AL has served on advisory boards for Clovis Oncology, Ability Pharmaceuticals, AstraZeneca, BIOCAD, GamaMabs, Genmab/Seattle Genetics, GlaxoSmithKline, Gritstone, Merck Serono, Merck Sharp & Dohme, and Tesaro; steering committee for Merck Sharp & Dohme; reports institutional support for clinical trials or academic research from Clovis Oncology, Ability Pharmaceuticals, Agenus, AstraZeneca, Incyte, Inivata, Iovance, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tesaro; and reports boarding and travel expenses for congress activities from Clovis Oncology, AstraZeneca, and Roche. RWH reports consulting fees from Clovis Oncology, AstraZeneca, and GlaxoSmithKline; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Clovis Oncology, AstraZeneca, and GlaxoSmithKline. MAG has served on speakers' bureaus for Clovis Oncology, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and PharmaMar; and reports support for attending meetings and/or travel from GlaxoSmithKline. PCF reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck Sharp & Dohme; support for attending meetings and/or travel from Merck Sharp & Dohme and Pfizer. JCG reports consulting fees from AstraZeneca, Bristol Myers Squibb, Eisai, and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bristol Myers Squibb, Ipsen, and Merck Sharp & Dohme Australia; support for attending meetings and/or travel from AstraZeneca; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb and Janssen; and stock or stock options for ICON Cancer Care, Australia. EMS reports institutional research funding from Clovis Oncology. LM, SG, KL, and TK are employees of Clovis Oncology and may own stock or have stock options in that company. JAL has received lecture fees from Clovis Oncology, AstraZeneca, GlaxoSmithKline, and Pfizer; served on advisory boards for Clovis Oncology, Amgen, Artios Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Merck/Merck Sharp & Dohme, Nuvation, Pfizer, Regeneron, VBL Therapeutics, and Tesaro/GlaxoSmithKline; and received research grants from AstraZeneca and Merck/Merck Sharp & Dohme. RLC reports grants or contracts from Clovis Oncology, AstraZeneca, Gateway Foundation, Genelux, Genmab, Janssen, Merck, and Roche/Genentech; consulting fees from Clovis Oncology, Agenus, Alkermes, AstraZeneca, Deciphera, Genelux, Genmab, GlaxoSmithKline, Immunogen, Janssen, OncoQuest, OncXerna, Onxeo, Regeneron, and Roche/Genentech., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib., Methods: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors., Results: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10-0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations., Conclusion: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants., Competing Interests: Declaration of Competing Interest E.M. Swisher has no conflicts to report. R.S. Kristeleit reports grants from MSD; reports personal fees from Clovis Oncology, Eisai, GSK, MSD, and Roche; and received non-financial support from GSK. A.M. Oza reports grants from AstraZeneca; has served on steering committee for Clovis Oncology; and has served as a principal investigator of an investigator initiated clinical trial from GSK. A.V. Tinker received grants and honoraria from AstraZeneca. I. Ray-Coquard reports grants from BMS, GSK, and Roche; received personal fees from Clovis Oncology, AstraZeneca, BMS, Deciphera Pharmaceuticals, GSK, and Roche; and received support for travel from AstraZeneca. A. Oaknin reports grants from Clovis Oncology, AbbVie Deutchland, Ability Pharma, Advaxis, Aeterna Zentaris, Amgen SA, Aprea Therapeutics AB, BMS, Eisai, F. Hoffmann - La Roche Ltd., Regeneron Pharmaceuticals, Immunogen, Merck Sharp & Dohme de España SA, Millennium Pharmaceutials, PharmaMar, and Tesaro; received personal fees from Clovis Oncology, AstraZeneca, Deciphera Pharmarceutial, Genmab, GSK, Immunogen, Mersana Therapeutic, Pharma Mar, Roche, and Tesaro; and received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche. R.L. Coleman reports grants from Clovis Oncology, AstraZeneca, Genmab, Janssen, Merck, and Roche/Genentech; and has served as a consultant to Clovis Oncology, Agenus, AstraZeneca, Genmab, GSK, Janssen, OncoQuest, Regeneron Pharmaceuticals, and Roche/Genentech. H.A. Burris reports payment for consulting services from AstraZeneca, Celgene, FORMA Therapeutics, and Incyte; has received payment for his expert testimony from Novartis; has performed non-compensated consulting services for Bayer, Daiichi Sankyo, GRAIL, Novartis, and Pfizer; and his institution has received grants for conduct of clinical trials from Clovis Oncology, Agios, Arch, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley Discoveries, Boehringer Ingelheim, Bristol-Myers Squibb, CicloMed, CytomX Therapeutics, eFFECTOR Therapeutics, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kyocera, Lilly, Macrogenics, MedImmune, Merck, miRNA Therapeutics, Moderna Therapeutics, Novartis, Pfizer, Revolution Medicines, Roche/Genentech, Seattle Genetics, Takeda/Millennium, Tesaro, TG Therapeutics, Verastem, and Vertex. Dr. Burris is employed by and has a leadership position at HCA Healthcare/Sarah Cannon Research Institute and owns stock in that company. C. Aghajanian has served on steering committees for AbbVie and Genentech; has served on advisory boards for and received honoraria from Clovis Oncology, AbbVie, AstraZeneca, AstraZeneca/Merck, Eisai/Merck, Immunogen, Mersana Therapeutics, Repare, Roche/Genentech, and Tesaro; has served as a National Coordinating Investigator to AstraZeneca; and reports grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech. D.M. O’Malley reports grants, personal fees, and other from Clovis Oncology during the conduct of the study; has served on advisory boards for Agenus, AstraZeneca, Eisai, Genentech/Roche, Immunogen, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Novartis Pharmaceuticals, Novocure, Regeneron Pharmaceuticals, SeaGen, Tarveda, and Tesaro/GSK; has served on steering committees for Amgen; has served as a consultant to AbbVie, Agenus, Ambry, AstraZeneca, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance Biotherapeutics, Merck, Mersana, Novartis Pharmaceuticals, Novocure, Seagen, and Tesaro/GSK; and his institution has received research support from AbbVie, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, BMS, Cerulean Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Genmab, Genentech/Roche, GOG Foundation, ImmunoGen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Ludwig Institute for Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Seagen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University. A. Leary reports grants from Clovis Oncology, Ability Pharma, Agenus, AstraZeneca, GSK, Inivata, Iovance Biotherapeutics, MSD, Roche, Sanofi, and Tesaro; and received personal fees from Clovis Oncology, Ability Pharma, AstraZeneca, Biocad, GSK, MSD, Tesaro, and Zentalis. S. Welch has served on advisory boards for AstraZeneca and Roche; reports institutional research support from Clovis Oncology, AstraZeneca, Merck, Regeneron, and Tesaro; and has received honoraria from AstraZeneca. D. Provencher has served on advisory boards for Clovis Oncology, AstraZeneca, GSK, Roche-Genentech, and Tesaro. G.I. Shapiro’s institution received reimbursement of study costs from Clovis Oncology for this clinical trial. He has received research funding from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology. He has served on advisory boards for Almac, Angiex, Artios, Asana, Astex, Atrin, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Concarlo Holdings, Cybrexa Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Fusion Pharmaceuticals, G1 Therapeutics, ImmunoMet, Ipsen, Merck KGaA/EMD-Serono, Pfizer, Roche, Seattle Genetics, Sierra Oncology, Syros, and Zentalis. In addition, he holds a patent entitled, “Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell. L.m. Chen has no conflicts to report. R. Shapira-Frommer has no conflicts to report. S.H. Kaufmann reports grants from Eli Lilly and from Cyteir outside the submitted work; In addition, Dr. Kaufmann has a patent (U.S. Patent No. 8,729,048) issued. S. Goble, L. Maloney, T. Kwan, and K.K. Lin are employees of Clovis Oncology and may own stock or have stock options in that company. I.A. McNeish has served on advisory boards for Clovis Oncology, Alkermes, AstraZeneca, GSK/Tesaro, and Roche. His institution receives funding from AstraZeneca., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2., Methods: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUC ss ) and maximum concentration (C max,ss ) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUC avg,ss and C max,avg,ss ) using a previously developed population pharmacokinetic model., Results: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUC avg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. C max,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05)., Conclusion: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma., Competing Interests: Declaration of competing interest G.E. Konecny has served on speaker bureaus for Clovis Oncology, GSK and AstraZeneca and received research funding from Lilly and Merck. A.M. Oza reports grants from AstraZeneca; has served on steering committee for Clovis Oncology; and has served as a principal investigator of an investigator initiated clinical trial from GSK. A.V. Tinker received grants and honoraria from AstraZeneca. A. Oaknin reports grants from Clovis Oncology, Abbie Deutchland, Ability Pharma, Advaxis, Aeterna Zentaris, Amgen SA, Aprea Therapeutics AB, BMS, Bristrol Meyers Squibb, Eisai, F. Hoffmann - La Roche Ltd., Regeneron Pharmaceuticals, Immunogen, Merck Sharp & Dohme de España SA, Millennium Pharmaceutials, PharmaMar, and Tesaro; received personal fees from Clovis Oncology, AstraZeneca, Deciphera Pharmarceutial, Genmab, GSK, Immunogen, Mersana Therapeutic, Pharma Mar, Roche, and Tesaro; and received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche. R. Shapira-Frommer has no conflicts to report. I. Ray-Coquard has reports grants from BMS, GSK, and Roche; received personal fees from Clovis Oncology, AstraZeneca, BMS, Deciphera Pharmaceuticals, GSK, and Roche; and received support for travel from AstraZeneca. C. Aghajanian has served on steering committees for AbbVie and Genentech; has served on advisory boards for and received honoraria from Clovis Oncology, AbbVie, AstraZeneca, AstraZeneca/Merck, Eisai/Merck, Immunogen, Mersana Therapeutics, Roche/Genentech, and Tesaro; has served as a National Coordinating Investigator to AstraZeneca; and reports grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech. R.L. Coleman reports grants from Clovis Oncology, AstraZeneca, Genmab, Janssen, Merck, and Roche/Genentech; and has served as a consultant to Clovis Oncology, Agenus, AstraZeneca, Genmab, GSK, Janssen, OncoQuest, Regeneron Pharmaceuticals, and Roche/Genentech. D.M. O'Malley reports grants, personal fees, and other from Clovis during the conduct of the study; has served on advisory boards for Agenus, AstraZeneca, Eisai, Genentech/Roche, Immunogen, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Novartis Pharmaceuticals, Novocure, Regeneron Pharmaceuticals, SeaGen, Tarveda, and Tesaro/GSK; has served on steering committees for Amgen; has served as a consultant to AbbVie, Agenus, Ambry, AstraZeneca, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance Biotherapeutics, Merck, Mersana, Novartis Pharmaceuticals, Novocure, Seagen, and Tesaro/GSK; and his institution has received research support from AbbVie, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Genmab, Genentech/Roche, GOG Foundation, ImmunoGen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Ludwig Institute for Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Seagen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University. A. Leary reports grants from Clovis Oncology, Ability Pharma, Agenus, AstraZeneca, GSK, Inivata, Iovance Biotherapeutics, MSD, Roche, Sanofi, and Tesaro; and received personal fees from Clovis Oncology, Ability Pharma, AstraZeneca, Biocad, GSK, MSD, Tesaro, and Zentalis. L.m. Chen has no conflicts to report. D. Provencher has served on advisory boards for Clovis Oncology, AstraZeneca, GlaxoSmithKline, Roche-Genentech, and Tesaro. L. Ma has no conflicts to report. J.D. Brenton has served as a leader to Tailor Bio; owns stock and other ownership interests in Inivata Ltd. and Tailor Bio; has received honoraria from GSK; has served as a consultant or on advisory boards for AstraZeneca; his institution has received research funding from Aprea; has patents, royalties, other intellectual property for TAm-Seq v2 method for ctDNA estimation and for enhanced detection of target DNA by fragment size analysis; and received support for travel, accommodation, and expenses from GSK. C. Castro received personal fees from Qiagen. M. Green is an employee of Certara and was a paid contractor to Clovis Oncology in connection with the analysis and development of this manuscript. A. D. Simmons, J. Beltman, T. Harding, K. K. Lin, S. Goble, L. Maloney, and J.J. Xiao are employees of Clovis Oncology and may own stock or have stock options in that company. R.S. Kristeleit reports grants from MSD; reports personal fees from Clovis Oncology, Eisai, GSK, MSD, and Roche; and received non-financial support from GSK. I.A. McNeish has served on advisory boards for Clovis Oncology. E.M. Swisher has no conflicts to report., (Copyright © 2021. Published by Elsevier Inc.)

Background: In the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3., Methods: Patients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (<65 years, 65-74 years, and ≥75 years)., Results: Investigator-assessed PFS was significantly longer with rucaparib than placebo in patients aged <65 years (rucaparib n = 237 vs placebo n = 117; median, 11.1 vs 5.4 months; hazard ratio [HR]: 0.33 [95% confidence interval (95% CI) 0.25-0.43]; P < 0.0001) and 65-74 years (n = 113 vs n = 64; median, 8.3 vs 5.3 months; HR 0.43 [95% CI 0.29-0.63]; P < 0.0001) and numerically longer in patients aged ≥75 years (n = 25 vs n = 8; median, 9.2 vs 5.5 months; HR 0.47 [95% CI 0.16-1.35]; P = 0.1593). QA-PFS and Q-TWiST were significantly longer with rucaparib than placebo across all age subgroups. Safety of rucaparib was generally similar across the age subgroups., Conclusions: Efficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age. https://clinicaltrials.gov/ct2/show/NCT01968213., Competing Interests: Declaration of competing interest Nicoletta Colombo: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, BIOCAD, Pfizer, PharmaMar, Roche, and Tesaro. Amit M. Oza: Served on advisory boards for Clovis Oncology, Amgen, AstraZeneca, GlaxoSmithKline, and Immunovaccine. Domenica Lorusso: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, and Tesaro and received support for travel or accommodation from PharmaMar and Roche. Carol Aghajanian: Served on a steering committee for Clovis Oncology, AbbVie, Genentech, and Mateon Therapeutics; served on advisory boards for Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, and Tesaro; received research grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech; and received honoraria from Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, Mateon Therapeutics, and Tesaro. Ana Oaknin: Served on advisory boards for Clovis Oncology, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, and Tesaro; received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and received research grants from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen SA, Aprea Therapeutics AB, Bristol-Myers Squibb, Eisai, F. Hoffmann-La Roche, ImmunoGen, Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals, PharmaMar, Regeneron Pharmaceuticals, and Tesaro. Andrew Dean: Served in a consulting or advisory role for Precision Oncology Australia, Shire Pharmaceuticals, and Specialised Therapeutics Australia. Johanne I. Weberpals: Received research support from AbbVie and AstraZeneca and served on advisory boards for AstraZeneca. Andrew R. Clamp: Served on advisory boards for AstraZeneca; received research funding from Clovis Oncology and AstraZeneca; and received support for travel and accommodation for congress attendance from Clovis Oncology, AstraZeneca, and Roche. Giovanni Scambia: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, PharmaMar, Roche, and Tesaro. Alexandra Leary: Served on advisory boards for Clovis Oncology, AstraZeneca, BIOCAD, GamaMabs, Genmab/Seattle Genetics, Merck Sharp & Dohme, Pfizer, PharmaMar, and Tesaro; received support for travel and accommodation from Clovis Oncology, AstraZeneca, Roche, and Tesaro; and reports institutional research grant support from Clovis Oncology, AstraZeneca, GamaMabs, Inivata, Merck Sharp & Dohme, Merus, Sanofi, and Tesaro. Robert W. Holloway: Served on speakers bureaus for Clovis Oncology, AstraZeneca, and Tesaro. Margarita Amenedo Gancedo: Served on advisory boards for Clovis Oncology and on speakers bureaus for AstraZeneca, PharmaMar, and Roche. Peter C. Fong: Served on advisory boards for Clovis Oncology and AstraZeneca and received honoraria from AstraZeneca. Jeffrey C. Goh: Served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb and Tesaro; served on speakers bureaus for Ipsen and Merck Sharp & Dohme; and received support for travel or accommodation from Astellas, AstraZeneca, and Bristol-Myers Squibb. David M. O'Malley: Served on advisory boards for Clovis Oncology, AbbVie, AstraZeneca, Eisai, Genentech/Roche, Genelux, Iovance Biotherapeutics, Janssen, Novocure, Regeneron, and Tesaro; has served on steering committees for Clovis Oncology, Agenus, Amgen, and Novocure; has served as a consultant for AbbVie, Ambry, AstraZeneca, Genentech/Roche, Gynecologic Oncology Group Foundation, and Tesaro; has given a presentation on ovarian cancer at the National Comprehensive Cancer Network; and his institution has received research support from Clovis Oncology, AbbVie, Agenus, Amgen, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, ERGOMED Clinical Research, Genentech, Gynecologic Oncology Group, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen Research and Development, Ludwig Institute for Cancer Research, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, TRACON Pharmaceuticals, VentiRx, and Yale University. Deborah K. Armstrong: Served as a scientific advisor for Morphotek and received research funding from Clovis Oncology, Advaxis, AstraZeneca, Pfizer, Syndax, and Tesaro. Susana Banerjee: Served on advisory boards and received honoraria from Clovis Oncology, AstraZeneca, PharmaMar, Seattle Genetics, and Tesaro; received honoraria from Merck Serono and Roche; and received support for travel or accommodation from NuCana and Tesaro. Jesus García-Donas: Received research funding from AstraZeneca, Pierre Fabre, and Pfizer; received personal fees from Clovis Oncology, Astellas, Pierre Fabre, and Pfizer; and received nonfinancial support from Astellas, Pierre Fabre, and Pfizer. Elizabeth M. Swisher: Has nothing to disclose. Juliette Meunier: Employee of Modus Outcomes, which was contracted by Clovis Oncology to conduct these analyses. Terri Cameron, Lara Maloney, Sandra Goble, and Josh Bedel: Employees of Clovis Oncology and may own stock or have stock options in that company. Jonathan A. Ledermann: Received lecture fees from Clovis Oncology, AstraZeneca, Merck/Merck Sharp & Dohme, Pfizer, and Tesaro; served on advisory boards for Clovis Oncology, Artios Pharma, AstraZeneca, Cristal Therapeutics, Merck/Merck Sharp & Dohme, Pfizer, Regeneron, Roche, Seattle Genetics, and Tesaro; and received research grants from AstraZeneca and Merck/Merck Sharp & Dohme. Robert L. Coleman: Reports grants from Clovis Oncology, AstraZeneca, Gateway Foundation, Janssen, Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund, Merck, National Institutes of Health, Roche/Genentech, and V-Foundation; has served as an advisor to Clovis Oncology, Agenus, AstraZeneca, GamaMabs, Genmab, Janssen, OncoQuest, Pfizer (Medivation), Regeneron, Roche/Genentech, and Tesaro; and has an endowment as the Ann Rife Cox Chair in Gynecology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC)., Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments., Results: In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred., Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)