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What Is This Summary About?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide., What Is Metastatic Castration-Resistant Prostate Cancer?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer., What Are the Aims of the Talapro-2 Trial?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study., What Are the Key Takeaways?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients). Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 ., (© 2023. The Author(s).)

Background: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing., Findings: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group., Interpretation: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations., Funding: Pfizer., Competing Interests: Declaration of interests NA has received an honorarium for consultancy since May, 2020, from the following: Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma, and research funding (institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON. AAA reports honoraria from Aculeus Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix Pharmaceuticals, and Tolmar; consulting fees from Aculeus Therapeutics, Astellas Pharma, Janssen, and Novartis; participation on advisory boards for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; participation on a data safety monitoring board for OncoSec; research funding (institution unless stated otherwise) from Aptevo Therapeutics, Astellas Pharma (investigator), AstraZeneca (investigator), Bionomics, Bristol Myers Squibb, Exelixis, Gilead Sciences, GlaxoSmithKline, Hinova Pharmaceuticals, Ipsen, Janssen, Lilly, MedImmune, Merck Serono (investigator), MSD, Novartis, Pfizer, Sanofi, and Synthorx; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; and receiving medical writing services from Astellas Pharma, Exelixis, and Pfizer; he is Chair of the Urologic Oncology Group for the Clinical Oncology Society of Australia, and Chair of the Translational Research Subcommittee and on the Scientific Advisory Committee for the ANZUP Cancer Trials Group. JC reports a consulting or advisory role for Advanced Accelerator Applications/Novartis, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Pfizer, Roche, and Sanofi; participation in speakers' bureau for Astellas Pharma, Bayer, and Johnson & Johnson; research funding (institution) from AB Science, Aragon Pharmaceuticals, AROG Pharmaceuticals, Astellas Pharma, AstraZeneca, AVEO Pharmaceuticals, Bayer, Blueprint Medicines, BN ImmunoTherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb International Corporation, Clovis Oncology, Cougar Biotechnology, Deciphera, Exelixis, Genentech, GlaxoSmithKline, Incyte, Janssen-Cilag International, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis, SFJ Pharmaceuticals Group, and Teva; and travel, accommodations, and/or expenses from AstraZeneca, BMS, Ipsen, and Roche. APF reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; a consulting or advisory role for Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; stock or stock options in Brazilian Information Oncology; and research funding from AstraZeneca, Bristol Myers Squibb, CAPES – CNPq, Foundation Medicine, Ipsen, MSD, and Roche; and travel, accommodations and/or expenses from Astellas Pharma, AstraZeneca, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. NM reports honoraria (personal) from Sanofi; research funding (institution) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Eisai, Janssen, Lilly, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and travel, accommodations, and/or expenses (personal) from Pfizer. DH reports honoraria (personal) from Advanced Accelerator Applications/Novartis, Astellas Pharma, Bayer, Bristol Myers Squibb, EUSA Pharma, Ferring, Ipsen, Janssen, MSD, and Novartis; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Novartis, Organon, Pfizer, and Roche; and research funding (institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, MSD, Pfizer, and Roche. UDG reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, and PharmaMar; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodations, and/or expenses from Ipsen and Pfizer. PCCF reports a consulting or advisory role for MSD and travel, accommodations, and/or expenses from Pfizer. RJJ reports honoraria from Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; a consulting or advisory role for Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, and Roche; research funding from Astellas Pharma, Bayer, Clovis Oncology, Exelixis, and Roche; and travel, accommodations, and/or expenses from Bayer and Janssen. NDS reports a consulting or advisory role for AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Ferring, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. CD reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. SZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen (personal and institution), Bayer, (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); participation on a data safety monitoring board or advisory board for Amgen (personal and institution), Bayer (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); research funding (institution) from Eisai; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, AstraZeneca, Ipsen, Janssen, Merck, MSD, and Pfizer. JO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, AstraZeneca, Bayer, BMS Norway, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; and travel, accommodations, and/or expenses from Astellas Pharma. XL, CGH, NDiS, and FZ are employees of Pfizer and may hold Pfizer stock/stock options. KF reports honoraria (institution) for participation in advisory boards and talks from Advanced Accelerator Applications/Novartis, Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and honoraria (personal) for participation in advisory boards from Arvinas, CureVac, MacroGenics, and Orion. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib., Patients and Methods: Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs., Results: In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127])., Conclusion: Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC., Clinicaltrials.gov Identifier: NCT03148795., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations., Methods: In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing., Findings: Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths., Interpretation: Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations., Funding: Pfizer/Medivation., Competing Interests: Declaration of interests JSdB reports consulting fees from Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genmab, GSK, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, MSD, Orion Pharma GmbH, Pfizer, Roche/Genentech, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; funding or support to his institution for laboratory and clinical work from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, Cellcentric, Daiichi Sankyo, Genentech, GSK, MedImmune, Medivation, Merck Serono, MSD, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; honoraria from Astellas Pharma, AstraZeneca, BioXcel Therapeutics, Daiichi Sankyo, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Roche/Genentech, Sanofi, and Sierra Oncology; travel, accommodation, and expenses from Astellas Pharma, AstraZeneca, Genmab, GSK, Orion Pharma GmbH, Qiagen, Sanofi, Taiho Pharmaceutical, and Vertex; and is named as an inventor, with no financial interest, on a patent (number 8,822,438). NM reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, Genzyme, Janssen-Cilag, MSD Oncology, and Roche; funding or clinical trial and laboratory research support to his institution from Astellas Pharma, Janssen-Cilag, Pfizer, Roche/Genentech, and Sanofi; and accommodation and expenses from Astellas Pharma, Bristol-Myers Squibb, MSD Oncology, and Roche. GVS reports payment or honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, and Takeda; consulting fees from Eli Lilly, BeiGene, and AstraZeneca; institutional grants or contracts from MSD and Tesaro; support for attending meetings and travel from Bayer; and is a past president of the International Association for the Study of Lung Cancer. EC reports consulting fees to her institution from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, MSD, and Pfizer; payment or honoraria to herself from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Roche; grants or contracts to her institution from AstraZeneca, Bayer, Janssen, and Synlab; support for attending meetings and travel from AstraZeneca, Bayer, and Janssen; and is an unpaid member of the European Society for Medical Oncology faculty. TD reports participation on a Data Monitoring Safety Board or Advisory Board for Advanced Accelerator Applications, Bayer, Bristol-Myers Squibb, Exelixis, and Janssen. ASte reports consulting fees (personal) from Ipsen Pharma, Janssen, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for Astellas Pharma, AstraZeneca, Ferring, and Synergo; and research grant funding from Amgen, Ipsen Pharma, and Karl Storz AG. CSH reports consulting fees from AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen, and Pfizer; funding for research work to her institution from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, eFFECTOR Therapeutics, Emergent BioSolutions, Ferring, Medivation, Pfizer, and Roche; honoraria from Astellas Pharma; and accommodation and expenses from Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen Oncology, and Pfizer. FS reports consulting fees to himself from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; grants or contracts to his institution from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; and payment or honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Myovant, Novartis, Janssen, Pfizer, and Sanofi. CB reports consulting fees from Astellas Pharma, Janssen, Merck, and Pfizer. IMvO reports consulting fees from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; grants or contracts from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; payment or honoraria from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; and support for attending meetings and travel from Astellas Pharma. ADL, MM, H-CC, CGH, and AC are employees of Pfizer and hold Pfizer stock and stock options. KF reports payment or honoraria to his institution from Astellas Pharma, Bayer, Janssen, and Sanofi, and participation on a Data Monitoring Safety Board or Advisory Board to his institution for Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Sanofi. ASti and MTF declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To understand migraine postdrome by directly interviewing migraine patients with postdrome symptoms. To document these symptoms, as well as impacts, as a prelude to developing a postdrome migraine questionnaire., Background: Migraine attacks are traditionally divided into 4 phases. Of these, the postdrome is the least studied, and no patient-reported outcomes to assess symptoms and impacts of this migraine phase have been published., Methods: Qualitative concept elicitation focus groups were conducted with 34 patients in 3 geographically diverse US cities to elicit the symptoms and burden of migraine postdrome. Data elicited from focus groups were coded using Atlas.ti software to facilitate identification of concepts and terminologies of migraine postdrome. A draft questionnaire was developed based on the symptoms and impacts of migraine postdrome described by patients. Cognitive debriefing interviews were conducted with 15 patients in Connecticut and Chicago to confirm content validity, relevance, and comprehension., Results: Patients defined the onset of postdrome as when they no longer experienced the migraine pain. Postdrome was often described as "[being] or [feeling] wiped out" and "headache hangover." The symptoms most frequently reported by the patients who participated in the focus groups and included in the draft post-migraine questionnaire were: tiredness, difficulty concentrating, weakness, dizziness, lightheadedness, and decreased energy. Patients also reported decreased activity level as a result of experiencing postdrome symptoms. Postdrome symptoms were reported to impact the ability to work, to affect family interactions and social life, and to cause cognitive impairment. A preliminary questionnaire measuring severity and duration of symptoms and severity of impacts of the post-migraine experience, with an 11-point (0 to 10) response scale, was developed. This preliminary questionnaire was tested for content validity, relevance, and comprehension using cognitive debriefing interviews. All patients reported that the questionnaire was relevant to their condition. Irrelevant and redundant items such as body tension and annoyance were eliminated., Conclusions: Migraine postdrome is debilitating for those who experience it. Concept elicitation and cognitive debriefing research support the relevance of the items in the post-migraine questionnaire. Future research will provide evidence of the post-migraine questionnaire's psychometric properties and interpretation guidelines., (© 2010 American Headache Society.)

Background: Our purpose was to compare the importance of over 22 measurements used in evaluating the clinical responses of patients with metastatic or locally recurrent prostate cancer, treated by dendritic cell (DC) infusions with prostate-specific membrane antigen (PSMA) peptides., Methods: Artificial neural networks (ANNs) were employed for assessment, as well as the traditional methods of logistic regression., Results: Twenty-six patients with metastatic disease and 37 patients with local recurrence were available for evaluation and comparison. ANN evaluation ranked the collective effects of DC infusion, immune responses (CD3+ cells, CD16+ cells, zeta chain+ cells), and cytokines, e.g., IL-6 and PSMA levels, very highly. Logistic regression identified all of these parameters to some degree, but in a different rank order. Patients with metastases showed a sharp rate of response secondary to the level of DC infusion, in contrast to those patients with local recurrence, in which it was more gradual., Conclusions: ANN analysis emphasizes the importance of level of DC infusion, immune parameters, cytokines, and markers such as PSMA in determining the response to PSMA peptide immunotherapy. The criteria of response were judged to be correct in 86% of metastatic patients and 83% of locally recurrent patients evaluated in this study., (Copyright 2000 Wiley-Liss, Inc.)

Detection of functional, circulating T cells and NK cells may serve as a clinical test for the selection of individuals who can benefit from immunotherapy. Incidence of the T-cell receptor zeta (TCRdelta) chain within these populations appears to correlate with adequate effector cell function. In patients with advanced malignancy, the absence or reduced expression of delta chain has been documented. Flow cytometric analysis in the present study revealed a significant reduction in delta chain expression in peripheral blood lymphocytes (PBL) of 14 of 22 prostate cancer patients (P < 0.000001) as compared to normal donors, apparent in both T cells (CD3+, CD4+, CD8+), and NK (CD16+) cells. Compared to normal donor PBL, patient PBL cultured in the presence of CD3 and CD28, also demonstrated reduced expression of CD69 and/or CD25, and in some cases, failed to activate at all. Furthermore, evidence of cell proliferation in activation-stimulated patient PBL was muted: average PCNA positivity equaled 14%, a marked difference from what was observed in normal donors (P < 0.0002). In 8 of 16 samples of PBL, where delta expression was originally low, delta levels returned to the normal range after 48 hour culture in serum-free medium, suggesting that the loss of delta is reversible and may be caused by a tumor-derived substance. These data support the premise that monitoring the expression of delta in a cancer patient may provide a unique insight into the immune status and functionality of the individual, with the potential to redirect or augment therapies and ultimately alter prognosis.

Flow cytometric bivariate analysis was used to evaluate the expression of PCNA, p120, and p145 during the G0 reentry of CHO-K1 cells into the cell cycle. CHO-K1 cells were placed in a G0-like state using serum depletion and stimulated to reenter the cell cycle by replating into fresh, serum-containing medium. At discrete intervals after stimulation, replicate samples were stained for either PCNA, p120, or 145; stained for DNA (Coulter DNA-Prep); evaluated on the EPICS Profile I; and analyzed on the EPICS ELITE workstation. PCNA stained less than 10% of the G0 cells; in contrast, however, 30-35% of the G0 cells were positive for p120 and p145. Eight hours after stimulating G0 cells to reenter the cell cycle (during G0/G1), p120 reached 88% positivity, while p145 and PCNA were 63% and 30% positive, respectively. Cells in S phase (12 and 16 h following G0 stimulation) were greater than 90% positive for all three antigens. PCNA had the greatest change throughout the G0 reentry process, both in percentage positive and quantitatively (mean channel fluorescence). This report indicates that all three proliferation-associated antigens studied are differentially expressed during the reentry of G0 cells into the cell cycle. Furthermore, these antigens may be useful in the early detection of G0 recruitment.

Flow cytometric bivariate analysis was used to investigate the expression of PCNA, p120 and p145 during the cell cycle of a mammalian cell line (CHO-K1). Initially, aliquots of cells in exponential and plateau (G0) phase were analyzed for proliferation associated antigen expression. Expression of PCNA and p145 during G0 was markedly depressed (less than 12% positive) while 54% of the G0 cells stained positive for p120. The fluorescent intensity (mean channel fluorescence) of these G0 positive p120 cells, however, was only slightly above the mean channel fluorescence (MCF) of cells stained with a negative isotype control. In asynchronous cultures, all three antigens were expressed in greater than 70% of the cells, with PCNA staining being greater than 95%. Cells were then synchronized using mitotic selection (mitotic index of 97%) and antigen levels were measured as cells progressed synchronously through the cell cycle. From DNA analysis histograms, it appeared that the degree of synchrony was approximately 90% throughout the remainder of the cell cycle. The bivariate DNA/PCNA, DNA/p120, and DNA/p145 histograms for mitotic cells indicated that both p120 and p145 expression were elevated (percent positive and MCF) while PCNA levels were near controls (MCF). In early G1, all three markers were depressed (less than 12% positive); however PCNA levels rose precipitously in mid-G1 (greater than 50% positive). In late G1 to early S, p145 levels increased concomitantly with increases in p120. All three antigens were elevated throughout S phase and began to decline as cells moved from G2/M to G1 of the next cell cycle with p145 expression decreasing first. This report indicates that all three proliferation associated antigens studied are differentially expressed in the cell cycle and therefore may be useful in detecting and assessing the proliferation state.