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Aim: Addition of abiraterone acetate plus prednisone (AAP) to androgen deprivation therapy (ADT) with or without docetaxel (D) improved overall survival in patients with de novo metastatic castration sensitive prostate cancer in the PEACE-1 trial. The protocol was amended during the course of the study to assess whether addition of AAP increases bone loss., Methods: Patients were randomized to receive either ADT + D with or without AAP. Bone mineral density (BMD) of the lumbar spine, femoral neck, and total hip were measured by dual X-ray absorptiometry at baseline, 6, 12, and 24 months (M). T-Scores and mean percent change in BMD values were assessed., Results: With 97 patients treated with AAP and 98 without, the median age was 65 years and 69 patients were ECOG 0 in each arm. Median baseline body mass index was 25.6 and 26.5 kg/m 2 in patients treated with or without AAP, respectively. Ten and 30 % presented with baseline osteoporosis and osteopenia, respectively. Mean T scores and mean percent changes in BMD measured on three anatomic sites decreased during the first year of treatment in both arms, without difference between arms. At M24, a numerical two-fold increase in patients with osteoporosis was observed in the AAP arm., Conclusions: This is the first prospective assessment of BMD in a randomized trial with an experimental treatment using AAP. Bone loss occurred rapidly in both arms, and addition of AAP did not increase bone loss significantly although a numerically higher rate of osteoporosis was observed at 2 years., Trial Registration: NCT01957436., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. GR reports Advisory Boards: Astellas, Astra Zeneca, Bayer, Pfizer. Consulting: AAA Novartis, Astra Zeneca, Janssen, Merck, Pfizer; Funding research: Bayer; Travel accomodations expenses: AAA Novartis, Astra Zeneca, Bayer, Janssen, and has served on a data safety monitoring board paid to his institution for Gilead, RMD reports honoraria from Astellas Pharma, Bristol Myers Squibb, Janssen, Ipsen, and MSD; and support for attending meetings from Bayer, Novartis, and Pfizer, AB-T reports speaker, consultancy or advisory role: AAA-Novartis, Janssen, MSD, Astrazeneca, Roche, Astellas, Bayer, Bouchara-Recordati; Travel accomodations expenses: AAA Novartis, Bayer, Orion, AF reports honoraria from Adacap, Astellas Pharma, AstraZeneca, Bayer, and Novartis, DB reports honoraria, support for attending meetings, and a fiduciary role in other boards from Janssen, with payment made to his institution, BT reports grants from Bayer and Ferring; personal fees from Amgen, Astellas Pharma, Bayer, Ferring, Myovant, Novartis, and Sanofi; and non-financial support from Astellas and Janssen, LM reports honoraria Sanofi, Astellas Pharma, Janssen, Pfizer, Ipsen, BMS, Astra Zeneca, AAA, Eisai, MSD; travel accomodations expenses AAA, Astellas Pharma, Astra Zeneca, BMS, EISAI, Janssen, MSD, Pfizer, Sanofi, GG reports Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events honoraria to her institution from BMS, Janssen, Pfizer, Alliance Merck-Pfizer, Novartis, MSD, IPSEN, Astra Zeneca, Astellas, EISAI, AMGEN, BAYER support for attending meetings and/or travel from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Ipsen, MSD, and Pfizer, BMS, and has served on a data safety monitoring board or advisory board paid to her institution for Alliance Merck-Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Novartis and Pfizer; SA-L reports Advisory Boards: janssen, Astra Zeneca, Bayer, Daiichi Sankyo Travel, Accommodations, Expenses: Janssen, MSD, AstraZeneca, Pfizer, Astellas; Funding research: Janssen, Astellas, Astra zeneca, Consulting: Janssen, Merck, Astellas, Daiichi Sankyo, MAC reports Advisory role: MSD, Pfizer, Recordati, Astellas, Sanofi, Roche, Merck, Astra Zeneca, Ipsen; Honoraria: Astra Zeneca, Pfizer, Ipsen, Recordati, MSD, Pfizer, Roche Astellas, Janssen; Travel expenses; Janssen, Roche, MSD, Ipsen, Pfizer, Astellas, Bayer, AB reports consulting fees from Astellas Pharma, Bayer, Elekta Brachytherapy, Ferring, and Recordati; honoraria from Accord, Astellas Pharma, Elekta Brachytherapy, Janssen, Ipsen, and Recordati; and research grants from Janssen and Ipsen, SF reports participation in the data and safety monitoring board of Gilead Science, with payment made to her institution, KF reports Honoraria: Janssen (Inst), Astellas Pharma (Inst), Bayer (Inst); Consulting or Advisory Role: Janssen Oncology (Inst), Bayer (Inst), Astellas Pharma (Inst), Sanofi (Inst), Orion, AstraZeneca (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Novartis (Inst), Pfizer (Inst), Arvinas, Daiichi Sankyo Europe GmbH (Inst), MacroGenics, MSD (Inst), CureVac; Travel, Accommodations, Expenses: Bayer, Janssen, MSD, AstraZeneca, Pfizer. All other authors declare no competing interests., (Copyright © 2025. Published by Elsevier Ltd.)

Background: MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes., Methods: IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model., Results: Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints., Conclusions: IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies., Trial Registration: NCT03748641 (MAGNITUDE)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GR: Received consulting or advisory role fees from Astellas, AstraZeneca, Janssen, Merck and Pfizer; research funding from Bayer; and travel, accommodations, or expense reimbursements from Janssen. GA: Received honoraria from Astellas and Janssen; consulting or advisory fees from Abbott Laboratories, Astellas, AstraZeneca, Bayer, ESSA, Ferring, Janssen, Medivation, Millennium, Novartis, Pfizer, Ventana Medical Systems and Veridex; speakers’ bureau fees from Astellas, AstraZeneca, Ferring, Ipsen, Janssen, Sanofi, Takeda and Ventana Medical Systems; research funding from Arno Therapeutics, Innocrin Pharma and Janssen; has patents or other intellectual property or received royalties for abiraterone acetate; received travel, accommodations, or expense reimbursements from Abbott Laboratories, Astellas, Bayer, ESSA, Ferring, Janssen, Medivation, Pfizer and Ventana Medical Systems; and is affiliated with the Institute of Cancer Research. MB: Received honoraria from Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer/Vital, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi/Aventis; consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Roche, and Sanofi; institution received research funding from Ipsen and Janssen; received travel, accommodation and expenses from Amgen, Bayer, Bristol Myers Squibb, and Janssen; employment at Janssen. DO: Received honoraria from Astellas, Bayer and Janssen; consulting or advisory role fees from AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen and Merck; research funding from Astellas, AstraZeneca, Bayer, Genentech/Roche, Janssen, Medivation, Merck, Pfizer and Tokai Pharmaceuticals; and travel, accommodations, or expense reimbursements from Astellas, AstraZeneca, Bayer, Ipsen, Janssen and Roche. KP: Employee of Janssen and shareholder of Johnson and Johnson. MT, LA, CC, SVS, MH: Employees of Janssen. SP: Received consultancy fees from Janssen for participation in advisory boards and general methodological advice. KC: Received honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, and Roche; consulting or advisory fees from Amgen, Astellas, AstraZeneca, Bayer, Constellation Pharmaceuticals, Daiichi Sankyo, ESSA, Janssen, Merck, POINT Biopharma, Roche, and Sanofi; research funding from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, ESSA, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi; and gave expert testimony for AstraZeneca and Novartis., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood., Objectives: To report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC., Methods: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021., Results: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC 95% =[4.2-7.1]) and 1.9 years (IC 95% =[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months., Conclusion: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC)., Methods: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities., Results: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients., Conclusion: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data., Competing Interests: Conflict of interest statement 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest., Methods: Patients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment., Results: 256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients., Conclusions: The four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit., Clinicaltrials: gov registration number: NCT02987543., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prior durvalumab (anti-PD-L1 agent) studies in platinum-refractory metastatic urothelial carcinoma evaluated a dose of 10 mg/kg administered every two weeks. The nonrandomised phase 3b STRONG study (NCT03084471) evaluated the safety and efficacy of fixed-dose durvalumab at a more convenient dosing schedule in a previously treated patient population, more similar to a real-world clinical setting., Patients and Methods: 867 patients with urothelial or nonurothelial urinary tract carcinoma (UTC) who progressed on or after platinum or nonplatinum chemotherapy were treated with durvalumab 1500 mg every four weeks; 87% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and 13% had an ECOG PS of 2. The primary end-point was the incidence of adverse events of special interest (AESIs), including immune-mediated AEs (imAEs). Secondary and exploratory end-points included overall survival (OS), objective response rate (ORR) and disease control rate (at six and 12 months) (DCR)., Results: AESIs of any grade were reported in 51% of patients (8% grade ≥ 3). The incidence of imAEs was 11% (2% grade ≥ 3). The median OS was 7.0 months (95% confidence interval [CI]: 6.4-8.2) and ORR was 18% (95% CI: 14.8-20.6), with complete responses in 5% of patients and a DCR at six months of 19% (95% CI: 16.1-22.1)., Conclusion: Fixed-dose durvalumab monotherapy every four weeks has an acceptable safety profile and yields durable clinical activity in previously chemotherapy-treated patients with UTC. Safety and efficacy are consistent with previous durvalumab studies and other anti-PD-1/PD-L1 agents in this setting. CLINICALTRIALS., Gov Identifier: NCT03084471https://clinicaltrials.gov/ct2/show/NCT03084471., Competing Interests: Conflict of interest statement The following 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: Sang Joon Shin and Guilhem Roubaud. The following authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Guru P. Sonpavde: Has received grants or contracts (institution) from AstraZeneca, Janssen, and Sanofi; Consulting fees from Astellas Pharma, AstraZeneca, Bicycle Therapeutics, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech, Janssen, Merck, Pfizer and Seattle Genetics; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Medscape, Onclive, Physicans' Education Resource and Research to Practice; Support for attending meetings and/or travel from Bristol-Myers Squibb; Other financial or non-financial interests from Astellas Pharma, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Debiopharm Group, Elsevier and QED Therapeutics. Cora N. Sternberg: Has received consulting fees from Astellas Pharma, AstraZeneca, Bayer, Genzyme, Immunomedics, Incyte, Medscape, Merck, Merck Sharp & Dohme, Pfizer, Roche and UroToday. Yohann Loriot: Has received grants or contracts (institution) from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte, Janssen Oncology, Medivation, Merck Sharp & Dohme Oncology, Nektar, Oncogenex, Pfizer and Sanofi; Consulting fees from Astellas Pharma, AstraZeneca; Clovis Oncology, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme Oncology, Roche and Seattle Genetics and institution consulting fees from Janssen and Merck Sharp & Dohme Oncology; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer and Sanofi; Support for attending meetings and/or travel Astellas Pharma, AstraZeneca; Janssen Oncology, Merck Sharp & Dohme Oncology, Roche and Seattle Genetics. Jae Lyun Lee: Has received grants or contracts (institution) from AstraZeneca/MedImmune, Bayer Schering Pharma, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech and Seattle Genetics; Consulting fees from Alteogen, Bristol-Myers Squibb, GI Innovation, Merck Sharp & Dohme, Pfizer and Sanofi/Aventis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer; Stock or stock options from Immunomedics and Myovant Sciences. Aurelien Marabelle: Has received grants or contracts (institution) from Boehringer Ingelheim, Bristol-Myers Squibb, MERUS, MSD and Transgene; Consulting fees from AstraZeneca Bayer, Boehringer Ingelheim, CERENIS THERAPEUTICS, Eisai, Gritstone Oncology, HiFiBiO Therapeutics, ImCheck therapeutics, Innate Pharma, Lytix Biopharma, Merck Serono, Molecular Partners, Merck Sharp & Dohme, OSE Immunotherapeutics, Pierre Fabre, Redx Pharma, Roche, Sanofi, SERVIER, Sotio, Symphogen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme; Support for attending meetings and/or travel from AstraZeneca and Merck Sharp & Dohme; Patents planned, issued or pending from Stanford University (Monoclonal antibodies against CD81); Stock or stock options from HiFiBiO Therapeutics and PEGASCY and PEGASCY (insitition); Other financial or non-financial interests from PEGASCY; Honoraria received from Elsevier as an editor for the European Journal of Cancer. AudeFléchon: Has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and/or support for attending meetings and/or travel rom Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck Sharp & Dohme Oncology, Pfizer, Roche/Genentech and Sanofi/Aventis. Damien Pouessel: Has received has received grants or contracts (institution) from AstraZeneca, Bristol-Myers Squibb, Incyte, Janssen Oncology, Merck Sharp & Dohme, Roche and Seattle Genetics; Consulting fees from Astellas Pharma, AstraZeneca, Janssen Oncology, Pfizer and Sanofi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen Oncology and Merck; Support for attending meetings and/or travel from AstraZeneca, Janssen Oncology and Pfizer. Vittorina Zagonel: Has received has received grants or contracts (institution) from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Lilly and Roche; Consulting fees from Bristol-Myers Squibb and Merck; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Roche and Servier; Support for attending meetings and/or travel from Bayer, Roche and Servier. Fabio Calabro: Has received consulting fees from Merck Sharp & Dohme Oncology and Pfizer. Giuseppe L. Banna: Has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen-Cilag and Roche; Support for attending meetings and/or travel from AstraZeneca/MedImmune, Bristol-Myers Squibb, Ipsen and Pierre Fabre; Patents planned, issued or pending with ST Microelectronics “Deep Learning Motion Algorithm for Lung Cancer Early Detection in Embedded Systems” and “Image processing method, corresponding system and computer program product”. Francisco E. Vera-Badillo: Has received grants or contracts (institution) from AstraZeneca/MedImmune. Thomas Powles: Has received has received grants or contracts, consulting fees and/or payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Seattle Genetics; Support for attending meetings and/or travel from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer and Roche. Eva Hellmis: Has received support for attending meetings and/or travel from Janssen-Cilag. Paulo A. P. Miranda is a current employee of AstraZeneca with AstraZeneca stock or stock options. Ugochi Emeribe and Sun Min Oh are current employees of AstraZeneca. Ana Rita Lima is currently employed as a Third Party Service Provider to AstraZeneca. Sebastien J. Hotte: Has received grants or contracts (institution) from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Janssen Oncology, Merck, Pfizer, Roche/Genentech, Seattle Genetics and SignalChem; Consulting fees from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Pfizer and Roche Canada; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Scientific and Medical Affairs Inc, Bayer, Janssen Oncology and Merck; Support for attending meetings and/or travel from Eisai., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status., Methods: This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated., Results: Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34-7.04] versus 5.75 months [95%CI 4.67-7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+)., Conclusions: Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mihaela Aldea – nothing to disclose. Laurent Lam – nothing to disclose. Emeline Orillard - Honoraria: Astellas, Janssen; Travel, Accommodations, Expenses: Pfizer, Amgen. Casilda Llacer Perez - Travel, Accommodations, Expenses: Astellas Pharma, Angelini Pharma. Mathilde Saint-Ghislain – nothing to disclose. Gwenaelle Gravis - Honoraria (Institution) - Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer; Advisory, Consultancy – BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, Bayer; Travel, Accommodations, Expenses: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, MSD. Aude Flechon - Honoraria and Travel, Accommodations, Expenses: AZ Sanofi, Astellas, Janssen AAA. Guilhem Roubaud – Honoraria, travel and advisory: Astellas, Sanofi, Janssen, Astra Zeneca, Ipsen, Pfizer Philippe Barthelemy – Honoraria: Astellas; Advisory, Consultancy: Janssen-Cilag, Sanofi, MSD, BMS, Pfizer, Novartis, Ipsen, Roche; Travel, Accommodations, Expenses: BMS, Amgen, Pfizer, Janssen-Cilag, Roche, Ipsen. Francesco Ricci – nothing to disclose. Frank Priou – nothing to disclose. Zoe Neviere – nothing to disclose. Mathilde Beaufils – nothing to disclose. Brigitte Laguerre – Honoraria and Travel, Accommodations, Expenses: SANOFI, ASTELLAS, BMS, AstraZeneca, Pfizer, JANSSEN. Anne Claire Hardy – Advisory Board: Roche, AstraZeneca, Pfizer, Novartis, GSK, Clovis, Seagen. Carole Helissey - Advisory board: Sanofi, Janssen, Astellas, Roche, Astra Zeneca. Raffaele Ratta – Consulting/Advisory board: AstraZeneca, Astellas, Pfizer, MSD, Bristol-Myers Squibb; Travel, Accommodations, Expenses: Pfizer, Ipsen, Astellas. Delphine Borchiellini - Principal/sub-Investigator of Clinical Trials for: Astellas, AstraZeneca, BMS, Exelixis, Infinity, Janssen, MSD, Novartis, Pfizer, Roche. Honoraria or Advisory/Consultancy: Astellas, AstraZeneca, BMS, Ipsen, MSD, Novartis, Pfizer, Sanofi. Travel, Accommodations, Expenses: BMS, Ipsen, Janssen, Roche. Cedric Pobel – Travel accommodations/Expenses from Amgen and Sandoz. Florence Joly - Expert Board and/or Lectures: Pfizer, GSK, AstraZeneca, Roche, Janssen, Astellas, IPSEN, MSD, BMS, Clovis, Sanofi Bayer. Elena Castro – Consulting/Advisory board: AstraZeneca, Astellas, Bayer, Janssen; Honoraria: Astellas, AstraZeneca, Bayer, Clovis, Janssen, MSD, Pfizer; Research funding (institution): AstraZeneca, Bayer, Janssen; Travel, Accommodations, Expenses: AstraZeneca, Bayer, Janssen. Antoine Thiery-Vuillemin – Honoraria: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche/Genentech, Bristol-Myers Squibb, MSD, Astellas Pharma; Consulting/Advisory board: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche, Bristol-Myers Squibb, MSD, Astellas Pharma; Research funding (institution): Pfizer; Travel, Accommodations, Expenses: Roche, MSD, Janssen, Bristol-Myers Squibb. Giulia Baciarello – Honoraria: Janssen, Roche; Consulting or Advisory Role: Amgen, Astellas Oncology, Janssen, Roche; Travel, Accommodations, Expenses: Astellas Oncology, Ipsen, Janssen, Roche. Karim Fizazi - Honoraria - Astellas Pharma, Bayer, Janssen, Sanofi; Consulting or Advisory Role - Amgen (Inst), Astellas Pharma, AstraZeneca (Inst), Bayer, Curevac (Inst), ESSA (Inst), Janssen Oncology, Orion Pharma GmbH, Sanofi; Travel, Accommodations, Expenses – Amgen, Janssen., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13., Methods: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain., Results: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy., Conclusions: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: There is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer., Patients and Methods: We performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004-May 2013., Results: The median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56-79) and 72% (95% CI, 59.5-88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens., Conclusion: Similar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)