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Background: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status., Objective: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone., Design, Setting, and Participants: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment., Intervention: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid)., Outcome Measurements and Statistical Analysis: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively., Results and Limitations: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone)., Conclusions: Olaparib plus abiraterone has a manageable and predictable safety profile., Patient Summary: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis., Methods: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m 2 ) and cisplatin (25 mg/m 2 ) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235., Findings: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%])., Interpretation: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer., Funding: AstraZeneca., Competing Interests: Declaration of interests D-YO reports advisory fees from Arcus Biosciences, Aslan Pharmaceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, Yuhan, and Zymeworks; and institutional research funding from Array BioPharma, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier. ARH reports consulting fees from AstraZeneca, Bristol Myers Squibb, and Genentech/Roche; research funding from Genentech and Merck; and speakers bureau fees from Eisai and Bristol Myers Squibb. MB reports consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, MSD, Roche, and Sirtex Medical; speakers bureau fees from Bayer, Eisai, and Roche; and support for travel and attending meetings from AstraZeneca, Bayer, and Sirtex Medical. TO reports advisory fees from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Pfizer, Taiho Pharmaceutical, and Takara Bio; and speaker fees from AstraZeneca, Baxter, Bayer, Bristol Myers Squibb, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. L-TC reports personal speaker fees from Bristol Myers Squibb, CStone, Eli Lilly, Ipsen, Ono Pharmaceutical, Novartis, PharmaEngine, and TTY; fees for medical monitoring for clinical trials for Taivex; fees received as a data and safety monitoring committee member for clinical trials for OBI Pharma; advisory fees from AstraZeneca, MSD, and SynCoreBio; speaker fees from AstraZeneca, HuniLife Biotechnology, Ono Pharmaceutical, ScinoPharm Taiwan, SynCoreBio, and TTY; and research funding from Celgene. MK reports research funding from AbbVie and Takeda; and honoraria from EA Pharma and AstraZeneca. JWK reports research funding from inno.N and Jeil Pharmaceutical; and consulting fees from AstraZeneca, BeiGene, BeyondBio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD Ono, Sanofi-Aventis, Servier, and TCUBEit. TS reports speaker fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Baxter, Eli Lilly, Mundipharma (Thailand), Janssen, MSD, Novartis, Roche, and Takeda; and advisory fees from Novartis and Roche. MI reports grant or research support from Aslan Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, EA Pharma, Eisai, Eli Lilly Japan, J-Pharma, Merck, Merus NV, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yakult; fees or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, MSD, Nihon Servier, Novartis, Otsuka, Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult; and fees for participation on a data safety monitoring board or advisory board from Aslan Pharmaceuticals, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, GlaxoSmithKline, Nihon Servier, Novartis, and Takeda. J-SC reports grant or research support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Eli Lilly, Merck KGaA, MSD, MSD Oncology, Oncologie, Ono Pharmaceutical, Roche, Senhwa Biosciences, SynCore, and TTY; and consulting fees from Ono Pharmaceutical. PP reports personal fees for an advisory board from AstraZeneca, Sanofi-Aventis, Bristol Myers Squibb, Janssen Oncology, MSD, Pierre Fabre, Roche, and Servier; personal fees as an invited speaker from AstraZeneca, Ipsen, Pierre Fabre, and Merck; and being a principal investigator for AstraZeneca and Roche. HAB reports research funding from AbbVie, Agios, Arch Pharmalabs, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, CicloMed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Infinity Pharmaceuticals, Janssen, Jiangsu Hengrui Pharmaceuticals, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, miRNA Therapeutics, Moderna, NGM Bio, Novartis, Pfizer, Revolution Medicine, Roche/Genentech, Ryvu Therapeutics, Seattle Genetics, Tesaro, TG Therapeutics, Verastem Oncology, Vertex Pharmaceuticals, XBiotech, and Zymeworks; and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Forma Therapeutics, Grail, Incyte, Novartis, Pfizer, and Vincerx Pharma. VO reports grant or research support from Dr Reddy's Laboratories and Zydus Cadila; institutional fees for advisory board participation from AstraZeneca, Panacea Biotec, Dr Reddy's Laboratories, and Zydus Cadila; travel reimbursement as an invited speaker from AstraZeneca; other institutional financial interests with Alkem Laboratories, Eisai, Intas Pharmaceuticals, and Micro Labs; and non-financial interests with the Indian Association of Supportive Care in Cancer. ST reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Novartis, and Roche; speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and non-financial interests with AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Roche. CM reports institutional grant or research support from AstraZeneca, Daiichi Sankyo, Eisai, J-Pharma, Hitachi, Merck BioReliance, MSD, Kyowa Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; personal fees for advisory board participation from AstraZeneca, Boehringer Ingelheim, Merck BioReliance, MSD, Servier, Taiho Pharmaceutical, and Yakult; and personal fees received as an invited speaker from AstraZeneca, Eisai, Kyowa Kirin, MSD, Novartis, Servier, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. REZ reports speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and travel grants from Pierre Fabre. MGM reports grant or research support from Ipsen, NuCana, and Servier; consulting fees from AstraZeneca and Incyte; and honoraria from Advanced Accelerator Applications and AstraZeneca. AA reports research funding from Amgen, Bayer, and Bristol Myers Squibb; and advisory fees from AstraZeneca, Amgen, Eisai, and MSD. JEC reports advisory fees from MSD; and fees as an invited speaker for AstraZeneca, Boehringer Ingelheim, Takeda, and Roche. VB reports consulting fees from Bayer, Bristol Myers Squibb Russia, Eisai, MSD, Novartis, Pfizer, Roche Russia, and Takeda; and travel expenses from Bayer, Bristol Myers Squibb Russia, MSD, and Roche Russia. BT reports research funding from Adaptimmune, AstraZeneca, Bristol Myers Squibb, and Exelixis. SS reports grant or research support from Delta-Fly Pharma and Incyte. DT reports personal fees for advisory board participation from Amgen, AstraZeneca, MSD, Pierre Fabre, Roche, Sanofi, and Servier. LE reports personal fees for advisory board participation from Amgen, Merk, MSD, and Servier. MP reports personal fees for advisory board participation from Roche and Servier; personal fees as an invited speaker from AstraZeneca, Ewopharma, and Takeda; and non-financial interests with AstraZeneca and Sanofi. DBZ reports advisory fees from Cornerstone Pharmaceuticals, Ipsen, Jazz Pharmaceuticals/Zymeworks, and QED Therapeutics; and research funding from AstraZeneca, Bayer, Bristol Meyers Squibb, Cornerstone Pharmaceuticals, Daiichi Sankyo, Eli Lily, Ipsen, Roche/Genentech, Legend Biotech, Merck, and Seagen. VGG holds stock in RPG Life Sciences and Zydus Lifesciences. FD reports grant or research support from Amgen, AstraZeneca, Bristol Myers Squibb, Exelixis, Genentech, Ipsen, Signatera, and Taiho Pharmaceutical; consulting fees from AstraZeneca, Eisai, Exelixis, Genentech, and Ipsen; and payment or honoraria from Astellas, Eisai, Exelixis, Ipsen, Servier, and Sirtex Medical. JOP reports advisory board fees from Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), MediRama, MedPacto, Merck Serono, and Servier; support for travel to meetings from Minneamrita Therapeutics; and grant or research support from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier. HK, CM, and MŻ are employees of AstraZeneca. JW and NR are employees of and hold stock in AstraZeneca. AV reports speaker fees from BeiGene, Bristol Myers Squibb, Eisai, Imaging Equipment, Incyte, Ipsen, Jiangsu Hengrui Pharmaceuticals, Eli Lilly, MSD, Novartis, Pierre Fabre, and Roche; and advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Daiichi Sankyo, Eisai, Ipsen, Incyte, Lilly, MSD, Pierre Fabre, Roche, and Sirtex Medical. JWV reports advisory fees from Agios, AstraZeneca, Autem Therapeutics, Baxter, Hutchison MediPharma, Image Equipment, NuCana, QED Therapeutics, Sirtex Medical, Servier, and Zymeworks; speaker fees from Incyte, Ipsen, and Mylan; and research funding from AstraZeneca and Redx. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS., Patients and Methods: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972)., Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS., Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race., (©2024 American Association for Cancer Research.)

Background: Bevacizumab-awwb was the first biosimilar approved for cancer treatment in the USA. Limited information is available on the real-world comparative safety and effectiveness of bevacizumab biosimilars, especially for indications granted approval through extrapolation., Objective: To evaluate the real-world outcomes of patients with metastatic colorectal cancer (mCRC) initiated on bevacizumab-awwb versus bevacizumab reference product., Patients and Methods: This was an observational, longitudinal cohort study of US adult patients with mCRC from four integrated care delivery systems who were newly initiated on bevacizumab-awwb between 1 July 2019 and 30 March 2020 or bevacizumab reference product between 1 July 2015 and 30 June 2018. Patients were followed until 1 year after treatment initiation, end of plan membership, or death, whichever occurred first. The primary outcome of overall survival (OS) was analyzed using a binary non-inferiority test with lower margin of 10% and adjusted Cox proportional hazards regression analysis to assess all-cause mortality if non-inferiority was met. Secondary outcomes included counts of doses received, treatment duration, all-cause hospitalizations, and incidence of serious adverse events., Results: A total of 1445 patients initiated on either bevacizumab-awwb (n = 239) or bevacizumab reference product (n = 1206) were included in the analysis. The mean overall age was 60 ± 13 years, 46% of patients were female, and 51% were white. The OS rate was 72.8% and 73.1% for patients receiving bevacizumab-awwb and bevacizumab reference product, respectively (p < 0.01 for non-inferiority). The adjusted hazard ratio for mortality was 1.01 (0.77-1.33, p = 0.93). There were no statistically significant differences in secondary outcomes between the study groups., Conclusions: These findings suggest that bevacizumab-awwb is as effective and safe as bevacizumab reference product for the real-world treatment of mCRC., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction., Methods: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients., Results: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low., Conclusions: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications., (© 2023. The Author(s).)

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss., Methods: We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238., Findings: Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo-abiraterone group and 547 (50%) to the ipatasertib-abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0-33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo-abiraterone group and 260 in the ipatasertib-abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9-17·0) in the placebo-abiraterone group and 18·5 months (16·3-22·1) in the ipatasertib-abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61-0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6-19·1) in the placebo-abiraterone group and 19·2 months (16·5-22·3) in the ipatasertib-abiraterone group (HR 0·84 [95% CI 0·71-0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo-abiraterone group and in 386 (70%) of 551 patients in the ipatasertib-abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo-abiraterone group and 116 (21%) in the ipatasertib-abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo-abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb-abiraterone group., Interpretation: Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial assistance from F Hoffmann-La Roche. CS reports grants or personal fees, or both from Janssen, F Hoffmann-La Roche and Genentech, Sanofi, Astellas, Pfizer, Bayer, and Lilly, during the conduct of the study; and has a patent abiraterone plus cabozantinib issued to Exelixis, a patent parthenolide as treatment for cancer licensed to Indiana University, and a patent dimethylaminoparthenolide as treatment for cancer licensed to Leuchemix, outside of the submitted work. SB reports serving as advisory board member for Astellas, Janssen, Pfizer, BMS, F Hoffmann-La Roche, Ipsen, MSD, Merck, AAA, and AstraZeneca, outside of the submitted work. CNS reports grants and non-financial support from F Hoffmann-La Roche during the conduct of the study; and personal fees from Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi and Genzyme, F Hoffmann-La Roche and Genentech, Incyte, and Clovis, outside of the submitted work. KNC reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Astellas, AstraZeneca, Constellation Pharma, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. DO reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas Pharma, Bayer, Janssen, AstraZeneca, Clovis Oncology, Astellas Medivation, F Hoffmann-La Roche and Genentech, Pfizer, Tokai Pharmaceuticals, Ipsen, MSD, and Daiichi Sankyo, outside of the submitted work. SS reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Amgen, MSD, Merck Serono, F Hoffmann-La Roche and Genentech, AstraZeneca, and Novartis, outside of the submitted work. CM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and personal fees from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Celgene, Debiopharm Group, F Hoffmann-La Roche and Genentech, Innate Pharma, Ipsen, Janssen, Lilly, MSD, Novartis, Orion, Pfizer, PharmaMar, Sanofi, and Taiho, outside of the submitted work. NM reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees, or both from Janssen, MSD, Chugai, Astellas, Eli Lilly, Taiho, Pfizer, and Sanofi, outside of the submitted work. BA reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, and Sanofi, outside of the submitted work. RG reports grants from F Hoffmann-La Roche, during the conduct of the study; and grants, personal fees, or non-financial support from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, MSD, Pfizer, F Hoffmann-La Roche, Sanofi, and Pierre Fabre, outside of the submitted work. LC reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study. GVA reports grants from MSD, BMS, Merck-Serono, F Hoffmann-La Roche, Pfizer, AstraZeneca, Beigene, Ipsen, and Janssen, outside of the submitted work. EB reports personal fees from Sanofi Aventis, Astellas Pharmaceuticals, Roche Hellas, Bayer, Janssen Pharmaceuticals, GlaxoSmithKline, Pierre Fabre, and Merck, outside of the submitted work. JP reports grants and non-financial support from F Hoffmann-La Roche, during the conduct of the study; and grants or personal fees from Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen-Cilag, MSD Oncology, Pierre Fabre, F Hoffmann-La Roche, Sanofi, Clovis Oncology, and MSD, and grants, personal fees, and non-financial support from Pfizer, outside of the submitted work. M-LH-Y, JGal, and JGar are employees of F Hoffmann-La Roche. GC, JH, and MJW are employees of Genentech. JSdB reports personal fees and grants from F Hoffmann-La Roche and Genentech, during the conduct of the study; grants, personal fees, or travel expenses from AstraZeneca, GlaxoSmithKline, Pfizer, Taiho, Daiichi, Bayer, Orion Pharma, F Hoffmann-La Roche and Genentech, Merck Serono, Sierra Oncology, MSD, Astellas, Cellcentric, Sanofi Aventis, and Vertex Pharmaceuticals, and personal fees or travel expenses from Terumo, Menarini and Silicon Biosystems, Bioexcel Therapeutics, Eisai, and Qiagen, outside of the submitted work; and has a patent for DNA damage repair inhibitors for treatment of cancer (patent number WO 2005 053662 licensed to AstraZeneca) and a patent for 17-substituted steroids useful in cancer treatment (patent number US 5604213 licensed to Janssen). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials., Methods: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001)., Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred., Interpretation: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours., Funding: Ignyta/F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: We compared high-dose cisplatin (HDC) vs. triweekly carboplatin (TC)-based chemoradiation in patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC)., Materials and Methods: A retrospective review was conducted from 2006 to 2015 of 421 patients with locally advanced p16-positive OPSCC receiving definitive radiotherapy concurrent with 3 cycles of HDC (100 mg/m 2 , n = 230) or TC (AUC = 5, n = 191). Three-year locoregional recurrence (LRR), distant metastasis (DM), overall recurrence rate (ORR), overall survival (OS), and cause-specific survival (CSS) are reported. HDC and TC were compared accounting for age, sex, comorbidity index score, smoking history, T stage, and N stage., Results: For all-comers, no difference was observed between HDC and TC for any outcome except for ORR which was lower in patients receiving HDC (12% vs. 17%, p = 0.03). On stage-based analysis, no difference was observed between agents for any outcome for stage I or II disease. However, patients with stage III disease receiving HDC had lower rates of LRR (9% vs. 21%, p = 0.03), DM (7% vs. 28%, p = 0.006), and ORR (14% vs. 40%, p = 0.002), and superior OS (89% vs. 78%, p = 0.04) and CSS (95% vs. 80%, p = 0.02). Patients receiving HDC experienced higher rates of grade 3 leukopenia (25% vs. 11%, p < 0.001), weight loss ≥20% from baseline (21% vs. 8%, p < 0.001), and gastrostomy-tube placements (66% vs. 27%, p < 0.001)., Conclusion: TC demonstrated comparable outcomes to HDC for stage I or II HPV-associated OPSCC but was inferior to HDC for stage III disease. TC was associated with less toxicity and may be a potential de-intensification agent for early-stage disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The addition of induction chemotherapy (ICT) to concurrent chemoradiation (CCRT) has been investigated as a method of improving outcomes among patients with locally advanced head and neck squamous cell carcinoma. Previous studies have consisted of heterogeneous populations with both p16-positive and p16-negative disease and varying extent of nodal disease burden. We evaluated the role of ICT in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) at high-risk of distant failure., Materials and Methods: A retrospective review was conducted of 88 consecutive patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy. Among these patients, 44 received ICT followed by CCRT, and 44 received CCRT alone with concurrent agents including Cisplatin, Carboplatin, and Cetuximab. Disease control and survival outcomes were reported after adjusting for age, T stage, N stage, and smoking status., Results: Median follow-up for surviving patients was 47 (range: 13-115) months. Patients who received CCRT alone were older than those who received ICT (61 years vs. 56 years; p = 0.02); the groups were otherwise similarly balanced. 3-year distant metastasis: 38% vs. 18% (adjusted hazard ratio (HR) = 0.32 [0.13-0.82]; p = 0.02). 3-year progression-free survival: 49% vs. 74% (adjusted HR = 0.46 [0.22-0.93]; p = 0.03). 3-year overall survival: 67% vs. 83% (adjusted HR = 0.48 [0.21-1.12]; p = 0.09)., Conclusion: Among patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy, ICT followed by CCRT may reduce the risk for distant failure over CCRT alone and lead to improved progression-free survival. Future trials should concentrate on patients at the highest risk of distant metastasis in order to appropriately assess the benefit of ICT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As various viral vector systems for gene transfer are developed, interest in using such systems in applied settings continues to grow. This Chapter is designed to provide background information for readers interested in learning about lentiviral vector systems for gene transfer applications but who lack a background in retrovirology. To assist those readers who are unfamiliar with retroviral vector systems, basic outlines of the retroviral replication cycle and of characteristics of retroviral vector systems are introduced here in order to present and define concepts and terms that are discussed in subsequent Chapters.

Much progress has been made in developing new and more efficient treatments for human immunodeficiency virus (HIV) infection, the cause of acquired immunodeficiency syndrome (AIDS). However, the scope of the HIV epidemic and the limitations of existing treatments necessitate the continued development of novel treatment strategies. Gene therapy is one such forward-looking strategy. Gene therapy approaches for HIV infection include efforts to interfere with viral replication directly by engineering HIV-resistant cells or indirectly by eliminating infected cells from the body, primarily by eliciting a therapeutic immune response to destroy HIV-infected cells. Although the prospect of gene therapy as a routine treatment for HIV infection remains distant, continuous progress is being made, which should also have implications for gene therapy strategies for a variety of other diseases. This article reviews some of the strategies for investigating the feasibility of gene transfer for the treatment of HIV infection.

Retroviral vectors derived from murine retroviruses are being used in several clinical gene therapy trials. Recently, progress has been made in the development of vectors based on the lentivirus genus of retroviruses, which ironically includes a major human pathogen, human immunodeficiency virus (HIV). As these vector systems for clinical gene transfer are developed, it is important to understand the rationale behind their design and development. This article reviews the fundamental features of retrovirus replication and of the elements necessary for development of a retroviral vector system, and it discusses why vector systems based on HIV or other lentiviruses have the potential to become important tools in clinical gene therapy. (Blood. 2000;95:2499-2504)

During the replication cycle of murine leukemia virus (MLV), Pol is normally synthesized as part of a Gag-Pol fusion protein. In this study, the ability of free MLV Pol to be incorporated into virions was examined. When MLV Gag and MLV Pol were coexpressed from separate plasmids in cells, reverse transcriptase (RT) activity associated with Gag core particles at a slightly lower level than did RT activity generated from wild-type Gag-Pol expression. Particles produced in this manner were somewhat less infectious than those produced with wild-type Gag-Pol. A smaller amount of MLV Pol also associated with heterologous human immunodeficiency virus type 1 Gag cores.

We have demonstrated previously that a human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein containing a Val-to-Glu substitution at the second amino acid of the transmembrane glycoprotein gp41 (termed the 41.2 mutant) dominantly interferes with wild-type envelope-mediated syncytium formation and virus infectivity. To understand the mechanism by which the 41.2 mutant exerts the dominant interfering phenotype and thereby determine further how the mutant might be used as an inhibitor of viral spread, additional mutations were made in the envelope gene, and the effects of these mutations on interference were determined. It was found that processing of the 41.2 mutant glycoprotein in gp120 and gp41 subunits and a functional CD4-binding domain are necessary for the interfering phenotype to be exhibited fully. However, neither a wild-type V3 loop nor the gp41 cytoplasmic tail is necessary for efficient interference. In addition, it was determined that the dominant interfering phenotype is not conferred exclusively by the glutamate substitution at amino acid 2 of gp41, since a substitution with a basic residue at this position also results in a dominant interfering envelope glycoprotein.

A cDNA clone derived from the altA locus, encoding one of several alpha-tubulins in Physarum, was sequenced and used to determine the developmental and cell cycle expression patterns of its corresponding gene. The predicted amino acid sequence of the altA gene product, alpha 1A-tubulin, is 92% identical to the other known Physarum alpha-tubulins, alpha 1B and alpha 2B, which are products of two tightly linked genes at the altB locus. The nucleotide sequence of the altA coding region is 82% identical to the two altB genes. Expression of the altA gene was found in all three cell types examined - amoeba, flagellate and plasmodium - but at substantially different levels in each. The peak level of altA message detected in flagellates was 14-fold higher than in amoebae, while the peak level in plasmodia was 5-fold lower than in amoebae. The expression pattern of altA and the predicted amino acid sequence of the alpha-tubulin it encodes suggest that alpha 1A is the substrate for post-translational acetylation, giving rise to the alpha 3-tubulin isoform found specifically in amoebae and flagellates. Northern blot analysis of plasmodial RNA samples from specific times in the cell cycle showed that the level of altA message varies over the cell cycle in a pattern similar to transcripts from other tubulin genes, with a peak at mitosis and little or no message detected during most of interphase.

Infectious HIV-1 particles containing replication-defective vectors that express the hygromycin B phosphotransferase gene were generated by transient complementation in COS-1 cells. A defective vector dependent only on trans-complementation with an env gene and a small vector containing a deletion of almost all of the trans region were used to examine pseudotyping of HIV-1 by an amphotropic murine retrovirus. Although pseudotyping by the heterologous envelope glycoprotein occurred with efficiency, no pseudotyping at the RNA level was observed. Genetic complementation was used to rapidly analyze the effect of env mutations in the V3, proteolytic processing site, fusion domain, and cytoplasmic tail on viral infectivity. Mutations decreasing syncytium formation usually also lowered infectivity. However, a mutation in the cytoplasmic tail and a separate mutation adjacent to the fusion domain dramatically decreased viral particle infectivity but did not appreciably decrease envelope glycoprotein-mediated cell-to-cell fusion. These results may indicate that these regions of the transmembrane peptide are necessary for acquisition of envelope glycoprotein by budding virus particles or for virus entry.

The feasibility of using a trans-dominant interfering human immunodeficiency virus type 1 (HIV-1) envelope mutant for inducible gene therapy of HIV infection was investigated. Genes encoding wild-type or mutant glycoproteins were introduced into CD4+ cells, where they were stably maintained but not expressed until induced. Envelope (env) gene expression was dependent upon the viral regulatory protein Tat. Induction of the mutant env resulted in resistance to cytopathic effects mediated by wild-type envelope and decreased infectious vector virus production. When cells containing the mutant env gene were infected with wild-type virus, viral spread was inhibited. The fact that maintenance of the env gene was stable over time suggests that inducible gene therapy using the dominantly interfering env mutant may be a feasible approach to slowing the progression of HIV-1 disease.

Tat-dependent expression of an endogenous lethal or deleterious foreign gene might be useful for abrogating the production of human immunodeficiency virus (HIV) from cells. This type of HIV-induced cellular killing, as well as other approaches to gene therapy for HIV infection, would be facilitated by simple HIV vectors that express introduced genes in a Tat-inducible manner. As part of studies to examine the feasibility of this concept, we constructed HIV-1 vectors that express the hygromycin B phosphotransferase gene (Hygr) in a Tat-dependent manner. Comparison of the efficiency of propagation of each vector indicates that sequences extending into the gag open reading frame are necessary in cis for efficient vector propagation. Southern blot analysis of genomic DNA isolated from vector-infected cells demonstrated that the vectors were capable of being propagated as expected without gross rearrangements or deletions. A fragment of the influenza A virus hemagglutinin (H5 HA) gene, capable of eliciting antibody and cytotoxic T-cell responses, was used as a marker for further characterization of the vector system. A Tat-dependent vector conferring the H5 HA+ phenotype was assayed by indirect immunofluorescence, and cells which contained but did not express the H5 HA gene were isolated. The activation of H5 HA expression following HIV infection of Tat- cells that stably contained but did not express the H5 HA construct was determined to be an efficient process.

Several domains of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein have been identified that are involved in HIV-1-mediated membrane fusion. One domain that is involved in membrane fusion is the hydrophobic amino terminus of the HIV-1 transmembrane glycoprotein gp41. Here we show that a polar substitution at gp41 amino acid 2 (the 41.2 mutation) results in an envelope glycoprotein that dominantly interferes with both syncytium formation and infection mediated by the wild-type HIV-1 envelope glycoprotein. The interference by the 41.2 mutant is not a result of aberrant envelope glycoprotein synthesis, processing, or transport. The 41.2 mutant elicits a dominant interfering effect even in the presence of excess wild-type glycoprotein, suggesting that a higher-order envelope glycoprotein complex is involved in membrane fusion. These results shed light on the process by which the HIV-1 envelope glycoproteins induce membrane fusion reactions and present a possible approach to anti-HIV therapy.

The microbial eukaryote Physarum polycephalum displays several distinct cell types in its life cycle, including amoebae, flagellates and plasmodia. Despite its relative simplicity, Physarum has a tubulin gene family of complexity comparable to that of Drosophila. We have identified beta-tubulin cDNAs from Physarum that are derived from the betA beta-tubulin locus and encode beta 1A tubulin. We have also identified a partial cDNA for the unlinked betB beta-tubulin gene, which encodes beta 1B tubulin. The polypeptide sequences encoded by betA and betB show 99% identity, but the nucleotide sequences show only 85% identity, consistent with an ancient duplication of these genes. The betB gene is expressed in amoebae, flagellates and plasmodia, whereas betA is expressed only in amoebae and flagellates. During the amoeba-flagellate transition the level of betA transcript increases over 100-fold, while the level of betB transcript changes very little. Thus Physarum has a mechanism for regulating the level of discrete beta-tubulin transcripts differentially during flagellate development. A need for this differential regulation could account for the maintenance of the virtually isocoding betA and betB beta-tubulin genes.