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Background: Multiple population-level studies have demonstrated an adverse effect of long wait times to surgery on survival for women with endometrial cancer. Other retrospective and nonrandomized prospective studies have shown that preoperative administration of depot medroxyprogesterone acetate decreases tumor glandular cellularity, which may be a surrogate marker for clinically meaningful tumor response.Objective: We sought to determine whether preoperative injection with depot medroxyprogesterone acetate decreases tumor glandular cellularity when compared to placebo injection in women awaiting hysterectomy for endometrial intraepithelial neoplasia or type I endometrial cancer, and to determine whether depot medroxyprogesterone acetate injection affects quality of life while waiting for surgery.Study Design: This was a double-blind, randomized controlled trial of 400-mg depot medroxyprogesterone acetate injection or 0.9% saline injection at the preoperative visit. Patients with recent use of progesterone analogs were excluded. A sample size of 76 patients (38 per arm) was calculated to detect a 20% difference in decreased glandular cellularity between arms. Pathologic characteristics including the primary outcome, tumor glandular cellularity, from patients' diagnostic biopsies were reviewed by 2 dedicated gynecologic pathologists and compared to posttreatment hysterectomy specimens. On the night prior to surgery, patients completed the Functional Assessment of Cancer Therapy-Endometrial Survey (Version 4) to report quality of life while waiting for surgery. In comparing characteristics between the intervention and control groups, t tests were used for continuous variables, and χ2 or Fisher exact tests were used where appropriate for categorical data.Results: From March 2015 through March 2016, 148 women were screened and 76 patients were enrolled. In all, 38 patients were randomized to and received depot medroxyprogesterone acetate injection and 38 were randomized to and received placebo injection. Demographics were similar between groups. Patients who received depot medroxyprogesterone acetate injection experienced a larger decrease in tumor glandular cellularity (mean change -64 [-31.8%] vs -14 [-5.5%] cells per quarter high-powered field in depot medroxyprogesterone acetate vs placebo groups, P = .002). This effect was most pronounced in women waiting ≥3 weeks for surgery. Several additional histologic and immunohistochemical markers of tumor differentiation and decreased cell proliferation were more pronounced in the depot medroxyprogesterone acetate group than in the placebo group. There were no significant differences in quality of life between groups on the Functional Assessment of Cancer Therapy-Endometrial Survey. Only 5.3% of patients who were approached declined to participate due to concerns regarding an intramuscular injection.Conclusion: Administration of depot medroxyprogesterone acetate prior to surgery for type I endometrial cancers caused greater tumor effect than placebo injection. Injection of depot medroxyprogesterone acetate was acceptable to and well tolerated by patients. Depot medroxyprogesterone acetate may represent a meaningful bridge to surgery in women who can expect long wait times. [ABSTRACT FROM AUTHOR]

Background: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.Methods: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population.Results: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.Conclusions: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.). [ABSTRACT FROM AUTHOR]

Background: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.Methods: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival.Results: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).Conclusions: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.). [ABSTRACT FROM AUTHOR]

Objective: Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group., Methods: From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed)., Results: Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [p < 0.001]. gBRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); sBRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to gBRCA was 35% vs 31% (p = 0.36)., Conclusions: HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of gBRCA was excluded; rates of sBRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications., Competing Interests: Declaration of competing interest The following authors have no disclosures relating to this manuscript: Omali Pitiyarachchi, Laura Holman, Paul DiSilvestro, Mark Morgan, William Tew, Christine Lee, Meredith Newton, Babak Edraki, Thomas Reid and Jay Carlson. Peter J. Ansell and Minh H Dinh are AbbVie employees receiving stock or stock options. Robert L. Coleman: has received grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech, Karyopharm; consulting fees from Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Karyopharm, Roche/Genentech, Novocure, Merck, Abbvie, Novocure; royalties or licenses with Up-To-Date; payment or honoraria for speakers bureaus from AstraZeneca, Clovis, Roche/Genentech, Merck; participation in data safety monitoring or advisory boards from NRG Oncology, Elsai/BMS; leadership or fiduciary role in Onxeo/Valerio, Vaniam Group, GOG Foundation, International Gynecologic Cancer Society, OCNA, Ovarcome. Charles A. Leath III: Grant to institution provided by National Institutes of Health (NCI UG1 CA233330). Theresa Werner has received consulting fees from Mersana; and research funding to the institution - AbbVie, Acrivon, Astra Zeneca, BluePrint, Clovis Oncology, Genmab, GSK-Tesaro, Mersana, Repare Therapeutics, Roche-Genentech. Mary Cunningham: funds to institution provided by Abbvie, AstraZeneca, Clovis Oncology, Tesaro, Vascular Biogenics; and spouse is a stockholder of Intuitive Surgical. Peter Lim: has received payment or honoraria for Speakers Bureau from Astra Zeneca and Merck and is on Advisory Boards for Astra Zeneca, Clovis, Mersana, OncoC4, Immunogen. Joyce Barlin: has received payment/honoraria for Speakers Bureaus from Astra Zeneca and Merck and is on Advisory Boards for Astra Zeneca, Clovis, Mersana, OncoC4, Immunogen. Nicola M. Spirtos: has received institutional grants from NRG and the GOG Foundation. Krishnansu S. Tewari: reports grants to institution (UC Irvine) provided by AbbVie; consulting fees from Merck, Astra Zeneca, Eisai, Seagen, GSK; and payment/honoraria for Speakers Bureaus from Merck, Astra Zeneca, Eisai, Seagen, GSK. Mitchell Edelson: has received funding to attend meetings from Intuitive Surgical; received stock options from Merck when employed. Spouse was a salaried employee at Merck until 8/2022 and spouse is a salaried employee at Pfizer since 3/2023. Michael Friedlander: has received consulting fees from Astra Zeneca, Novartis and GSK; has consulted without payment for Incyclix; has received payment or honoraria for Speakers Bureaus from Astra Zeneca, GSK and MSD; has participated on Data Safety Monitoring or Advisory Boards for AGITG IDSMB and ENDO-3; received institutional support in the form of research grants from Astra Zeneca, Beigene and Novartis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Objective: The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants., Methods: The LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics., Results: The LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%., Conclusion: The LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported., Trial Registration: ClinicalTrials.govNCT00719303., Competing Interests: Declaration of Competing Interest Dr. Austin Miller reports that his institution received grants from the following: Vascular Biogenics LTD, Advaxis, Abbvie. Dr. Miller also reports participating on the Steering Committee for AstraZeneca as well as receiving institutional support from both Regeneron and GSK. Dr. Michael Gold received honoraria from ASCCP as an Educational Course Speaker. Dr. Matthew Powell received support from the NIH/NIH to NCTN NRG Oncology Network. Dr. Powell also reports participating on Advisory Boards for the following entities: GSK/Tesaro, Clovis Oncology, Merck, AstraZeneca, Eisai and SeaGen. Dr. Kristin Bixel reports receiving intuitive unrestricted research grant to the GOG for funding of randomized controlled trial (ROCC). Additionally, Dr. Bixel reports serving on Advisory Boards for Intuitive and Merck and receiving honoraria from both of these entities. Dr. Ratner reports receiving consulting fees from Aspire and has stock in same. Dr. Warner Huh reports receiving consulting fees from AstraZeneca and receiving payment for expert testimony from Shook, Hardy & Bacon LLP. Dr. Basen-Engquist reports MPI, R01CA186700, Study of biomarkers in ovarian cancer: Modulation by activity & diet intervention, MD Anderson subcontract from University of Arizona. She also receives grant from NCI, R21CA239079, Reducing breast cancer risk through modifying boy composition and decreasing inflammation in normal weight women. Dr. Basen-Engquist also reports pilot study grant from NCI, R21 CA215410 as well as receiving funding from Cancer Prevention & Research Institute of Texas: PP170023 &PP200028, Active Living After Cancer: Combining a physical activity program with survivor navigation and she received honoraria for Speaking from the both NCI as well as the University of New Mexico Cancer Center, Gynecologic Oncology Group and Yale University for Faculty TREC training program. Dr. Basen-Engquist also reports receiving support for travel from the National Cancer Policy Forum, National Academies of Science, Engineering, and Medicine and Yale University. She also participated as an Independent Safety Monitor for Boston University, digital health supported weight management intervention delivered by community health workers among public housing residents (R01CA238335). Dr. Basen-Engquist reports serving as President of the American Society of Preventive Oncology. Dr. Walker reports serving in a leadership role for NCORP. Dr. Lisa Kachnic reports NCI NCORP Funding and serving as Associate NCORP PI Support and Chair of Cancer Control Support. All other authors have no conflict of interest related to this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN., Methods: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up., Results: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence., Conclusion: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up., Methods: SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants., Findings: Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2-24·9) in the olaparib group and 13·9 months (8·0-24·8) in the placebo group; median follow-up was 4·8 years (2·8-5·3) in the olaparib group and 5·0 years (2·6-5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9-not reached) with olaparib versus 13·8 months (11·1-18·2) with placebo (hazard ratio 0·33 [95% CI 0·25-0·43]). The most common grade 3-4 adverse events were anaemia (57 [22%] of 260 patients receiving olaparib vs two [2%] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period., Interpretation: For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting., Funding: AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA., Competing Interests: Declaration of interests SB reports clinical trial support paid to her institution from AstraZeneca for this study; grants to her institution from AstraZeneca, GlaxoSmithKline and Tesaro; personal consulting fees from Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Mersana, Merck Sharpe & Dohme, Merck Serono, Oncxerna, Pfizer, and Roche; personal fees from Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Pfizer, Takeda, and Tesaro; support for attending a meeting or travel from Nucana; unpaid participation on a Epsilogen advisory board; and an unpaid role as director of membership for the European Society of Medical Oncology. KNM reports clinical trial support paid to her institution for this study; contracts from Genentech/Roche, Lilly Pharmaceuticals, and PTC Therapeutics for ovarian cancer investigator-initiated trials; consulting fees from IMab; payment to her institution for educational content in gynaecological cancers from Onc Live, Physician Education Resource (PER), PRIME Oncology, and Research to Practice; payment to her institution for advisory boards for use of assets in gynaecological cancers from Alkemeres, Aravive, Blueprint Pharmaceuticals, Eisai, Genentech/Roche, Immunogen, Mersana, Mereo, and VBL Therapeutics; participation on a data safety monitoring board for Incyte; and payments to her institution for being an associate director of GOG partners and committee chair for NRG Ovarian Cancer. NC reports grants from AstraZeneca, PharmaMar, and Roche; personal consulting fees from AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Oncxerna, Pfizer, PharmaMar, Roche, and Tesaro; and personal fees from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tesaro. GS reports grants and research support from Merck Sharpe & Dohme Italia; consulting fees from Johnson & Johnson and Tesaro Bio Italy; and speakers bureau fees and honoraria from Clovis Oncology Italy. AOa reports grants paid to her institution from AbbVie Deutschland, Abililty Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, F Hoffmann-La Roche, Immunogen, Merck Sharp & Dohme de España, Millennium Pharmaceuticals, Pharmamar, Regeneron Pharmaceuticals, and Tesaro; personal fees from AstraZeneca, Clovis Oncology, Deciphera Pharmarceutia, Genmab, GlaxoSmithKline, Immunogen, Mersana Therapeutic, PharmaMar, Roche, Sutro, and Tesaro; and support for attending meetings or travel, or both from AstraZeneca, Pharmamar, and Roche. MF reports personal advisory board and lecture fees, support to travel to a meeting and a grant to his institution from AstraZeneca; personal advisory board fees and a grant to his institution from Novartis; personal advisory board fees from GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, and Takeda; personal lecture fees from Act Genomics and GlaxoSmithKline; research support to his institution from BeiGene; consulting for AbbVie (not renumerated); and participation on the Australasian Gastro-Intestinal Trials Group Independent Data Monitoring and Safety Committee. AF reports support for attending a medical congress from AstraZeneca. ALe reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria or reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GlaxoSmithKline, Medscape, Merck Serono, Merck Sharpe & Dohme, TouchCongress, and Zentalis; and support for attending meetings or travel, or both, from AstraZeneca, Clovis Oncology, GlaxoSmithKline, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. GSS reports institutional research support from AstraZeneca and Merck for this study; institutional research support from Novartis and Roche; and consulting fees paid to his institution from Biovica and Seagen. CG reports clinical trial funding for this study to his institution from AstraZeneca; clinical research grants to his institution from Aprea, AstraZeneca, BergenBio, Clovis, GlaxoSmithKline, Medannexin, Merck Sharpe & Dohme, Novartis, Nucana, and Tesaro; personal consulting fees from AstraZeneca, GlaxoSmithKline, Merck Sharpe & Dohme, and Tesaro; honoraria for lectures or presentations from AstraZeneca, Chugai, Clovis Oncology, GlaxoSmithKline, Merck Sharpe & Dohme, Nucana, Roche, Takeda, and Tesaro; honoraria for lectures, presentations, or preparing educational materials from Cor2Ed; advisory board attendance for AstraZeneca, Chugai, GlaxoSmithKline, Merck Sharpe & Dohme, Nucana, Roche, and Tesaro; and being a committee member on the Scottish Medicines Consortium. AOz reports a grant from AstraZeneca to his institution outside the submitted work. AG-M reports clinical trial funding from GlaxoSmithKline and Roche; consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Immunogen, Mersana, Merck Sharpe & Dohme, Oncoinvent, Pharmamar, Roche, Sotio, and Takeda; personal fees from AstraZeneca, Clovis, GlaxoSmithKline, Merck Sharpe & Dohme, and Roche; support for attending meetings or travel, or both, from AstraZeneca, GlaxoSmithKline, Merck Sharpe & Dohme, Pharmamar, and Roche; and being the current chairman of GEICO and the chairman of ENGOT from 2018 to 2020. CA reports receiving advisory board fees from AbbVie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech; participation on an advisory board for Blueprint Medicine; participation on the board of directors for GOG Foundation and NRG Oncology; clinical trial funding to her institution from AstraZeneca for this study; and clinical trial funding to her institution from AbbVie, AstraZeneca, Clovis, and Genentech. ESL reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. EH reports full-time employment with AstraZeneca, contracted by PHASTAR, during the conduct of the study. B-GK, ALi, WHB, and PDS declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.

Background: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm)., Methods: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses., Results: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95)., Conclusions: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm., Competing Interests: Conflict of interest statement Ignace Vergote: reports consulting fees, paid to his institution, from Advaxis, Eisai, MSD Belgium, F. Hoffman-La Roche, Millennium Pharmaceuticals, Oncoinvent and Sotio; consulting fees, paid to his institution, and travel support from Roche, Genmab, PharmaMar, Clovis Oncology, AstraZeneca, Tesaro and Immunogen; grant support, paid to his institution, from Amgen, Stichting tegen Kanker and Roche; research support from Oncoinvent and Genmab; and travel support from Takeda Oncology. Isabelle Ray-Coquard: reports consulting fees, grant and travel support from AstraZeneca and Roche, consulting fees and travel support from GlaxoSmithKline, consulting fees from Clovis Oncology, PharmaMar, Mersana Therapeutics, Deciphera Pharmaceutical, Amgen and Chugai Pharmaceutical, grant support from Bristol Myers Squibb, and consulting fees and grant support from Merck Sharp & Dohme. Daniel M. Anderson: reports nothing to disclose. Guilherme Cantuaria: reports nothing to disclose. Nicoletta Colombo: reports personal fees from AstraZeneca, MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad and Immunogen. Claire Garnier-Tixidre: reports personal fees from Roche, AstraZeneca, Pfizer and Lilly and non-financial support from MSD and Pfizer. Lucy Gilbert: reports consulting fees from GSK, Merck, Eisai, Astra Zeneca and Alkermes, and grant support from Alkermes, Immunogen, AstraZeneca, Esperas Pharma Inc, Merck Sharp & Dohme, Marsan Therapeutics, Roche, Tesaro, Pfizer and Karyopharm Therapeutics. Philipp Harter: reports consulting fees and grant support from AstraZeneca, Roche, Tesaro, and GlaxoSmithKline, consulting fees from Sotio, Zai Lab, Merck Sharp & Dohme, Clovis Oncology and Immunogen, and grant support from Boehringer Ingelheim, Medac, Genmab, the European Union, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft. Robert Hettle: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. Domenica Lorusso: reports consultancy fees from Amgen and PharmaMar; advisory board fees and speaker fees from AstraZeneca; advisory board fees, speaker fees and grant support for academic trials (institutional) from GSK and MSD; speaker fees, grants (institutional) and financial support for trial co-ordination (institutional) from Clovis Oncology; and non-financial support from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Roche and the Gynecological Cancer InterGroup. Johanna Mäenpää: reports consulting fees from AstraZeneca, Clovis, MSD and Orion Pharma; and consulting fees and travel support from Roche and Tesaro/GSK. Christian Marth: reports personal fees from AstraZeneca, MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Seagen and Biocad. Koji Matsumoto: reports institutional fees for clinical trials from AbbVie, AstraZeneca, Chugai, Eisai, Lilly, ICON, MSD and ONO and personal fees from AbbVie, AstraZeneca, Chugai, Kyowa-Kirin, Lilly and Pfizer. Mario Ouwens: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. Andrés Poveda: reports grants and personal fees from AstraZeneca and personal fees from PharmaMar, AstraZeneca, Roche, Clovis Oncology and Tesaro. Francesco Raspagliesi: reports grants and travel support from Astra Zeneca, MSD, Clovis, Pharmamar, Roche and GSK. Kirsty Rhodes: reports full-time employment with AstraZeneca and AstraZeneca stock ownership. María Jesus Rubio Pérez: reports nothing to disclose. Ronnie Shapira-Frommer: reports advisory board fees from MSD, VBL Therapeutics, Eisai and Clovis Oncology, research grant from MSD; and speaker honoraria from MSD, BMS, Novartis, Roche, Medison, Neopharm and AstraZeneca. Ayumi Shikama: reports nothing to disclose. Magdalena Sikorska: reports nothing to disclose. Kathleen Moore: reports personal fees from AstraZeneca, AbbVie, Aravive, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar and Tarveda, outside the submitted work. Paul DiSilvestro: reports personal fees from AstraZeneca., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1., Methods: Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130)., Results: Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily., Conclusions: Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients., Competing Interests: Declaration of competing interest NC reports personal fees from AstraZeneca during the conduct of the study; and personal fees from MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad and Immunogen outside the submitted work. KM reports personal fees from Astra-Zeneca, AbbVie, Aravive, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar and Tarveda, outside the submitted work. AOaknin reports personal fees, other and grants from PharmaMar and Clovis Oncology, personal fees and other from Roche and AstraZeneca, personal fees and grants from Tesaro and Immunogen, personal fees from Genmab, and grants from AbbVie Deutchland, Ability Pharmaceuticals, Advaxis, Æterna Zentaris, Amgen SA, Aprea Therapeutics AB, Eisai, F. Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals and Bristol Myers Squibb, outside the submitted work. MF reports grants, personal fees and other from AstraZeneca, grants and personal fees from Novartis, personal fees from Takeda, GSK, Lilly and MSD, and other from AbbVie, outside the submitted work. AF reports personal fees and other from AstraZeneca, MSD and GSK outside the submitted work. ALeary reports grants and personal fees from AstraZeneca, Clovis Oncology, MSD, Tesaro, GSK and Ability, personal fees from Biocad and Zentalis, and grants from Iovance, Agenus, Sanofi, Inivata and Roche, outside the submitted work. GSS reports institutional reimbursement for patient accrual and medical writing assistance from AstraZeneca during the conduct of the study, and institutional research support from Merck, Novartis and Roche outside the submitted work. CG reports grants from AstraZeneca during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, Tesaro, Nucana and Sierra Oncology, grants from Aprea and Novartis, and personal fees from Roche, Foundation One, Chugai, MSD and Cor2Ed, outside the submitted work; and patents for molecular diagnostic tests for cancer. SB reports grants and personal fees from AstraZeneca and Tesaro, personal fees from Clovis Oncology, GSK, MSD, Pfizer, Mersana, Merck Serono, Roche, Seattle Genetics, Genmab, Amgen and Immunogen, and other from Nucana, outside the submitted work. AOza reports being a principal investigator of investigator-initiated studies with AstraZeneca, that his institution has received grant funding from AstraZeneca, and being a steering committee member (noncompensated) for trials with AstraZeneca, Clovis Oncology, Tesaro and Merck. AGM reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, MSD, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche and Sotio and grants and personal fees from GSK-Tesaro, outside the submitted work. CA reports personal fees from AstraZeneca/Merck, Tesaro, Immunogen, Eisai/Merck, Mersana Therapeutics and Roche, grants from Genentech, and grants and personal fees from AstraZeneca, Clovis Oncology and AbbVie, outside the submitted work. CM reports grants from Syros, Deciphera, AstraZeneca, Astellas Pharma, Tesaro/GSK, Seattle Genetics and Regeneron outside the submitted work. JL reports personal fees from AstraZeneca, Clovis Oncology, Genentech, Regeneron and Tesaro/GSK, and other from Merck, outside the submitted work; and funding to her institution as Principal Investigator on trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro and Vigeo Therapeutics. ESL and RB report full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. PDS reports personal fees from AstraZeneca outside the submitted work. All other authors (GS, ALisyanskaya, WB and JWK) declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status., Methods: SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986., Findings: Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo., Interpretation: The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo., Funding: AstraZeneca and Merck Sharp & Dohme., Competing Interests: Declaration of interests MF reports institutional research support, personal fees, consulting fees, and travel support from AstraZeneca; institutional research support and personal fees from Novartis; institutional research support from Beigene; personal fees from Takeda, GlaxoSmithKline, Lilly and Merck Sharp & Dohme, and being on a trial management committee for AbbVie, outside the submitted work. KNM reports personal fees from AstraZeneca, AbbVie, Aravive, Eisai, GlaxoSmithKline, Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar, and Tarveda, outside the submitted work. NC reports personal fees from AstraZeneca during the conduct of the study; and personal fees from Merck Sharp & Dohme, Roche, Tesaro, GlaxoSmithKline, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad, and Immunogen, outside the submitted work. AOa reports personal fees, travel and accommodation support, and grants from PharmaMar and Clovis Oncology; personal fees, and travel and accomodation support from Roche and AstraZeneca; personal fees and grants from Tesaro and Immunogen; personal fees from Genmab; and grants from AbbVie Deutchland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Eisai, F Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de España, Millennium Pharmaceuticals, and Bristol Myers Squibb, outside the submitted work. GSS reports institutional reimbursement for patient accrual and medical writing assistance from AstraZeneca, during the conduct of the study; and institutional research support from Merck, Novartis, and Roche, outside the submitted work. CG reports grants from AstraZeneca during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Tesaro, Nucana, and Sierra Oncology; grants from Aprea and Novartis; personal fees from Roche, Foundation One, Chugai, Merck Sharp & Dohme, and Cor2Ed, outside the submitted work; and patents for molecular diagnostic tests for cancer. SB reports grants and personal fees from AstraZeneca and Tesaro; personal fees from Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Mersana, Merck Serono, Roche, Seattle Genetics, Genmab, Amgen, and Immunogen; and travel support from Nucana, outside the submitted work. AOz reports being a principal investigator of investigator-initiated studies with AstraZeneca, that his institution has received grant funding from AstraZeneca, and being a steering committee member (non-compensated) for AstraZeneca, Clovis Oncology, and GlaxoSmithKline. AG-M reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, and Sotio; and grants and personal fees from GlaxoSmithKline, and Tesaro, outside the submitted work. CA reports personal fees from AstraZeneca/Merck, Tesaro, Immunogen, Eisai/Merck, Mersana Therapeutics, and Roche/Genentech; grants from Genentech; and grants and personal fees from AstraZeneca, Clovis Oncology, and AbbVie, outside the submitted work. JL reports personal fees from AstraZeneca, Clovis Oncology, Genentech, Regeneron, Tesaro, and GlaxoSmithKline; and advisory board fees from Merck, outside the submitted work; and funding to her institution as principal investigator on trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics. CM reports grants from Syros, Deciphera, AstraZeneca, Astellas Pharma, Tesaro, GlaxoSmithKline, Seattle Genetics, Regeneron, and Moderna, outside the submitted work. FS reports personal fees and non-financial support from Roche, AstraZeneca, Tesaro, Merck Sharp & Dohme, and PharmaMar; and personal fees from GlaxoSmithKline and Clovis Oncology, outside the submitted work. ESL, RH, and EF report full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. EP reports employment with Parexel, which has received consultancy fees from AstraZeneca, during the conduct of the study. PDS reports personal fees from AstraZeneca, GlaxoSmithKline, Tesaro, and AbbVie, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy., Methods: QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline., Findings: Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related., Interpretation: We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations., Funding: Tesaro., (Copyright © 2019 Elsevier Ltd. All rights reserved.)