Publications by authors named "Alison Birtle"

62 Publications

Real-World Safety and Efficacy Outcomes with Abiraterone Acetate Plus Prednisone or Prednisolone as the First- or Second-Line Treatment for Metastatic Castration-Resistant Prostate Cancer: Data from the Prostate Cancer Registry.

Target Oncol 2021 Apr 7. Epub 2021 Apr 7.

Guy's and St Thomas' NHS Foundation Trust and Sarah Cannon Research Institute, London, UK.

Background: Despite standard-of-care androgen-deprivation therapy and an increasing number of treatment options, the mortality rate for prostate cancer remains high. Progress to metastatic castration-resistant prostate cancer (mCRPC) necessitates additional treatments. Abiraterone acetate plus prednisone or prednisolone (AAP) prolongs survival in chemotherapy-naive and docetaxel-experienced patients.

Objective: To evaluate the real-world safety and efficacy of AAP as first-line and second-line [post-docetaxel only (AAP-PD)] treatment in patients with mCRPC.

Patients And Methods: The Prostate Cancer Registry (PCR) was a prospective, international, observational study of patients with mCRPC in routine clinical practice. Men aged ≥ 18 years with confirmed mCRPC were included. Baseline characteristics, safety (treatment-emergent adverse events, treatment-emergent severe adverse events), and efficacy [progression-free survival (PFS) and overall survival (OS)] were analyzed.

Results: At baseline, patients who received first-line AAP (n = 754) were generally older than patients who received AAP-PD (n = 354); median age was 76 years and 70 years, respectively. However, the rate of visceral metastasis was higher in the AAP-PD cohort than in the AAP cohort (17.7% vs. 9.6%, respectively). Demographics and disease characteristics of patients with baseline cardiovascular disease were similar to those of the overall registry population. Efficacy outcomes were similar for all patients, regardless of the line of AAP therapy. For first-line AAP and AAP-PD, respectively, the median PFS was 8.9 and 5.8 months for all patients and 9.1 and 6.0 months for patients with cardiovascular comorbidities; median OS was 27.1 and 23.4 months for all patients, and 27.4 and 23.1 months for patients with cardiovascular comorbidities. There were no unexpected adverse events in any patient subgroup.

Conclusions: These real-world data complement the findings from randomized controlled trials, indicating that first- and second-line AAP is well tolerated and effective in patients with mCRPC, including those with underlying CV comorbidities.

Trial Registration Number: NCT02236637, registered 8 September 2014.
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http://dx.doi.org/10.1007/s11523-021-00807-4DOI Listing
April 2021

Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE).

Clin Cancer Res 2021 Apr 20;27(7):1882-1892. Epub 2021 Jan 20.

Southampton Clinical Trials Unit, University of Southampton, Southampton, England, United Kingdom.

Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.

Patient And Methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m, i.v., day 8 and gemcitabine 1,000 mg/m, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.

Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.

Conclusions: The guadecitabine RP2D was 20 mg/m, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3946DOI Listing
April 2021

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

J Clin Oncol 2021 Jan 16;39(3):190-201. Epub 2020 Dec 16.

University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.

Purpose: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel.

Patients And Methods: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status.

Results: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash.

Conclusion: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.
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http://dx.doi.org/10.1200/JCO.20.01576DOI Listing
January 2021

Clinical Outcomes of a Randomized Trial of Adaptive Plan-of-the-Day Treatment in Patients Receiving Ultra-hypofractionated Weekly Radiation Therapy for Bladder Cancer.

Int J Radiat Oncol Biol Phys 2020 Dec 11. Epub 2020 Dec 11.

The Institute of Cancer Research, London, United Kingdom.

Purpose: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.

Methods: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.

Results: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).

Conclusions: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.068DOI Listing
December 2020

Management of Muscle-Invasive Bladder Cancer During a Pandemic: Impact of Treatment Delay on Survival Outcomes for Patients Treated With Definitive Concurrent Chemoradiotherapy.

Clin Genitourin Cancer 2021 02 22;19(1):41-46.e1. Epub 2020 Jun 22.

Department of Radiation Oncology, Washington University School of Medicine in St Louis, St Louis, MO; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making to ensure that the benefit of early intervention for muscle-invasive bladder cancer exceeds the risk of contracting COVID-19 in the clinical setting. It is unknown whether treatment delays for patients eligible for curative chemoradiation (CRT) compromise long-term outcomes.

Patients And Methods: We used the National Cancer Data Base to investigate whether there is an association between a ≥ 90-day delay from transurethral resection of bladder tumor (TURBT) in initiating CRT and overall survival. We included patients with cT2-4N0M0 muscle-invasive bladder cancer from 2004 to 2015 who underwent TURBT and curative-intent concurrent CRT. Patients were grouped on the basis of timing of CRT: ≤ 89 days after TURBT (earlier) vs. ≥ 90 and < 180 days after TURBT (delayed).

Results: A total of 1387 (87.5%) received earlier CRT (median, 45 days after TURBT; interquartile range, 34-59 days), and 197 (12.5%) received delayed CRT (median, 111 days after TURBT; interquartile range, 98-130 days). Median overall survival was 29.0 months (95% CI, 26.0-32.0) versus 27.0 months (95% CI, 19.75-34.24) for earlier and delayed CRT (P = .94). On multivariable analysis, delayed CRT was not associated with an overall survival difference (hazard ratio, 1.05; 95% CI, 0.87-1.27; P = .60).

Conclusion: Although these results are limited and require validation, short, strategic treatment delays during a pandemic can be considered on the basis of clinician judgment.
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http://dx.doi.org/10.1016/j.clgc.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306737PMC
February 2021

The implementation and utility of patient screening logs in a multicentre randomised controlled oncology trial.

Trials 2020 Jul 8;21(1):629. Epub 2020 Jul 8.

Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU), London, SM2 5NG, UK.

Background: The utility of patient screening logs and their impact on improving trial recruitment rates are unclear. We conducted a retrospective exploratory analysis of screening data collected within a multicentre randomised controlled trial investigating chemotherapy for upper tract urothelial carcinoma.

Methods: Participating centres maintained a record of patients meeting basic screening criteria stipulated in the trial protocol, submitting logs regularly to the clinical trial coordinating centre (CTC). Sites recorded the number of patients ineligible, not approached, declined and randomised. The CTC monitored proportions of eligible patients, approach rate (proportion of eligible patients approached) and acceptance rate (proportion recruited of those approached). Data were retrospectively analysed to identify patterns of screening activity and correlation with recruitment.

Results: Data were collected between May 2012 and August 2016, during which time 71 sites were activated-a recruitment period of 2768 centre months. A total of 1138 patients were reported on screening logs, with 2300 requests for logs sent by the CTC and 47% of expected logs received. A total of 758 patients were reported as ineligible, 36 eligible patients were not approached and 207 declined trial participation. The approach rate was 91% (344/380), and the acceptance rate was 40% (137/344); these rates remained consistent throughout the data collection. The main reason patients provided for declining (99/207, 48%) was not wanting to receive chemotherapy. There was a moderately strong correlation (r = 0.47) between the number reported on screening logs and the number recruited per site. Considerable variation in data between centres was observed, and 54/191 trial participants (28%) enrolled during this period were not reported on logs.

Conclusions: Central collection of screening logs can identify reasons for patients declining trial participation and help monitor trial activity at sites; however, obtaining complete data can be challenging. There was a correlation between the number of patients reported on logs and recruitment; however, this was likely confounded by sites' available patient population. The use of screening logs may not be appropriate for all trials, and their use should be carefully considered in relation to the associated workload. No evidence was found that central collection of screening logs improved recruitment rates in this study, and their continued use warrants further investigation.

Trial Registration: ISRCTN98387754 . Registered on 31 January 2012.
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http://dx.doi.org/10.1186/s13063-020-04559-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346417PMC
July 2020

Real-World Outcomes in First-Line Treatment of Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer Registry.

Target Oncol 2020 06;15(3):301-315

Oncology Division, Hospital de Santa Maria, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-035, Lisbon, Portugal.

Background: Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, particularly in the real-world setting and among patients who are under-represented in clinical trials.

Objective: We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases.

Patients And Methods: Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Registry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes [overall survival (OS) and time to progression (TTP)] of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, "abiraterone"), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mellitus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population.

Results: The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen-deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population.

Conclusions: This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies.

Trial Registration: ClinicalTrials.gov identifier NCT02236637; registered September 2014.
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http://dx.doi.org/10.1007/s11523-020-00720-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283204PMC
June 2020

Corrigendum to 'EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees' [European Urology 77 (2020) 223-250].

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Peter-Paul M Willemse Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 Jul 21;78(1):e48-e50. Epub 2020 May 21.

Emeritus Professor, The Institute of Cancer Research, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2020.03.017DOI Listing
July 2020

A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin.

BJU Int 2020 08 19;126(2):292-299. Epub 2020 May 19.

Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.

Objectives: To assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first-line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.

Patients And Methods: From 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double-blind, placebo-controlled randomised Phase II trial, receiving six 21-day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression-free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention-to-treat and per-protocol analyses were used to analyse the primary endpoint.

Results: The 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65-1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79-2.52; P = 0.88); and radiological response rates were 50% and 55%.

Conclusion: There is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first-line treatment in patients with UC who were unfit for cisplatin.
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http://dx.doi.org/10.1111/bju.15096DOI Listing
August 2020

ATLANTIS: a randomised multi-arm phase II biomarker-directed umbrella screening trial of maintenance targeted therapy after chemotherapy in patients with advanced or metastatic urothelial cancer.

Trials 2020 Apr 19;21(1):344. Epub 2020 Apr 19.

Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK.

Background: Metastatic urothelial cancer (UC) is the eighth most common cause of cancer death in the UK. Standard first-line treatment, for most patients, is cytotoxic chemotherapy. Although UC is initially sensitive to chemotherapy, relapse is almost inevitable and outcomes are poor; median overall survival is 8 months. Therefore, there is an urgent need for novel therapies to improve outcomes for this patient group.

Methods: ATLANTIS is a randomised phase II umbrella-design screening trial of maintenance therapy in biomarker-defined subgroups of patients with advanced UC. The primary end point is progression-free survival, and the study involves over 30 UK cancer centres.

Discussion: ATLANTIS is the first study in the UK to employ a precision-medicine approach to patients with UC for maintenance treatment. Agents with a positive efficacy signal will proceed to randomised phase III trials to confirm the activity of novel, biologically stratified therapies in UC.

Registration: ATLANTIS trial EudraCT number 2015-003249-25. ISRCTN25859465.
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http://dx.doi.org/10.1186/s13063-020-04283-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168999PMC
April 2020

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

Lancet 2020 04 5;395(10232):1268-1277. Epub 2020 Mar 5.

The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, UK.

Background: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.

Methods: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.

Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30-0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0-47·5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.

Interpretation: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S0140-6736(20)30415-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181180PMC
April 2020

Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.

Lancet Oncol 2020 01 2;21(1):162-174. Epub 2019 Dec 2.

The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.

Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.

Findings: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.

Interpretation: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.

Funding: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
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http://dx.doi.org/10.1016/S1470-2045(19)30684-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941219PMC
January 2020

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

Eur J Cancer 2020 01 29;125:153-163. Epub 2019 Nov 29.

European Georges Pompidou Hospital, Paris, France. Electronic address:

Aim Of The Study: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry.

Methods: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence.

Results: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes.

Conclusions: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.
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http://dx.doi.org/10.1016/j.ejca.2019.10.030DOI Listing
January 2020

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 02 19;77(2):223-250. Epub 2019 Nov 19.

Emeritus Professor, The Institute of Cancer Research, London, UK.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

Setting: Online Delphi survey and consensus conference.

Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

Outcome Measurements And Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

Results And Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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http://dx.doi.org/10.1016/j.eururo.2019.09.035DOI Listing
February 2020

Impact of Abiraterone Acetate plus Prednisone or Enzalutamide on Patient-reported Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer: Final 12-mo Analysis from the Observational AQUARiUS Study.

Eur Urol 2020 03 5;77(3):380-387. Epub 2019 Oct 5.

Academic Uro-Oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.

Background: Few studies have examined patient-reported outcomes (PROs) with abiraterone acetate plus prednisone (abiraterone) versus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC).

Objective: To determine the impact of abiraterone and enzalutamide on PROs.

Design, Setting, And Participants: AQUARiUS (NCT02813408) was a prospective, 12-mo, observational study in patients with mCRPC from Denmark, France, and the UK.

Intervention: Abiraterone or enzalutamide treatment according to routine practise.

Outcome Measurements And Statistical Analysis: PROs were collected over 12 mo using Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Brief Fatigue Inventory-Short Form (BFI-SF), Brief Pain Inventory-Short Form, and European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (QLQ-C30) at baseline and routine visits. Outcomes included mean change in PROs, patients with clinically meaningful worsening (CMW) in PROs, and safety. Data were analysed using repeated measures linear and logistic models adjusted for baseline characteristics.

Results And Limitations: Abiraterone-treated (N = 105) and enzalutamide-treated (N = 106) patients were included. Key PRO items (cognitive impairments and fatigue) were significantly (p < 0.05) in favour of abiraterone versus enzalutamide during the study. "Perceived cognitive impairment" and "comments from others" (FACT-Cog); "fatigue right now", "usual level of fatigue", and "worst level of fatigue" (BFI-SF); and "cognitive functioning" and "fatigue" (QLQ-C30) were significantly in favour of abiraterone over enzalutamide for three or more consecutive periods up to month 12. From study initiation, significantly fewer patients receiving abiraterone experienced one or more CMW episode in cognition and fatigue. Fatigue and asthenia (adverse events) were lower with abiraterone than with enzalutamide (5% vs 15% and 10% vs 11%, respectively). There were no treatment-related deaths. Limitations included lack of randomisation.

Conclusions: In a real-world setting, this 12-mo analysis suggests an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive function; this finding occurred early after treatment initiation. This difference should be considered when choosing treatment.

Patient Summary: This study looked at the effect of two treatments (abiraterone acetate plus prednisone and enzalutamide) for metastatic castration-resistant prostate cancer on patient quality of life over 12 mo. Using established questionnaires, patients reported that they experienced less fatigue and cognitive impairments (including memory loss and reduced thinking abilities) with abiraterone acetate plus prednisone than with enzalutamide.
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http://dx.doi.org/10.1016/j.eururo.2019.09.019DOI Listing
March 2020

From Clinical Trials to Real-life Clinical Practice: The Role of Immunotherapy with PD-1/PD-L1 Inhibitors in Advanced Urothelial Carcinoma.

Eur Urol Oncol 2018 12 2;1(6):486-500. Epub 2018 Jul 2.

Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Context: A number of PD-1/PD-L1 inhibitors have recently been approved for use in patients with locally advanced or metastatic urothelial carcinoma (UC) on the basis of results from several clinical trials.

Objective: To review the evidence from these trials and consider what it means for the use of these drugs in first-line and post-platinum settings in real-life clinical practice.

Evidence Acquisition: PubMed was searched for full reports of clinical trials of single-agent PD-1/PD-L1 inhibitors in advanced UC. Twelve publications were included.

Evidence Synthesis: Responses to PD-1/PD-L1 inhibitors appear to be durable but are only achieved in 17-26% of patients. These drugs offer different toxicity and efficacy profiles to standard chemotherapy regimens. This should be considered when choosing a treatment strategy for each patient.

Conclusions: PD-1/PD-L1 inhibitors represent a major step forward in the management of advanced UC, although several questions remain regarding their optimal use in routine clinical practice. A validated predictive biomarker of response is yet to be defined, and this is perhaps the most significant unmet need for currently available drugs.

Patient Summary: We reviewed the results from clinical trials that investigated how well certain types of anticancer drugs called PD-1/PD-L1 inhibitors worked in patients with bladder cancer. We found that more research is required to identify (1) the factors that might predict which patients with bladder cancer will respond to PD-1/PD-L1 inhibitors and (2) the optimum duration of treatment with these drugs.
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http://dx.doi.org/10.1016/j.euo.2018.05.011DOI Listing
December 2018

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

Eur Urol Oncol 2018 12 8;1(6):467-475. Epub 2018 Jun 8.

European Georges Pompidou Hospital, Paris, France. Electronic address:

Background: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.

Objective: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.

Design, Setting, And Participants: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.

Outcome Measurements And Statistical Analysis: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.

Results And Limitations: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.

Conclusions: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.

Patient Summary: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.
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http://dx.doi.org/10.1016/j.euo.2018.05.009DOI Listing
December 2018

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness.

Eur Urol Oncol 2018 12 14;1(6):449-458. Epub 2018 Sep 14.

Centre for Health Economics, University of York, York, UK.

Background: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources.

Objective: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting.

Design, Setting, And Participants: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy.

Intervention: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m) was administered alongside SOC for six three-weekly cycles.

Outcome Measurements And Statistical Analysis: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Results And Limitations: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled.

Conclusions: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available.

Patient Summary: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.
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http://dx.doi.org/10.1016/j.euo.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692495PMC
December 2018

Abiraterone acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-world retrospective cohort study.

BMC Cancer 2019 Jan 14;19(1):60. Epub 2019 Jan 14.

The Christie Hospital, Manchester, UK.

Background: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.

Methods: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.

Results: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0-81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2-133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2-11.1) and the median PFS was 10.8 months (95%CI: 9.6-11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).

Conclusions: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.
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http://dx.doi.org/10.1186/s12885-019-5280-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332550PMC
January 2019

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Lancet 2018 12 21;392(10162):2353-2366. Epub 2018 Oct 21.

Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London, UK. Electronic address:

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.

Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476.

Findings: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy).

Interpretation: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer.

Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.
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http://dx.doi.org/10.1016/S0140-6736(18)32486-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269599PMC
December 2018

Impact of abiraterone acetate plus prednisone or enzalutamide on fatigue and cognition in patients with metastatic castration-resistant prostate cancer: initial results from the observational AQUARiUS study.

ESMO Open 2018 3;3(5):e000397. Epub 2018 Aug 3.

Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

Introduction: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are commonly prescribed for metastatic castration-resistant prostate cancer (mCRPC). Data comparing their effects on patient-reported outcomes (PROs) from routine clinical practice are limited.

Methods: AQUARiUS (NCT02813408) is an ongoing, two-cohort, prospective, observational, non-randomised, multicentre, phase IV European study assessing the effects of AAP and ENZ on PROs in 211 patients with mCRPC over 12 months. Patients receive AAP or ENZ per routine clinical practice. Data on cognition, fatigue, pain and health-related quality of life are measured using the Functional Assessment of Cancer Therapy-Cognitive Function, Brief Fatigue Inventory-Short Form, Brief Pain Inventory-Short Form and European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaires, respectively.

Results: This 3-month analysis was conducted in 105 patients; 46 received AAP and 59 received ENZ. There were statistically significant differences in mean change from baseline favouring AAP over ENZ at months 1, 2 and 3 for perceived cognitive impairments and cognitive functioning. At each time-point, ENZ-treated patients had a significantly higher risk of experiencing clinically meaningful worsening in perceived cognitive impairments versus those receiving AAP.Statistically significant differences in mean change from baseline favouring AAP over ENZ were seen for usual level of fatigue and fatigue interference at months 2 and 3 and for current fatigue and worse level of fatigue at month 3. Differences favouring AAP versus ENZ were seen for the fatigue scale of the QLQ-C30 questionnaire (months 1 and 3). There was a significantly higher risk of clinically meaningful worsening in usual level of fatigue with ENZ versus AAP at month 3.No significant differences between cohorts were observed for pain (BPI-SF) at any time-point.

Conclusion: This analysis suggests more favourable outcomes with AAP versus ENZ for cognition and fatigue in the first 3 months of treatment initiation for mCRPC. These findings require confirmation from future analyses of data from AQUARiUS from a larger number of patients with a longer follow-up period.
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http://dx.doi.org/10.1136/esmoopen-2018-000397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088345PMC
August 2018

The Efficacy and Safety of Conventional and Hypofractionated High-Dose Radiation Therapy for Prostate Cancer in an Elderly Population: A Subgroup Analysis of the CHHiP Trial.

Int J Radiat Oncol Biol Phys 2018 04 9;100(5):1179-1189. Epub 2018 Jan 9.

The Institute of Cancer Research, London, UK.

Purpose: Outcome data on radiation therapy for prostate cancer in an elderly population are sparse. The CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer) trial provides a large, prospectively collected, contemporary dataset in which to explore outcomes by age.

Methods And Materials: CHHiP participants received 3 to 6 months of androgen deprivation therapy and were randomly assigned (1:1:1) to receive 74 Gy in 37 fractions (conventional fractionation), 60 Gy in 20 fractions, or 57 Gy in 19 fractions. Toxicity was assessed using clinician-reported outcome (CRO) and patient-reported outcome questionnaires. Participants were categorized as aged < 75 years or ≥ 75 years. Outcomes were compared by age group.

Results: Of 3216 patients, 491 (15%) were aged ≥ 75 years. There was no difference in biochemical or clinical failure rates between the groups aged < 75 years and ≥ 75 years for any of the fractionation schedules. In the group aged ≥ 75 years, biochemical or clinical failure-free rates favored hypofractionation, and at 5 years, they were 84.7% for 74 Gy, 91% for 60 Gy, and 87.7% for 57 Gy. The incidence of CRO (grade 3) acute bowel toxicity was 2% in both age groups. The incidence of grade 3 acute bladder toxicity was 8% in patients aged < 75 years and 7% in those aged ≥ 75 years. The 5-year cumulative incidence of CRO grade ≥ 2 late bowel side effects was similar in both age groups. However, in the group aged ≥ 75 years, there was a suggestion of a higher cumulative incidence of bowel bother (small or greater) with 60 Gy compared with 74 Gy and 57 Gy. Patient-reported bladder bother was slightly higher in the group aged ≥ 75 years than the group aged < 75 years, and there was a suggestion of a lower cumulative incidence of bladder bother with 57 Gy compared with 74 Gy and 60 Gy in patients aged ≥ 75 years, which was not evident in those aged < 75 years.

Conclusions: Hypofractionated radiation therapy appears to be well tolerated and effective in men aged ≥ 75 years. The 57-Gy schedule has potential advantages in that it may moderate long-term side effects without compromising treatment efficacy in this group.
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314452PMC
April 2018

Efficacy of cabazitaxel rechallenge in heavily treated patients with metastatic castration-resistant prostate cancer.

Eur J Cancer 2018 07 7;97:41-48. Epub 2018 Apr 7.

European Georges Pompidou Hospital, Paris, France; René Descartes University, Paris V, France. Electronic address:

Background: Treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC.

Patients And Methods: Clinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Data on toxicities were collected.

Results: A total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0-1 69%) were rechallenged with CABA (25 mg/m q3w, 58%; 20 mg/m q3w, 27.5%; other, 14.5%) for 1-10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3-15.7) from the first CABA rechallenge cycle, 59.9 months (47.8-67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4-90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders.

Conclusions: CABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections.
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http://dx.doi.org/10.1016/j.ejca.2018.03.008DOI Listing
July 2018

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents.

Clin Genitourin Cancer 2018 08 23;16(4):e777-e784. Epub 2018 Feb 23.

Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France. Electronic address:

Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

Patients And Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined.

Results: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.

Conclusion: OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.
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http://dx.doi.org/10.1016/j.clgc.2018.02.016DOI Listing
August 2018

An observational study showed that explaining randomization using gambling-related metaphors and computer-agency descriptions impeded randomized clinical trial recruitment.

J Clin Epidemiol 2018 07 2;99:75-83. Epub 2018 Mar 2.

Population Health Sciences, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, Bristol, United Kingdom; National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West), University Hospitals Bristol NHS Trust, Bristol, United Kingdom.

Objectives: To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment.

Study Design And Setting: Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties.

Results: One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was "best for them". Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation.

Conclusions: The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation.
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http://dx.doi.org/10.1016/j.jclinepi.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015122PMC
July 2018

Development of a framework to improve the process of recruitment to randomised controlled trials (RCTs): the SEAR (Screened, Eligible, Approached, Randomised) framework.

Trials 2018 Jan 19;19(1):50. Epub 2018 Jan 19.

School of Social and Community Medicine, University of Bristol, 39 Whatley Road, Bristol, BS8 2PS, UK.

Background: Research has shown that recruitment to trials is a process that stretches from identifying potentially eligible patients, through eligibility assessment, to obtaining informed consent. The length and complexity of this pathway means that many patients do not have the opportunity to consider participation. This article presents the development of a simple framework to document, understand and improve the process of trial recruitment.

Methods: Eight RCTs integrated a QuinteT Recruitment Intervention (QRI) into the main trial, feasibility or pilot study. Part of the QRI required mapping the patient recruitment pathway using trial-specific screening and recruitment logs. A content analysis compared the logs to identify aspects of the recruitment pathway and process that were useful in monitoring and improving recruitment. Findings were synthesised to develop an optimised simple framework that can be used in a wide range of RCTs.

Results: The eight trials recorded basic information about patients screened for trial participation and randomisation outcome. Three trials systematically recorded reasons why an individual was not enrolled in the trial, and further details why they were not eligible or approached, or declined randomisation. A framework to facilitate clearer recording of the recruitment process and reasons for non-participation was developed: SEAR - Screening, to identify potentially eligible trial participants; Eligibility, assessed against the trial protocol inclusion/exclusion criteria; Approach, the provision of oral and written information and invitation to participate in the trial, and Randomised or not, with the outcome of randomisation or treatment received.

Conclusions: The SEAR framework encourages the collection of information to identify recruitment obstacles and facilitate improvements to the recruitment process. SEAR can be adapted to monitor recruitment to most RCTs, but is likely to add most value in trials where recruitment problems are anticipated or evident. Further work to test it more widely is recommended.
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http://dx.doi.org/10.1186/s13063-017-2413-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775609PMC
January 2018

Informed consent in randomised controlled trials: development and preliminary evaluation of a measure of Participatory and Informed Consent (PIC).

Trials 2017 07 17;18(1):327. Epub 2017 Jul 17.

School of Social and Community Medicine, University of Bristol, 39 Whatley Road, Clifton, Bristol, BS8 2PS, UK.

Background: Informed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding.

Methods: Published guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above.

Results: DevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained.

Conclusions: The DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further.
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http://dx.doi.org/10.1186/s13063-017-2048-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513045PMC
July 2017

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

N Engl J Med 2017 07 3;377(4):338-351. Epub 2017 Jun 3.

From the Institute of Cancer and Genomic Sciences, University of Birmingham (N.D.J.), and University Hospital Birmingham (A.Z.), Birmingham, the Institute of Cancer Research (J.S.B., D.P.D., G.A.), Medical Research Council Clinical Trials Unit at University College London (M.R. Spears, C.L.A., C.G., C.B., M.K.B.P., M.R. Sydes), King's College London and Guy's and St. Thomas' NHS Foundation Trust (S.C.), and Royal Marsden NHS Foundation Trust (C.C.P.), London, Salford Royal NHS Foundation Trust, Salford (N.W.C.), Cardiff University School of Medicine (M.D.M.) and Velindre Cancer Centre (J.F.L.), Cardiff, Gloucestershire Royal Hospital (A.W.S.R.) and Gloucestershire Hospitals NHS Foundation Trust (J.B.), Gloucester, University of Glasgow, Glasgow (R.J.J., J.M.R.), St. James's University Hospital, Leeds (W.R.C.), University Hospital of North-Midlands, Stoke-on-Trent (F.A.), Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter (S.A.), Rosemere Cancer Centre, Royal Preston Hospital, Preston (A.J.B.), Dorset Cancer Centre, Poole Hospital, Poole (S.B.), Royal Derby Hospital, Derby (P.C.), Weston Park Hospital, Sheffield (C.F.), Portsmouth Oncology Centre, Queen Alexandra Hospital, Portsmouth (J.G.), Musgrove Park Hospital, Taunton (E.G.), Hull and East Yorkshire Hospitals NHS Trust, Hull (M.H.), Mount Vernon Cancer Centre, Northwood (P.J.H.), Clatterbridge Cancer Centre, Wirral (Z.I.M.), Brighton and Sussex University Hospitals NHS Trust (F.M.) and Sussex Cancer Centre, Royal Sussex County Hospital (A.R.), Brighton, NHS Highland, Inverness (N.M.), Royal Surrey County Hospital, Guildford (J.M.-K.), Northern Ireland Cancer and Queens University, Belfast (J.O.), Lancashire Teaching Hospitals NHS Trust, Preston (O.P.), Churchill Hospital, Oxford (A.P.), Shrewsbury and Telford Hospitals NHS Trust, Shrewsbury (N.N.S.), East Kent Hospitals NHS Trust, Canterbury (C.T.), Swansea University College of Medicine, Swansea (J. Wagstaff), and Christie NHS Foundation Trust, Manchester (J. Wylie) - all in the United Kingdom; and the Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen (S.G.), and University Hospital of Lausanne, Lausanne (D.R.B.) - both in Switzerland. Two of the authors (D.M., R.M.) were unaffiliated lay members of the STAMPEDE investigators.

Background: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).

Results: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).

Conclusions: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).
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http://dx.doi.org/10.1056/NEJMoa1702900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216PMC
July 2017