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Abstract Background The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5) melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN), were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO) was determined using GRIES reagent. Results We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC), MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin-deficient (PKO) effector T cells induced macrophages to secrete nitric oxide (NO), providing an additional effector mechanism for T cell-mediated tumor regression. Conclusion These data suggest two possible sources for chemokine secretion that stimulates macrophage recruitment to the site of tumor metastases. Both appear to be initiated by T cell recognition of specific antigen, but one is dependent on the tumor cells to produce the chemokines that recruit macrophages.

Abstract Background Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells. Methods Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays. Results Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-α, was greatly reduced when IFN-γ production was neutralized. While recombinant LT-α1β2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages. Conclusion The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.

Background: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.Methods: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.Results: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).Conclusions: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .). [ABSTRACT FROM AUTHOR]

Background and Objective: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC., Methods: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS)., Key Findings and Limitations: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design., Conclusions: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents., Patient Summary: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety., (Copyright © 2024 Merck Sharp and Dohme LLC., a subsidiary of Merck and Co., Inc., Rahway, NJ, USA., The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis., Methods: This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC., Results: Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes., Conclusions: Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies., (© 2024 Wiley Periodicals LLC.)

Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.

Background: PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis., Methods: This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting., Findings: Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related., Interpretation: Overall survival was not significantly different between treatment groups at this final prespecified analysis., Funding: Supported by AstraZeneca and Merck Sharp & Dohme., Competing Interests: Declaration of interests FS received honoraria from AAA, AbbVie, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Knight Therapeutics, Merck, Myovant Sciences, Novartis, Pfizer, and Sanofi; acted in a consulting or advisory role for AAA, AbbVie, Astellas Pharma, AstraZeneca–MedImmune, Bayer, Janssen Oncology, Knight Therapeutics, Myovant Sciences, Novartis, Pfizer, and Sanofi; and received research funding (institutional) from Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Merck, Novartis, Pfizer, and Sanofi. NWC received honoraria from AstraZeneca, Bayer, Janssen, and Pfizer; acted in a consulting or advisory role for AstraZeneca; and received travel and accommodation expenses from AstraZeneca. MO received honoraria from Astellas, AstraZeneca, Bayer, MSD, Janssen, Takeda, and Nippon Kayaku; acted in a consulting or advisory role for Bayer; and received research funding from Bayer and AstraZeneca. NS acted in a consulting or advisory role for AbbVie, Accord, Alessa Therapeutics, Antev, Arquer, Asieris, Amgen, Astellas, AstraZeneca, Aura biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Boston Scientific, CGOncology, Clarity, Dendreon, Exact Imaging, Ferring, Fize Medical, Genentech–Roche, Foundation Medicine, Genesis Care, Immunity Bio, Incyte, Invitae, Janssen, Lantheus, Lilly, mDxhealth, Merck, Minomic, Myovant, Myriad, Nonagen, Novartis, Nymox, Palette Life, Platform Q, Pacific Edge, Pfizer, Profound Medical, Promaxo, Protara, Photocure, Sanofi Genzyme, Specialty Networks, Telix, Tolmar, and Urogen; and acted in a leadership or fiduciary role for Photocure. GP acted in a consulting or advisory role for Astellas, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer. JDG received honoraria from Agenus, AstraZeneca–Merck, Daiichi-Sankyo, Merck, Pierre Fabre, and Pint Pharma; research funding from Agenus, Amgen, AstraZeneca, Bayer, Blau Farmacêutica, Boehringer-Ingelheim, Bristol Myers Squibb, BRAVA, Daiichi-Sankyo, Eurofarma, ARO-Einstein, Genetech, HUYABIO, Incyte, Lilly, MSD, Novartis, Pfizer, Polyphor, PTC Therapeutics, Roche, Sanofi, Seagen, Takeda, and Tigermed; and travel and accommodation expenses from Daiichi Sankyo and Gilead. NM received honoraria from Bureau Prevents, Medscape, and MedTalks; acted in a consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Janssen-Cilag, and MSD Oncology (institutional); received research funding (institutional) from Astellas Pharma, AstraZeneca–Merck, Janssen-Cilag, Pfizer, Roche/Genentech, and Sanofi; received travel and accommodation expenses from Astellas Pharma, Bristol Myers Squibb, Janssen-Cilag, MSD Oncology, and Roche; acted in a leadership–fiduciary role for Dutch Uro-Oncology study Group; and participated in a data safety monitoring–advisory board for the GLOW trial (glioblastoma). FP acted in a consulting or advisory role for Ipsen, Janssen Oncology, and Merck Serono. FS received honoraria from Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer, Janssen, and Merck; acted in a consulting or advisory role for Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer, Janssen, MSD/Merck, and Lilly; received travel and accommodations expenses from Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer, and Janssen; and provided expert testimony for Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Janssen, MSD/Merck, and Lilly. MS received honoraria from Astellas, AstraZeneca, Janssen Pharmaceuticals, and Takeda; research funding from Astellas, AstraZeneca, Bristol Myers Squibb, Janssen, MSD, and Pfizer; and travel and accommodation expenses from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, and MSD. OS acted in a consulting or advisory role for AAA, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Muenchen, Janssen, Myovant, Myriad, Noria Therapeutics, Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, and Theragnostics; received research funding from AAA, Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio; provided expert testimony for Sanofi; received travel and accommodation expenses from Lantheus and North Start; participated in a data safety monitoring–advisory board for AstraZeneca and Pfizer; and holds stock options with Ratio, Convergent, Fusion, and Telix. Y-ZL, LB, and PMdR are AstraZeneca employees and shareholders. CP is an employee and shareholder of Merck. AJA has acted in a consulting or advisory role for Astellas Scientific and Medical Affairs, AstraZeneca, Bayer, Bristol Myers Squibb, Dendreon, Exelixis, FORMA Therapeutics, GoodRx, Janssen, Merck, Myovant Sciences, Novartis, and Pfizer; has received research funding (institutional) from Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Constellation Pharmaceuticals, Dendreon, FORMA Therapeutics, Gilead Sciences, Janssen Oncology, Merck, Novartis, Pfizer, and Roche–Genentech; owns patents, receives royalties, or other intellectual property for circulating tumour cell novel capture technology (institutional); and has received travel and accommodation expenses from Astellas Scientific and Medical Affairs. CA, EB, and JYJ declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment., Patients and Methods: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A., Results: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients' baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21-0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25-0.47)., Conclusions: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment., (©2022 The Authors; Published by the American Association for Cancer Research.)

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TH reports scientific advisory boards for AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen. IV reports consulting for Agenus, Akesobio China, Amgen (Europe) GmbH, AstraZeneca, Bristol Myers Squibb, Clovis Oncology Inc., Carrick Therapeutics, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche Ltd, Genmab, GSK, Immunogen Inc., Jazzpharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AS, Seagen, Sotio a.s., Verastem Oncology and Zentalis; contracted research (via KU Leuven) for Oncoinvent AS and Genmab; grant (i.e. corporate sponsored research) for Amgen and Roche and accommodations and/or travel expenses for Amgen, MSD, Tesaro, AstraZeneca and Roche. LGG reports scientific advisory boards for AstraZeneca, Merck, Lantheus and Exelixis. TM is an employee of AstraZeneca. TF is an employee and stockholder of AstraZeneca. RT is a former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA. CP is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA. MH reports scientific advisory boards for Astra Zeneca, Merck, Janssen, Novartis, TEMPUS, Bayer, GSK, Pfizer and BMS., (Copyright © 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points. RESULTS: At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea. CONCLUSIONS: At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)

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.)

Purpose: Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies., Patients and Methods: An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation., Results: A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages >10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact., Conclusions: The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment., (©2022 American Association for Cancer Research.)

Background: The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial., Methods: In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543., Findings: Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; p nominal =0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; p nominal =0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; p nominal =0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; p nominal =0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; p nominal =0·0013)., Interpretation: Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound., Funding: AstraZeneca and Merck Sharp & Dohme., Competing Interests: Declaration of interests FS reports grants from AstraZeneca and Merck Sharp & Dohme for the submitted work; grants from Astellas, Bayer, Bristol Myers Squibb, Janssen, Pfizer, and Sanofi; consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, and Sanofi; honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, and Sanofi; and is an advisory board member for Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. GR reports an advisory board role for Gilead; meeting support from Astellas, AstraZeneca, and Janssen; honoraria from AstraZeneca, Janssen, and Sanofi; and consulting fees from Astellas, AstraZeneca, and Merck Sharp & Dohme. GP reports consultant fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Janssen, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi; and honoraria from Bristol Myers Squibb, Eisai, Janssen, Ipsen, Merck Sharp & Dohme, and Pfizer. NS reports support for research site and medical writing from AstraZeneca and Merck Sharp & Dohme for the submitted work; consulting fees from AstraZeneca and Merck; and is an advisory board member for AstraZeneca and Merck. KF reports consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Novartis, Orion, and Sanofi; and honoraria from Astellas, AstraZeneca, Bayer, Janssen, Novartis, and Sanofi. AT-V reports medical writing support from and holds an advisory role with AstraZeneca, associated with the submitted work; grants from Bayer, Ipsen, and Pfizer; consulting fees from Astellas, AstraZeneca, BMS, Ipsen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, and Roche; meetings support from Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen, Johnson & Johnson, Merck Sharp & Dohme, and Roche; is a data safety monitoring board member for the BIONIKK trial (NCT02960906); and is a member of the steering committee of the French Genitourinary Tumour Group academic group. GG reports honoraria from Amgen, Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen Oncology, MSD Oncology, Sanofi/Aventis; meetings support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Pfizer, Janssen Oncology, and Sanofi; and is an advisory board member for AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen Oncology, Merck Sharp & Dohme Oncology, Pfizer, and Sanofi/Aventis. NM holds an advisory board role for Chugai, Janssen, and Sanofi; payment or honoraria from Janssen and Sanofi; grant and institution funding from Astellas, Amgen, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Takeda, and Taiho. DC reports consulting or advisory roles for Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen Oncology, Lilly, Merck Sharp & Dohme Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi; research funding by Janssen Oncology; and travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, Pfizer, and Roche. MH reports funding and medical writing support from AstraZeneca for the submitted work; and grants, consulting fees, and honoraria from AstraZeneca. AD, CG, JK, and AK are employees of and have stock ownership with AstraZeneca. CP is an employee of Merck Sharp & Dohme, a subsidiary of Merck and holds stock ownership in Merck. JdB reports funding and medical writing support from AstraZeneca and Merck Sharp & Dohme for the submitted work; grants from Amgen, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Harpoon, ImCheck Therapeutics, Janssen, Merck Sharp & Dohme, Serono, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; royalties or licences (no personal income) from abiraterone, poly(adenosine diphosphate–ribose) polymerase inhibition, and P13K/AKT; consulting fees from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex; grants and personal fees from AstraZeneca during the study; personal fees and non-financial support from Astellas Pharma; grants, personal fees and non-financial support from AstraZeneca; personal fees from Bayer, Boehringer Ingelheim, Genentech/Roche, Merck Serono, Merck Sharp & Dohme, Janssen, and Pfizer; personal fees and non-financial support from Sanofi; non-financial support from Genmab, GlaxoSmithKline, Orion, Qiagen, Taiho Pharmaceutical, and Vertex; and personal fees from Cellcentric, Daiichi, GlaxoSmithKline, Menarini/Silicon Biosystems, and Sierra Oncology outside the submitted work. In addition, JdB has a patent for abiraterone and steroids for the treatment of prostate cancer with royalties paid to Janssen, and a patent for PARP inhibitors and DNA repair defects with royalties paid to AstraZeneca. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population., Methods: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety., Results: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%., Conclusion: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

From our way of thinking the problem facing vaccine strategies for cancer is not that we do not have "enough" tumour antigens. The problem is we cannot induce an immune response that is sufficient to mediate tumour regression. The normal "checks and balances" found in the body prevent the sustained expansion and subsequent persistence of immune killer cells. If vaccine strategies are going to become effective treatments for cancer patients, they will need to overcome this substantial roadblock. Recent developments in immunology have provided insights into the mechanisms that regulate the expansion and persistence of T cells. This has allowed investigators to reinterpret decades-old observations suggesting that chemotherapy administered before vaccination often led to a stronger immune response. This manuscript will review experiments that offer an explanation for these observations and present pre-clinical data from our laboratory that describes an innovative new approach to combining chemotherapy and vaccination. This approach is readily translatable to the clinic and is broadly applicable to any vaccine strategy for advanced cancer.

Background: Donor pigs transgenic for human decay-accelerating factor (hDAF) were used in a xenogeneic ex vivo liver perfusion model to study the effect of this modification on the development of hyperacute rejection., Methods: Three transgenic pigs were hepatectomized after hypothermic portal and transaortal gravity perfusion. Livers from six nontransgenic pigs served as controls. All livers were perfused for 3 hr with human blood from two donors diluted to a hematocrit of 30%. Particular importance was placed on the use of an optimal perfusion technique incorporating the floating suspension of the organs in a waterbath and intermittent external pressurization. Biochemical, physiological, and immunological parameters were assessed. Tissue specimens taken before and after perfusion were analyzed using routine histology, electron microscopy, and immunohistology., Results: Complement activation was more pronounced in the control group. AP50 and CH50 values fell to about 60% of the initial levels in control experiments, whereas they remained at 80% of the initial levels during perfusion of hDAF livers. After 180 min, pig tumor necrosis factor alpha levels were 7862+/-1645 pg/ml for unmodified livers and 2830+/-734 pg/ml in the hDAF group. Human tumor necrosis factor alpha levels were similar in both groups. Control livers showed marked morphological alterations and distinct deposition of complement factors, whereas livers expressing hDAF showed no signs of hepatocellular necrosis and almost no complement deposition beyond C3 activation., Conclusions: These results confirm that the transgenic expression of the human complement regulatory protein hDAF reduces complement activation and prevents hyperacute rejection in a xenogeneic liver perfusion model over the 3-hr evaluation period used in this study.

Background: Extracorporeal liver perfusion in hepatic coma, used to eliminate toxic metabolites causing hepatic encephalopathy, is limited by the antibody (Ab) and complement-mediated hyperacute rejection of discordant xenografts. Thus, the efficacy of highly selective immunoadsorption columns to deplete xenoreactive human anti-porcine antibodies before ex vivo liver perfusion was examined in this study., Methods: Eighteen domestic pigs were hepatectomized according to standard techniques. The livers were ex vivo perfused for 4 hr. The perfusion protocol closely followed the physiological conditions of a human liver. Parameters of liver function and damage were analyzed. Three groups were formed differing in the treatment of the perfusate. As basic control, livers were perfused with heparinized human blood (group 1; n=6). Immunoapheresis was applied in group 3 (n=6). Immunoapheresis was performed using Ig Therasorb columns consisting of sheep-anti-human IgG Abs covalently coupled to Sepharose CL-4B. Additionally, the effect of pure Sepharose CL-4B without immobilized Ab was tested in group 2 (n=6)., Results: The use of Ig Therasorb 100 columns in group 3 resulted in a reduction of IgG, IgM, and IgA in the order of 95.0%, 72.3%, and 81.5%, respectively. In group 2, IgG, IgM, and IgA were lowered by 30% to 39%. Determination of liver-specific enzymes and tolerance tests revealed a significant reduction of cellular damage and functional restrictions in group 3 compared with the control groups., Conclusions: Immunoapheresis conducted according to this protocol appears to be an effective approach for delaying antibody-mediated hyperacute xenogeneic rejection.

Ex vivo perfusions of human decay accelerating factor-expressing transgenic (n = 3), and nontransgenic (n = 6) porcine livers with human blood revealed a higher degree of organ damage in non-transgenic pig livers. Transgenic livers were protected from immunohistologically detectable complement deposition, despite corresponding IgM and IgG deposits in both groups. Complement activation and consumption of C3 and C4 turned out to be lower in transgenic pig livers. In contrast to livers of normal landrace pigs, livers from genetically manipulated pigs showed no morphological alterations after perfusion.