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Objective: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study., Methods: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021)., Results: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1 - and BRCA2 -mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions)., Conclusions: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy., Trial Registration Number: NCT02655016., Competing Interests: Competing interests: WSG reports consulting and speaker fees from GSK. BPB reports honoraria, support for attending meetings and/or travel from AstraZeneca, Clovis, GSK, MSD, and PharmaMar and advisory board fees from AstraZeneca, Clovis, GSK, and MSD. DMO reports personal fees (consulting and/or advisory boards) and funding for clinical research from AbbVie, Amgen, AstraZeneca, Clovis, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance, Janssen/J&J, Merck, Mersana, Novocure, Regeneron, SDP Oncology (BBI), Seagen, and Tesaro/GSK; funding for clinical research from Ajinomoto, Array Biopharma, Bristol-Myers Squibb, Cerulean Pharma, EMD Serono, Ergomed, Genmab, INC Research, inVentiv Health Clinical, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA Intl, Serono, Stemcentrx, TRACON Pharmaceuticals, VentiRx, and Yale University; personal fees from Myriad Genetics, Rubis, and Tarveda; personal fees and funding for clinical research from Agenus; and personal fees (consulting and/or advisory boards) from Ambry, Arquer Diagnostics, Celsion, Corcept Therapeutics, Elevar, InxMed, Novartis, Roche Diagnostics MSA, Sorrento, Takeda, and Toray. IV reports institutional payments for corporate-sponsored research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent AS, Sotio AS, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharma, and Oncoinvent AS; honoraria payment from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Jazz Pharma, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio AS; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; and advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, MSD, Novartis, Novocure, Seagen (2021), and Sotio AS. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. AA reports advisory board fees from GSK and MSD. LJC reports institutional research funding from AbbVie, Advaxis, Agenus, Ajinomoto, Arcus Biosciences, Array BioPharma, AstraZeneca, BeiGene USA, BMS, Cerulean Pharma, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Hoffman–LaRoche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentiv Health Clinical, Jansen R&D, Karyopharm, Leap Therapeutics, Ludwig Institute of Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, OncoQuest, OvaGene, Pfizer, PharmaMar, PRA International, Precision Therapeutics, Regeneron, Sanofi, Seattle Genetics, Serono, Stemcentrx, Sumitomo Dainippon Pharma Oncology, Sutro Biopharma, Tesaro (GSK), TRACON Pharm, and Verastem; personal advisory board fees from A28 Therapeutics, Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, GSK, Immunogen, InxMed, Luzsana Biotechnology, Myriad Genetics, Onconova, Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, and VBL Therapeutics; and member of the data monitoring committee for Corcept Therapeutics. RS reports support for attending meetings from MSD and advisory board fees from Clovis Oncology, GSK, and MSD. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. PF reports payment or honoraria and payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. EIB reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). CM reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. AY reports a GEICO grant by GSK. RGM reports personal fees from Fujirebio Diagnostics and research funding from Angle plc. PV reports payment of honoraria to self from MSD, Novartis, and Roche. NR-J reports advisory board fees from Eisai. WY and JH are employees of GSK. AG-M reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Eisai, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy., Methods: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment., Results: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires., Conclusions: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL., Competing Interests: Declaration of competing interest Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, GSK, I-Mab, Immunogen, Incyte, Karyopharm, Merck, Mersana, Onconova, Seagen, Sutro Biopharma, and Toray; consulting fees from AstraZeneca, GSK, GOG Foundation, Merck, and Seagen; support for attending meetings from GOG Partners; advisory board fees from Arquer Diagnostics, Atossa, Clovis Oncology, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab, Immunogen, Lily, Merck, Mersana, Natera, Onconova, Regeneron, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutic. Dr. Han has nothing to disclose. Dr. Chase reports consultant fees from AstraZeneca and GSK, and honoraria from AstraZeneca, GSK, Immunogen, and Seagen/Genmab. Dr. Heitz reports honoraria from AstraZeneca, GSK, Roche, and Tesaro; consulting fees from AstraZeneca, GSK, Roche, and Tesaro. Dr. Burger reports receiving travel support from Genentech and Mersana Therapeutics, stock from Genentech and Mersana Therapeutics, and is an employee of Genentech and Mersana Therapeutics. Dr. Gaba reports consulting fees, advisory board, and honoraria fees from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar, and support for attending meetings from AstraZeneca, Clovis Oncology, GSK, and MSD. Dr. Van Le has nothing to disclose. Dr. Guerra reports AstraZeneca, Clovis Oncology, GSK, Merck, Pharmamar, Roche, and Tesaro; honoraria from AstraZeneca, Clovis Oncology, GSK/Tesaro, and Merck; payment for expert testimony from AstraZeneca, Clovis Oncology, GSK, Merck, Tesaro; travel support from GSK, Roche, and Tesaro; advisory board participation for AstraZeneca, GSK, Merck, and Tesaro. Dr. Bender reports institutional grants from AbbVie, AstraZeneca, Clovis Oncology Inc., Genentech, MSD, and Tesaro. Dr. Korach serves in a leadership role for ISGO. Dr. Cloven reports advisory board fees from Aadii, GSK, Kartos 2022, Novita Pharmaceuticals 2023, Tarveda Therapeutics, Toray, Umoja 2022, and Zentalis. Dr. Churruca reports payment for expert testimony from PharmaMar and support for attending meetings from GSK, and MSD. Dr. Follana reports payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis; and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. Dr. DiSilvestro reports consulting fees from AstraZeneca, GSK, and Immunogen; travel support from AstraZeneca; and leadership roles in the GOG Foundation Board of Directors and NRG Oncology Board of Directors. Dr. Baurain reports consulting fees from AstraZeneca, Bristol-Myers Squibb, GSK, Immunocore, Merck, MSD, Novartis, Pfizer, Pierre-Fabre, Regeneron, Sanofi, and Sun Pharma. Dr. Jardon has nothing to disclose (deceased). Dr. Pisano has nothing to disclose. Dr. Peen has nothing to disclose. Dr. Mäenpää reports honoraria from AstraZeneca, Eisai, and GSK. Dr. Gupta was an employee of GSK at the time the analysis was conducted; currently an employee of Mersana Therapeutics. Dr. Bacqué was an employee of GSK at the time the analysis was conducted; currently an employee of Repare Therapeutics. Dr. Li was an employee of GSK at the time the analysis was conducted and reports GSK stock ownership; currently an employee of Adagio Therapeutics. Ms. Compton is a former employee of GSK and currently receiving consulting fees from GSK. Dr. Antonova is a former employee of GSK. Dr. Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; and speakers' bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. Dr. González-Martín reports manuscript funding from GSK; research/grant funding from Roche and Tesaro/GSK; advisory/consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illunina, MacroGenics, Mersana, MSD, Novartis, Novocure, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Seagen, Sotio, Sutro, Takeda, and Tubuli; speaker bureau fees from AstraZeneca, Clovis Oncology, GSK, PharmaMar, and Roche; and support for attending meetings from AstraZeneca, GSK, PharmaMar, and Roche., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer., Methods: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose., Results: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD., Conclusions: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Current standards for toxicity reporting do not fully capture the impact of adverse events (AEs) on patients' quality of life (QoL). This study aimed to evaluate the association between toxicity and QoL by using toxicity scores that take into account CTCAE grade grouping and AE duration and cumulation., Methods: Analyses were performed on the AURELIA trial dataset, including 361 patients with platinum-resistant ovarian cancer treated with chemotherapy alone or with bevacizumab. Global and physical functioning QoL were issued from the EORTC QoL Questionnaire-Core 30 (QLQ-C30), collected at baseline and 8/9 and 16/18 weeks after treatment initiation. Four toxicity scores were computed: the total number of AEs, multiplied by their grade and not, and the cumulative duration of AEs, weighted by their grade and not. Each score included all AEs or only grade 3/4 nonlaboratory or treatment-related AEs. The relationship between toxicity scores and QoL was assessed through linear mixed regression., Results: We found that 171 (47.5%) and 43 (11.9%) patients experienced at least one grade 3 or 4 AE, respectively, whereas 113 (31.4%) experienced grade 2 AEs only. Physical QoL was negatively associated with all toxicity scores when computed with all grades of AEs (all P<.01), with a weaker association when treatment-related AEs were considered. Global QoL was negatively associated with toxicity scores computed with nonlaboratory all-grade AEs only (β, -3.42 to -3.13; all P<.01). Degrees of association were lower when considering the AE duration., Conclusions: In this analysis of patients with platinum-resistant ovarian cancer, toxicity scores based on the cumulative number of AEs, modulated or not by grade, were more effective at predicting QoL changes than those based on AE duration. Toxicity impact on QoL was better reflected when grade 2 AEs were taken into account together with grade 3/4 AEs, whatever their treatment imputability, and when laboratory AEs were excluded.

Aim: The oral anti-angiogenic therapy nintedanib prolongs progression-free survival (PFS) when combined with chemotherapy after primary surgery for advanced epithelial ovarian cancer. The randomized phase II CHIVA trial evaluated the impact of combining nintedanib with neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer., Methods: Patients with newly diagnosed unresectable FIGO stage IIIC-IV epithelial ovarian cancer received 3-4 cycles of carboplatin plus paclitaxel every 3 weeks as NACT before interval debulking surgery (IDS), followed by 2-3 post-operative cycles. Patients were randomized 2:1 to receive either nintedanib 200 mg twice daily or placebo on days 2-21 every 3 weeks during NACT (omitting peri-operative cycles), and then as maintenance therapy for up to 2 years. The primary endpoint was PFS., Results: Between January 2013 and May 2015, 188 patients were randomized (124 to nintedanib, 64 to placebo). PFS was significantly inferior with nintedanib (median 14.4 versus 16.8 months with placebo; hazard ratio 1.50, p = 0.02). Overall survival (OS) was also inferior (median 37.7 versus 44.1 months, respectively; hazard ratio 1.54, p = 0.054). Nintedanib was associated with increased toxicity (grade 3/4 adverse events: 92% versus 69%, predominantly hematologic and gastrointestinal), lower response rate by RECIST (35% versus 56% before IDS), and lower IDS feasibility (58% versus 77%) versus placebo., Conclusions: Adding nintedanib to chemotherapy and in maintenance as part of NACT for advanced epithelial ovarian cancer cannot be recommended as it increases toxicity and compromises chemotherapy efficacy (IDS, PFS, OS)., Clinicaltrials: govregistration: NCT01583322., Competing Interests: Declaration of Competing Interest Gwénaël Ferron: Advisory boards (Clovis, AstraZeneca, GSK, MSD, Roche, RanD Biotech, Olympus), lectures/symposia (AstraZeneca, Clovis, GSK, MSD, PharmaMar). Nicolas Delanoy: Advisory boards/honoraria (GSK, AstraZeneca, MSD, Clovis Oncology). Florence Joly: Advisory boards (Clovis, AstraZeneca, GSK, MSD, Seagen), lectures/symposia (AstraZeneca, Clovis, GSK, MSD); non-gynecology: Ipsen, Janssen, Sanofi, Bayer, Astellas, Pfizer, Amgen. Alain Lortholary: Advisory board fees (AstraZeneca, MSD Tesaro), speaker honoraria (Clovis Oncology, Roche), congress participation (Novartis, Pfizer, MSD, Lilly, Roche), member of CS3 sein UNICANCER. Benoît You: Consulting (MSD, AstraZeneca, GSK–Tesaro, Bayer, Roche/Genentech, ECS Progastrin, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, Seagen, Myriad). Nadine Dohollou: Consulting/expert (Daiichi, Lilly, Roche, Seagen), conferences/training (Daiichi, Lilly, Roche, Seagen), research grants/clinical trials (AstraZeneca, BMS, Boehringer Ingelheim, Genomic Health, Lilly, MSD, Novartis, Pfizer, Roche). Anne Floquet: Advisory boards (MSD, AstraZeneca, GSK, Clovis Oncology), congress participation (AstraZeneca, GSK, MSD, PharmaMar, Roche). Michel Fabbro: AstraZeneca, GSK, Clovis. Jérôme Alexandre: AstraZeneca, GSK, Clovis, MSD, Eisai, Novartis. Isabelle Ray-Coquard: Advisory/consultancy (Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Mersana, Deciphera, Novocure, Eisai, Sutro Pharma, Merck Sharp & Dohme, Pfizer/Merck Serono, PharmaMar, Roche), research grant/funding (Roche, BMS, MSD, GSK), travel/accommodation/expenses (AstraZeneca, Roche, GSK, Clovis)., (Copyright © 2023. Published by Elsevier Inc.)

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA -mutated (non-g BRCA m) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-g BRCA m cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA- mutated (s BRCA m; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type ( BRCA wt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCA wt tumors with other non- BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCA wt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCA wt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with s BRCA m, other non- BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA /HRR mutation status or myChoice CDx GIS., Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA -mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non- BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo., Competing Interests: G. Lindahl reports personal fees from Honoraria for lectures outside the submitted work. S. Mahner reports grants, personal fees, and other from AbbVie, AstraZeneca, Clovis, Eisai, GSK, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, and Tesaro outside the submitted work. A. Redondo reports personal fees from GSK, MSD; personal fees and other from AstraZeneca; other from Clovis; grants and personal fees from Pharmamar; and grants from Eisai outside the submitted work. M. Fabbro reports personal fees from GSK and AstraZeneca outside the submitted work. B.J. Rimel reports other from GSK, Merck, Immunogen, and personal fees from Deep6AI outside the submitted work. A.M. Oza reports PI and Steering Committees with AstraZeneca, GSK, and Clovis; advisory Board member with AstraZeneca and Morphosys. U. Canzler reports personal fees from AstraZeneca, Lilly, and Roche outside the submitted work. J.S. Berek reports grants from Tesaro during the conduct of the study. A. González-Martín reports personal fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, Sutro and grants from GSK and Roche outside the submitted work. P. Follana reports personal fees from GSK, AstraZeneca, and Clovis outside the submitted work. R. Lord reports personal fees from GSK outside the submitted work. Z. Wang reports other from GSK during the conduct of the study; other from GSK outside the submitted work. D. Gupta reports other from GSK during the conduct of the study; other from GSK outside the submitted work; and D. Gupta is an employee of GSK which sponsored the NOVA trial. U. Matulonis reports personal fees from GSK, AstraZeneca, Merck, Novartis, Next Cure, Agenus, 2X oncology, Symphogen, Alkermes, and Morphosys during the conduct of the study; personal fees from Clearity Foundation and Ovarian Cancer Research Alliance outside the submitted work. B. Feng is an employee of GSK. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: There are limited treatment options for ovarian cancer patients with early relapse after platinum chemotherapy. In preclinical studies, we previously demonstrated the promising activity of ABT-737, a Bcl-2/Bcl-x L anti-apoptotic protein inhibitor, in chemo-resistant ovarian cancer cells and tumors, suggesting its potential activity in platinum-resistant patients., Methods: We conducted a prospective multicenter single-arm phase II study to assess the efficacy of Navitoclax (orally available ABT-737 analogue) monotherapy in 46 heavily pretreated (2-12 lines, median = 4) patients with high-grade serous platinum-resistant ovarian tumors. Navitoclax was administered at the daily dose of 150 mg during a lead-in period (7-14 days) and then increased to 250 mg daily in the absence of dose-limiting thrombocytopenia (95% CI: 13.2-39.2], median PFS was 1.64 months [ 95% CI: 1.58-2.30]. There were 16 (35.6%, 95% CI: 22.3-51.3) overall responses (RECIST v1.1): 1 partial response and 15 stable diseases. No correlation between the expression of Bim, Mcl-1 and P-ERK with clinical response was found in this study. Thrombocytopenia was the major side-effect (G3/4: n = 12; 26%), leading to pursue at the daily dose of 150 mg in 8 patients and to discontinue treatment in 3 patients. Neither significant bleeding nor toxic death were observed., Conclusions: Navitoclax monotherapy had poor activity that was not correlated with the expression of Bim, Mcl-1 and P-ERK, without unacceptable toxicity., Trial Registration: Clinicaltrials.gov identifier: NCT02591095., Competing Interests: Declaration of Competing Interest F. Joly: Abbvie for Navitoclax provision, consulting for Roche, GSK, Astra Zeneca, Clovis, MSD, Ipsen, Janssen, Astellas, Pfizer, Sanofi, BMS, Bayer. M. Fabbro: Consulting for GSK, Astra-Zeneca, and Clovis Oncology. P. Follana: GSK, Astra Zeneca, Clovis, MSD, Novartis, DAIICHI. J.S. Frenel: Consulting for Novartis, Pfizer, Astra Zeneca, Lilly, Roche, BIOCAD, DAIICHI, GSK-Tesaro, Pierre Fabre, and Clovis oncology. B.You: Consulting for MSD, Astra-Zeneca, GSK-TESARO, BAYER, Roche-Genentech, ECS Progastrine, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN, and Myriad. J. Lequesne, J. Medioni, A. Lesoin, S. Abadie-Lacourtoisie, A. Floquet, L. Gladieff, C. Gavoille, E. Kalbacher, M. Briand, P.E. Brachet, F. Giffard, L-B. Weiswald, P.A. Just, C. Blanc-Fournier, A. Leconte, B. Clarisse, A. Leary, L. Poulain: no conflicts of interest to disclose in relation with this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS)., Methods: 166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM)., Results: Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT)., Conclusions: VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical-surgical treatment., Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin-paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests., Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03-0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11-0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery., Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432 ., (©2020 American Association for Cancer Research.)

Purpose: In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy., Patients and Methods: A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCA mut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCA mut (non-g BRCA mut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCA mut status and response to their last platinum-based therapy. Ovarian cancer-specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index., Results: Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCA mut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non-g BRCA mut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes., Conclusion: Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

Background: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women., Patients and Methods: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS., Results: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01)., Conclusion: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial., Methods: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors., Results: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%)., Conclusions: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma., Methods: Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented., Results: In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached., Conclusion: The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer., Methods: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival., Results: Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications., Conclusions: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

Purpose: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines., Patients and Methods: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses., Results: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life., Conclusion: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable., (© 2016 by American Society of Clinical Oncology.)

Purpose: In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC., Patients and Methods: Eligible patients had measurable/assessable OC that had progressed < 6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes., Results: The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients., Conclusion: Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.