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Background: Androgen receptor signalling inhibitors (ARSIs) abiraterone acetate (AA) enzalutamide (Enza), are currently the standard first-line (L1) treatments for metastatic castration-resistant prostate cancer (mCRPC), and docetaxel (D) is reserved as second-line (L2) after ARSI failure. Nonetheless, D use in men ≥ 75 years old is restricted owing to treatment toxicities and patient comorbidities, and a L2 alternative ARSI is frequently used. We aimed to evaluate real-life survival and toxicity outcomes of these elderly patients after failure of L1 ARSI treatment., Material and Methods: We retrospectively evaluated efficacy and safety in a real-world international cohort of consecutive patients ≥ 75 years old when starting L1 ARSI for mCRPC according to the choice of L2 treatment (D versus alternative ARSI)., Results: Of the 122 identified patients, 57 (46.7%) had received L2 ARSI and 65 (53.3%) L2 D. No difference was found in the L1 overall survival (OS) for the ARSI and D groups (32.8 vs. 30.0 months, respectively; Hazard ratio [HR] = 1.22; 95% CI, 0.77-1.95; P = .40) or in the L2 OS (18.5 vs. 17.8 months, respectively; HR = 1.09; 95% CI, 0.69-1.74; P = .71). No difference was observed for rPFS from L2 (P = .12), although a trend was observed for a numerically improved rPFS on D., Conclusion: Within the limitations of a retrospective design and small population, our study suggests that D or ARSI after failure of L1 alternative ARSI are clinically comparable L2 options for elderly patients with mCRPC., Competing Interests: Disclosure Loana Bueno Valencia received consulting fees from Janssen and travel grants from Janssen, Astellas, and Bayer. The other authors report no competing interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Clinical trials are categorized as industry sponsored trials (ISTs) or investigator-initiated trials (IITs) based on the source of funding and sponsor of the trial. ISTs are usually run by pharmaceutical companies, and are primarily aimed at developing new drugs that ultimately gain regulatory approval. IITs are developed by academic investigators or cooperative groups, often sparked by a clinical need. Both are vital in advancing the field of oncology. To date, little has been published about current trends in ISTs or IITs in genitourinary (GU) oncology. The aim of this study was to assess growth trends of GU oncology ISTs and IITs in 4 countries with similar healthcare infrastructures., Methods: We searched ClinicalTrials.gov for bladder, kidney, and prostate cancer trials conducted in the United States (US), Canada, France, and United Kingdom (UK) from January 2007 to December 2021. Trials were determined to be ISTs or IITs based on their funding source and sponsor. Trials were characterized based on type, purpose, phase, participants, masking, assignment, and allocation., Results: Overall, 5,834 GU trials were identified, with a balanced distribution of ISTs (n = 3064, n = 52.5%) and IITs (n = 2770, 47.4%). By country, the US conducted the most GU trials (n = 3814) followed by Canada (n = 709), France (n = 677), and the UK (n = 634). Most ISTs were phase 3 trials with over 500 participants while most IITs were open-label phase 2 studies with only 20-49 participants. From 2017 onwards, there was a shift towards more ISTs, most noticeably in Canada and the UK. The COVID-19 pandemic did not have a major impact on the growth of ISTs and IITs., Conclusion: The gap between ISTs and IITs continues to widen, likely driven by resource and funding challenges faced by investigators. Barriers to completing IITs need to be better understood to promote IIT development and maintain their academically driven intentions., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background: The 2 × 2 PEACE-1 study showed that combining androgen-deprivation therapy with docetaxel and abiraterone improved overall and radiographic progression-free survival in patients with de novo metastatic castration-sensitive prostate cancer. We aimed to examine the efficacy and safety of adding radiotherapy in this population., Methods: We conducted an open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Europe. Eligible participants were male patients (aged ≥18 years) with de novo metastatic castration-sensitive prostate cancer confirmed by bone scan, CT, or MRI, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 in the case of bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen-deprivation therapy alone or with six cycles of intravenous docetaxel 75 mg/m 2 every 3 weeks), standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), standard of care plus radiotherapy (74 Gy in 37 fractions to the prostate), or standard of care plus radiotherapy and abiraterone. Participants and investigators were not masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival, analysed by intention to treat in patients with low-volume metastatic disease and in the overall study population. This ongoing study is registered with EudraCT, 2012-000142-35., Findings: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled and 1172 were randomly assigned to receive standard of care (n=296 [25·3%]), standard of care plus abiraterone (n=292 [24·9%]), standard of care plus radiotherapy (n=293 [25·0%]), and standard of care plus abiraterone and radiotherapy (n=291 [24·8%]). Median follow-up was 6·0 years (IQR 5·1-7·0) at the time of radiographic progression-free survival and overall survival analysis. A qualitative interaction between radiotherapy and abiraterone for radiographic progression-free survival in the population of patients with low-volume disease prevented the pooling of intervention groups for analysis (p=0·026). Adding radiotherapy to standard of care improved radiographic progression-free survival in patients with low-volume disease treated with abiraterone (median 4·4 years [99·9% CI 2·5-7·3] in the standard of care plus abiraterone group vs 7·5 years [4·0-not reached] in the standard of care plus abiraterone and radiotherapy group; adjusted hazard ratio [HR] 0·65 [99·9% CI 0·36-1·19]; p=0·019), but not in patients not treated with abiraterone (median 3·0 years [99·9% CI 2·3-4·8] in the standard of care group vs 2·6 years [1·7-4·6] in the standard of care plus radiotherapy group; 1·08 [0·65-1·80]; p=0·61). For overall survival, the predefined threshold for a statistical interaction was not reached (p=0·12); therefore, the two intervention groups receiving radiotherapy were pooled together for analysis. In patients with low-volume disease, the overall survival was not influenced by radiotherapy (median 6·9 years [95·1% CI 5·9-7·5] for standard of care with or without abiraterone vs 7·5 years [6·0-not reached] for standard of care plus radiotherapy with or without abiraterone; HR 0·98 [95·1% CI 0·74-1·28]; p=0·86). In the overall safety population, 339 (56·1%) of 604 patients who did not receive radiotherapy and 329 (58·8%) of 560 patients who received radiotherapy developed at least one severe adverse event (grade ≥3), the most common being hypertension (110 [18·2%] patients in the standard of care with or without abiraterone group and 127 [22·7%] in the standard of care plus radiotherapy with or without abiraterone group) and neutropenia (40 [6·6%] and 29 [5·2%])., Interpretation: Combining radiotherapy with standard of care plus abiraterone improves radiographic progression-free survival and castration resistance-free survival, but not overall survival in patients with low-volume de novo metastatic castration-sensitive prostate cancer. Radiotherapy reduces the occurrence of serious genitourinary events, regardless of metastatic burden and without increasing the overall toxicity, and could become a component of standard of care in patients with both high-volume and low-volume de novo metastatic castration-sensitive prostate cancer., Funding: Janssen-Cilag, Ipsen, Sanofi, and Institut National du Cancer., Competing Interests: Declaration of interests AB reports consulting fees from Astellas Pharma, Bayer, Elekta Brachytherapy, Ferring, and Recordati; honoraria from Accord, Astellas Pharma, Elekta Brachytherapy, Janssen, Ipsen, and Recordati; and research grants from Janssen and Ipsen. SF reports participation in the data and safety monitoring board of Gilead Science, with payment made to her institution. PS reports consulting fees and honoraria from Astellas Pharma, Bayer, and Janssen; and support for attending meetings from Bayer and Janssen. RMD reports honoraria from Astellas Pharma, Bristol Myers Squibb, Janssen, Ipsen, and MSD; and support for attending meetings from Bayer, Novartis, and Pfizer. AF reports honoraria from Adacap, Astellas Pharma, AstraZeneca, Bayer, and Novartis. BT reports grants from Bayer and Ferring; personal fees from Amgen, Astellas Pharma, Bayer, Ferring, Myovant, Novartis, and Sanofi; and non-financial support from Astellas and Janssen. SS reports honoraria from Adacap, Astellas Pharma, AstraZeneca, Bayer, Curium, Janssen, Ipsen, MSD, and Recordati; and support for attending meetings from Accord, Adacap, Astellas Pharma, AstraZeneca, Bayer, Curium, Janssen, Ipsen, and MSD. DB reports honoraria, support for attending meetings, and a fiduciary role in other boards from Janssen, with payment made to his institution. KF reports consulting fees from Amgen, AstraZeneca, Astellas, Bayer, CureVac, Janssen, Novartis, Orion, Pfizer, and Sanofi; honoraria from AstraZeneca, Astellas, Bayer, Janssen, Novartis, and Sanofi; and participation in a data and safety monitoring board for Lilly, with payment made to his institution. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177 Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer., Methods: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177 Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177 Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff., Findings: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177 Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177 Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177 Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177 Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177 Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177 Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related])., Interpretation: 177 Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177 Lu-PSMA-617 may be an effective treatment alternative., Funding: Novartis., Competing Interests: Declaration of interests MJM declares receiving consulting or advisory fees from Amgen, AstraZeneca, Blue Earth Diagnostics, Clarity Pharmaceuticals, Convergent Therapeutics, Daiichi, ITM Isotope Technologies Munich, Lantheus Medical Imaging, Pfizer, POINT Biopharma, Progenics, Telix Pharmaceuticals, and Z-Alpha; stock and other ownership in Doximity; travel, accommodations, and expenses from APCCC, AstraZeneca, and Memorial Sloan-Kettering Cancer Center; institutional research funding from Astellas Pharma, Bayer, Celgene, Corcept Therapeutics, Janssen, Novartis, Progenics, and Roche/Genentech; patents pending with Novartis; and royalties from Telix. DC declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Exelisis, GlaxoSmithKline, Ipsen, Janssen, Lilly, MSD, Pfizer, QED Therapeutics, and Roche; travel or other expenses from Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; participation on a data safety monitoring or advisory board for Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; and other financial or non-financial interests in Spanish Oncology Genito-Urinary Group Foundation and GUARD Consortium Spanish group. KH declares receiving grants or contracts from Boston Scientific, Janssen, and Novartis; consulting fees from Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, Novartis, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and Y-mAbs Therapeutics; and stock or other ownership in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences. JSdB declares receiving grants or contracts from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi Aventis; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi-Sankyo, Genentech/Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion, Pfizer, Sanofi Aventis, and Taiho; payment or honorarium from Astellas, AstraZeneca, Bayer, Cellcentric, Crecendo, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Mycrix, MSD, Orion, Pfizer, Sanofi Aventis, and Taiho; being an inventor on patent 8822438 for a method for treating cancer; participating on a data safety monitoring or advisory board for Amgen, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Oncternal, Pfizer, and Sanofi Aventis; and receiving institutional royalties or licences related to abiraterone, PARP inhibitor, and PI3K/AKT. NDS declares receiving support for the present manuscript from Novartis; consulting fees from AbbVie, Accord, Amgen, Antev, Arquer, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Clarity, Cold Genesys, Curium, Dendreon, Exact Imaging, Ferring, Fize Medical, Invitae, Janssen, Lantheus, Lilly, MDXHealth, Merck, Minomic, Myriad, Novartis, PlatformQ, Pfizer, POINT Biopharma, Preview, Promaxo, Propella, Protara, Sanofi Genzyme, Siemens, Speciality Networks, Sumitomo, Telix, Tolmar, and Urogen; having a leadership or fiduciary role for Photocure, and Alessa; and having stock or stock options with Photocure, and Alessa. KNC declares receiving grants or contracts from AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche. MC declares receiving support for the present manuscript from Novartis; consulting fees from Astellas, AstraZeneca, Blue Earth Diagnostics, Boston Scientific, Elekta, Johnson & Johnson, Lantheus, Macrogenics, Pfizer, Profound Medical, Sumitomo, Telix, Tolmar, and Tempus; payment or honorarium from Johnson & Johnson, Pfizer, Profound Medical, and Telix; participating on an advisory board for Telix; and having a leadership or fiduciary role for the Society of Nuclear Medical and Molecular Imaging, and the American Urological Association. JMP declares receiving grants or contracts from BeiGene, Bristol Myers Squibb, Immunocore, Mirati, MSD, and Pfizer; consulting fees from Astellas, AstraZeneca, BeiGene, Bristol Myers Squibb, Clovis, Ideaya, Immunocore, Janssen, MSD, Novartis, and Pfizer; and travel expenses from AstraZeneca, Janssen, and Pfizer. AF declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, and Pfizer; and travel expenses from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, SD, Novartis, and Pfizer. XXW declares receiving institutional grants or contracts from Bristol Myers Squibb; consulting fees from Dendreon and Novartis; honorarium from Novartis; travel or other expenses from Novartis; and participating on a data safety monitoring or advisory board for Dendreon and Novartis. HM declares receiving payment or honorarium from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer; travel or other expenses from AstraZeneca, Novartis, Pfizer, Roche; and acting on a scientific steering committee for Curium. GR declares receiving grants or contracts from Bayer; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Pfizer. HŠ declares receiving consulting fees from Astellas, Bayer, Janssen, Novartis, and Pfizer. JN declares receiving contracts or grants from ABX, and Novartis; consulting fees from Curium, and POINT Biopharma; and payment or honorarium from Bayer AG, and Pfizer. BM declares receiving grants or contracts from Astellas, Bayer, Janssen, Roche, and Sanofi; payment or honorarium from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Pfizer, Roche, and Sanofi; travel or other expenses from Ipsen, Janssen Pfizer, and Roche; and other financial or non-financial interests in Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Pfizer, Roche, and Sanofi. ÁM-P declares receiving personal fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Novartis, and Pfizer; and non-financial support from Bayer, Ipsen, Merck, and Pfizer. EK, SG, TNK, CW, and KL declare being employed by and receiving restricted stock options from Novartis. OS declares receiving support for the present manuscript from Novartis; institutional grants or contracts from Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Novartis, Progenics, and Tenebio; consulting fees from ARTBIO, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, Isotopen Technologien Muenchen, Janssen, Merck, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Pfizer, POINT Biopharma, Sanofi, Telix, and Tenebio; travel and accommodation expenses from Lantheus, NorthStar, and Novartis; participation on a data safety monitoring or advisory board for AstraZeneca, Merck, and Pfizer; and stock or stock options in ARTBIO, Clarity Pharmaceuticals, Convergent, Fusion, Lilly, Pfizer, Ratio, and Telix. KF declares receiving institutional honorarium or payments to Gustave Roussy Institute from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Sanofi; institutional participation on data safety monitoring or advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and personal participation on a data safety monitoring or advisory board for Arvinas, CureVac, Macrogenics, Orion., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC., Patients and Methods: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R 2 ≥ 0.7 defined a priori as clinically relevant., Results: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R 2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R 2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81., Conclusions: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established., Patients and Methods: Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions., Results: The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events., Conclusions: Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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.)

Competing Interests: Disclosure KF reports personal fees for advisory board membership from Curevac and Orion; fees paid to his institution as an invited speaker from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, Pfizer and Sanofi; fees paid to his institution for advisory board membership from AAA, Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis/AAA and Pfizer; institutional funding as Trial Chair from AstraZeneca, Bayer, Bristol Myers Squibb (BMS), Janssen, MSD, Orion and Pfizer; non-remunerated role as PI and Trial Chair for Bayer, BMS, Merck, Novartis/AAA and Orion. SG reports personal fees for advisory board membership from Amgen, MSD, Orion, Roche and Sanofi; personal speaker honoraria from ESMO, Janssen Cilag, the Swiss Group for Clinical Cancer Research (SAKK) and Swiss Academy of Multidisciplinary Oncology (SAMO) – International Breast Cancer Study Group (IBCSG); personal travel grants from ProteoMEdiX; and other personal honoraria from Radiotelevisione svizzera (RSI; Swiss television). Her institution has received fees for advisory board membership from AAA International, Astellas Pharma, Bayer, BMS, Janssen Cilag, Menarini Silicon Biosystems, Modra Pharmaceuticals Holding B.V., Novartis, Orion, Pfizer, Roche, Telixpharma and Tolero Pharmaceuticals; speaker honoraria from DESO and Silvio Grasso Consulting; a research grant from Astellas and honoraria from Amgen for Steering Committee membership. She has held/holds non-remunerated advisory roles with Aranda, Menarini Silicon Biosystems and ProteoMediX.

Competing Interests: Disclosure AK reports personal fees as an invited speaker from Roche; fees paid to his institution for advisory board membership from Roche; institutional funding from Bristol Myers Squibb (BMS); non-remunerated role as a principal investigator for Roche. TB reports fees paid to his institution as a study oncologist, for expert testimony and study-related travel expenses from Roche. CP reports fees paid to her institution as an invited speaker from Roche; institutional funding as a coordinating principal investigator from Roche. GB reports personal fees for advisory board membership from Gensenta; institutional funding as a Steering Committee member from Bayer; non-remunerated roles as a principal investigator for Eli Lilly, Merck Sharp & Dohme (MSD) and Roche; member of the American Society of Clinical Oncology (ASCO). SD reports personal fees as an invited speaker from Bracco Germany; non-remunerated leadership role as President (2010-2012) and Vice-President (2012-2014) of DEGUM (German Ultrasound Society); non-remunerated role as member and chairman of the ‘Radiation Protection in Medicine’ (2017-2020) working group for the Radiation Protection Commission (SSK) at the German Federal Ministry of Environmental Protection. KH has reported no potential conflicts of interest. LM reports a non-remunerated role as co-chair of the Steering Committee for the CUPISCO trial from Roche. HM reports personal fees as an invited speaker from Amgen and Roche; personal fees for advisory board membership from AstraZeneca, Janssen and Merck; institutional funding from Roche. KO reports institutional funding from BioClavis, BioTheranostics and Leica; non-remunerated advisory role as member of Steering Group for Early Detection and Diagnosis of Cancer Roadmap for Cancer Research UK and as member of Innovation Expert Advisory Group (EAG) for NHS England Cancer Innovation Programme; co-author of the RCPath dataset on CUP and malignancy of unknown origin for the Royal College of Pathologists; Cancer Research UK affiliate at the Beatson Institute; member of the National Cancer Research Institute (UK). AP reports personal fees for a congress subscription from Amgen; personal fees for advisory board membership in urothelial cancer from Basilea; personal fees for congress expenses from Janssen. HW reports personal fees as an invited speaker and for advisory board membership from Array BioPharma, Bayer, BMS, Celgene, Erytech, Incyte, Merck KGaA, Pierre Fabre, Servier Sirtex Medical and Roche/Genentech; personal fees for consultancy from OnoSil; personal fees for an advisory role and as a Trial Steering Committee member from Zymeworks; personal fees and institutional funding for an advisory role, as a coordinating principal investigator and member of Trial Steering Committee from Sirtex Medical; non-remunerated advisory roles with Bayer, Pfizer and Pierre Fabre. GZ reports personal fees as an invited speaker from Amgen, Ipsen, Leo Pharma and Merck. GP is the Chief Medical Officer for ESMO and member of ASCO and the Hellenic Cooperative Oncology Group and the Hellenic Society of Medical Oncology (HeCOG). KF reports personal fees for advisory board membership from Curevac and Orion; fees paid to his institution as an invited speaker from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, Pfizer and Sanofi; fees paid to his institution for advisory board membership from AAA, Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis/AAA and Pfizer; institutional funding as trial chair from AstraZeneca, Bayer, BMS, Janssen, MSD, Orion and Pfizer; non-remunerated role as principal investigator and trial chair for Bayer, BMS, Merck, Novartis/AAA and Orion. TO has declared no conflicts of interest.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia., Competing Interests: Disclosure RK declares institutional payments from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck and support for meeting attendance or travel from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck. EC declares an institutional grant from Janssen, consulting fees from Astellas, AstraZeneca, Bayer, MSD and Pfizer, fees and honoraria for lectures, presentations from Astellas, AstraZeneca, Bayer, Janssen, MSD and Pfizer and support for attending meetings or travel from AstraZeneca and Janssen. AW declares personal fees from MS, MSD, Pfizer, Eisai and IPSEN and participation on a data safety monitoring or advisory board for BMS, MSD, Pfizer, Eisai and IPSEN. KF declares institutional honoraria for participation in advisory boards and talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis/AAA, Pfizer and Sanofi, and personal honoraria for participation to advisory boards for CureVac and Orion. MLKC declares payments or honoraria from ImmunoScape, IQVIA, Telix, Atsellas, AstraZeneca, Bayer, Illumina, Janssen, MSD, Pfizer and Varian, participation on a data safety monitoring or advisory board for AstraZeneca, Astellas, Bayer Pharma, Illumina, Janssen Pharma, MSD Oncology and Varian, a grant from Ferring, stock option in Digital Life Line, a role with the F1000—Head and Neck Cancer Section, Singapore Society of Oncology and Head Neck Caner International Group and other financial interests in Medlever and Varian. HM declares personal fees from CIPLA, Novartis, AstraZeneca, Roche, Eli Lilly, Merck, Pfizer, MSD, CADILA, Bard India and Somex Research. YM declares payments or honoraria from BMS, MSD and Takeda, participation on an advisory board for Chugai Pharmaceutical and Takeda and local PI, institutional, financial interest from MSD. JLL declares institutional grants or contracts from Pfizer, Novartis BMS, Janssen, MSD, Roche/Genetech, AstraZeneca/MedImmune, Seagen Astellas, Bayer, Schering Pharma, Lilly and Merck and participation on a data safety monitoring or advisory board from Pfizer Korea, Astella Korea, BMS, Merck, MSD, AstraZeneca, stocks or stock options from Myovant Sciences, Amgen, Johnson and Johnson and Merck. YSP declares honoraria and consulting fees from MSD, Roche, Merck, Ipsen, BMS/ONO, Novartis, Pfizer, Astellas, Janssen and GSK and support for attending meetings and/or travel from Ipsen, BMS/ONO, Novartis, Pfizer, Astellas and Janssen. MS declares research grants from Johnson and Johnson, payments or honoraria from Johnson and Johnson, AstraZeneca, Amgen and CIPLA, support for meeting attendance from Astellas, fees for participation in data monitoring or advisory boards from Johnson and Johnson, Amgen and AstraZeneca and receipt of equipment/materials for a compassionate programme for drugs/drug samples from Johnson and Johnson, AstraZeneca and Astellas. HJL declares participation on a data safety monitoring or advisory board for Astellas Korea. HK declares payments or honoraria from Astellas, AstraZeneca, Janssen, Sanofi and Takeda and payment for expert testimony and participation in an advisory board for Janssen. KP declares institutional research funding from Dr Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd and Roche Holding AG and a role with ICON and the FHNO. GC declares institutional grants from Merck, consulting fees from BMS, Roche, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis Ellipsis and Seagen, payment or honoraria from Pfizer and Lilly and support for attending meetings from Roche and Pfizer. EP declares grants and contracts form the National Cancer Centre research fund and Singapore Health Duke-NUS Oncology Academic Clinical Programme Sarcoma Research Fund award and Vice Presidency of the SSO. SPC declares consulting fees from BMS, AstraZeneca, Roche and Eisai and payment or honoraria from BMS, AstraZeneca, Roche, MSD, Eisai and Servier. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics and Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, Pfizer, Phosplatin Therapeutics and Roche/Genentech. TY declares institutional grants or contracts from Taiho Pharmaceuticals, Sumitomo Dainippon, Ono Pharmaceuticals, Chugai Pharmaceuticals, Amgen K.K., Parexel International, MSD K.K., Daiichi Sankyo and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care., Methods: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m 2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436., Findings: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone., Interpretation: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients., Funding: Janssen-Cilag, Ipsen, Sanofi, and the French Government., Competing Interests: Declaration of interests KF reports consulting fees from Amgen, AstraZeneca, Astellas, Bayer, CureVac, Janssen, Novartis, Orion, Pfizer, and Sanofi; honoraria from AstraZeneca, Astellas, Bayer, Janssen, Novartis, and Sanofi; and participation on a Data Safety Monitoring Board for Lilly. JC reports grants from AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Astellas Pharma, AstraZeneca, Aveo Pharmaceuticals, Bayer, Blueprint Medicines Corporation, BN Immunotherapeutics, Boehringer Ingelheim, Esperia, Bristol Myers Squibb, Clovis Oncology, Cougar Biotechnology, Deciphera Pharmaceuticals, Exelixis, F Hoffmann-La Roche, Genentech, GlaxoSmithKline, Incyte Corporation, Janssen-Cilag, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, Medimmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Sanofi-Aventis, SFJ Pharma, and Teva Pharma; consulting fees from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Novartis, Pfizer, Roche, and Sanofi; honoraria from Bayer, Johnson & Johnson, and Astellas Pharma; payment for expert testimony from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Novartis, Pfizer, Roche, and Sanofi; and participation on a Data Safety Monitoring Board or Advisory Board for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Novartis, Pfizer, Roche, and Sanofi. GR reports honoraria from Astellas Pharma, AstraZeneca, Janssen, Ipsen, and Sanofi; and support for attending meetings from Janssen and Ipsen. RM reports grants from Bayer; honoraria from MSD; and participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb, Clovis, Janssen, MSD, and Pfizer. AF reports honoraria from Astellas Pharma, AstraZeneca, Janssen, Novartis, and Sanofi. BT reports grants from Ferring and Bayer; personal fees from Amgen, Astellas Pharma, Ferring, Bayer, Novartis, Myovant, and Sanofi; and non-financial support from Astellas and Janssen. SS reports grants from Astellas Pharma, AstraZeneca, and Janssen; and consulting fees, honoraria, and receipt of equipment from Astellas Pharma, AstraZeneca, Bayer, Ipesen, Janssen, and Takeda. DB reports honoraria from Amgen, Astellas Pharma, Bayer, Janssen, and Novartis. GK reports grants from Astellas Pharma and Janssen; and participation on an Advisory Board and honoraria from Astellas Pharma, AstraZeneca, Janssen, and Sanofi. FC reports honoraria from Bristol Myers Squibb and MSD; and participation on an Advisory Board for AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, and Ipsen. AT-V reports grants from Bayer, Ipsen, and Pfizer; and consulting fees or honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, JNJ, Novartis, MSD, and Roche. BL reports honararia from Janssen; and support for attending meetings from Astellas Pharma, Janssen, and Pfizer. AR reports honoraria from Astellas Pharma, Bayer, and Janssen; and support for attending meetings from Astellas Pharma, Ipsen, and Janssen. NM reports honoraria from Astellas Pharma, Bayer, Ipsen, and MSD. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker., Patients and Methods: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m 2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS., Results: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608)., Conclusions: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR., Competing Interests: Disclosure RdW provided an advisory role for Sanofi, Janssen, Merck, Bayer, and Astellas, and received institutional grants from Sanofi and Bayer. DC has received personal fees from Pfizer, Roche, Sanofi, Janssen, Astellas, Bayer, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Merck Serono, Pierre Fabre, AstraZeneca, and Lilly. GK received personal fees from Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, and AstraZeneca, and has received grants from Sanofi and Bayer. J-CE has received honoraria from and provided an advisory role for Astellas, BMS, Ipsen, Janssen, Pfizer, and Sanofi Aventis, and has received travel and accommodation fees from Pfizer and BMS. CNS has received honoraria from Janssen, AstraZeneca, Sanofi and Astellas, received consultancy fees from Sanofi, Bayer, and Pfizer, and received institutional funding from Genentech/Roche, Bayer, Sanofi Genzyme, Janssen, Medivation, MSD, and Exelixis. KF has received honoraria and provided an advisory role for Astellas, AAA Pharmaceutical Inc, Bayer, Essa, Janssen, Orion, CureVac, Clovis, Sanofi, and Endocyte. BT has received personal fees and research grants from Astellas, Janssen, Sanofi Genzyme, Amgen, and Ferring, and received non-financial support from Sanofi Genzyme. AB has received honoraria and research support from and provided an advisory role to Astellas, Janssen, and Sanofi. JC has provided an advisory role for Astellas, AstraZeneca, Bayer, BMS, MSD Oncology, Johnson & Johnson, Sanofi, Roche, and Pfizer, and has attended speaker bureaus for Asofarma, Astellas, Bayer, and Johnson & Johnson. RI received honoraria and provided an advisory role for Sanofi, Janssen, Pfizer, Ipsen, Novartis, BMS, and MSD. BM received travel fees, honoraria, and provided an advisory role for BMS and Merck Serono, and received honoraria and provided an advisory role for MSD, Sanofi, Roche, Janssen, Bayer, Astellas, Amgen, Novartis, Servier, AstraZeneca, Eisai, E. Lilly, Ipsen, Pierre Fabre, and Pfizer. CH has received consultancy fees from Sanofi, Janssen, and Astellas. MCF and CG-R are employees of Sanofi. AO is an employee and stockholder of Sanofi. JdB has received honoraria from AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, and BioXcel Therapeutics, and provided an advisory role for AstraZeneca, Sanofi, Genentech/Roche, Astellas Pharma, Bayer, Pfizer, MSD, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biosystems, Celgene, Taiho Pharmaceutical, Daiichi Sankyo, Janssen Oncology, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Eisai, and BioXcel Therapeutics. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients' outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the "true" CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Men with metastatic castration-resistant prostate cancer (mCRPC) are living longer, therefore optimizing health-related quality of life (HRQL), as well as survival outcomes, is important for optimal patient care. The aim of this study was to assess the HRQL in patients with mCRPC receiving docetaxel or cabazitaxel., Patients and Methods: PROSELICA (NCT01308580) assessed the non-inferiority of cabazitaxel 20 mg/m 2 (C20) versus 25 mg/m 2 (C25) in patients with mCRPC after docetaxel. FIRSTANA (NCT01308567) assessed the superiority of C25 or C20 versus docetaxel 75 mg/m 2 (D75) in patients with chemotherapy-naive mCRPC. HRQL and pain were analyzed using protocol-defined, prospectively collected, Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack questionnaires. Analyses included definitive improvements in HRQL, maintained or improved HRQL, and HRQL over time., Results: In total, 2131 patients were evaluable for HRQL across the two studies. In PROSELICA, 38.8% and 40.5% of patients receiving C20 and C25, respectively, had definitive FACT-P total score (TS) improvements. In FIRSTANA, 43.4%, 49.7%, and 44.9% of patients receiving D75, C20, and C25, respectively, had definitive FACT-P TS improvements. In both trials, definitive improvements started after cycle 1 and were maintained for the majority of subsequent treatment cycles. More than two-thirds of patients maintained or improved their FACT-P TS., Conclusions: In PROSELICA and FIRSTANA, >40% of the 2131 evaluable patients with mCRPC had definitive FACT-P TS improvements; improvements occurred early and were maintained. More than 75% of patients maintained or improved their FACT-P TS., Competing Interests: Disclosure AT: AstraZeneca (employment), Novartis, Sanofi, Astellas Pharma, Pfizer, Janssen, Ipsen (consulting or advisory role), Pfizer (research funding), and Novartis, Sanofi, Pfizer (travel, accommodations, expenses). KF: Janssen, Sanofi, Astellas Pharma (honoraria), Janssen Oncology, Bayer, Astellas Pharma, Sanofi, Orion Pharma GmbH, Curevac, AstraZeneca (consulting or advisory role), and Amgen, Janssen (travel, accommodations, expenses). OS: Bayer, Bellicum Pharmaceuticals, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca (Inst), Progenics (Inst), Dendreon (consulting or advisory role), Bayer (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Endocyte (Inst), Innocrin Pharma (Inst), Progenics (Inst) (research funding), Bayer, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca, Progenics (travel, accommodations, expenses). SO: Sanofi, Janssen, Bayer, and Astellas (advisory board or board of directors). DB, KT, AO, and EMP: Sanofi employees. ME: VERU Inc. (board of directors). JB: Sanofi (honoraria), Sanofi, AstraZeneca, GlaxoSmithKline, Genentech, Roche, Merck (consulting or advisory role), AstraZeneca/MedImmune (speakers’ bureau), AstraZeneca/MedImmune (Inst), GlaxoSmithKline (Inst), Sanofi (Inst), Merck Sharp & Dohme (Inst), Genmab (Inst), Genentech (Inst) (research funding) and patent on abiraterone acetate with prednisone., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects., Patients and Methods: Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected., Results: Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms., Conclusion: Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This prospective study collected quality of life (QoL) and pain data during cabazitaxel treatment in patients with advanced metastatic or castration-resistant prostate cancer (mCRPC)., Patients and Methods: Functional Assessment of Cancer Therapy-Prostate (QoL) and Brief Pain Inventory-Short Form (pain) questionnaires were collected over 6 months., Results: In 61 patients with mCRPC (median age, 72 years) from 22 centers, metastatic sites were bones (97%), lymph nodes (36%), and visceral (20%); 25% received cabazitaxel in the second line, 29% in the third line, and 46% in the fourth line or beyond. All had been previously treated with docetaxel, except one with paclitaxel, and 75% also with abiraterone, enzalutamide, or both. The median cabazitaxel duration was 3.4 months. Forty-nine patients were evaluable for QoL and 44 for pain. QoL was improved in 37%, maintained in 35%, and deteriorated in 37%. In 27%, pain decreased ≥ 1 level and remained stable in 52%. A total of 34% lowered analgesic drug level. Prostate-specific antigen response ≥ 50% was observed in 11 (32.6%) patients, of whom 7 improved QoL and 1 was stable. At 6 months, 83.6% survived (95% confidence interval, 71.7%-90.8%). A total of 46% had ≥ 1 grade ≥ 3 adverse events, mainly anemia and neutropenia., Conclusion: Although cabazitaxel was given as the third line and beyond for three-quarters of patients, over one-third had improved QoL and/or decreased pain during treatment., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure CP has reported honoraria from Bayer, Janssen and Advanced Accelerator Applications (AAA) and research grants from Bayer; EC has reported honoraria from Astellas, AstraZeneca, Bayer, Janssen and Pfizer and research grants from AstraZeneca, Bayer and Janssen; KF has reported participation to advisory boards/honoraria for Astellas, AAA, Bayer, Clovis, Curevac, Incyte, Janssen, Merck Sharp & Dohme, Orion, Sanofi; AH has reported paid consultancy for Amgen, Astellas, Ferring, Ipsen, Jansen, Pfizer, Sanofi, Takeda and has received research grants from Astellas and Sanofi; PO has reported institutional honoraria from Janssen, Bayer, Ferring Pharmaceuticals for consultancy and research grants from Merck and Varian; GP has reported advisory boards/honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme, Novartis and Pfizer; BT has reported paid consultancy for Amgen, Bayer, Astellas, Ferring Pharmaceuticals, Janssen, Sanofi-Genzyme, Steba and that he is an investigator for Bayer, Astellas, Ferring Pharmaceuticals, Myovant Sciences, Janssen, Sanofi-Genzyme and Steba; SG has reported advisory role (including independent data monitoring committees) and speakers bureau for AAA International, Active Biotech AB, Amgen, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch, Clovis, CureVac, Dendreon, ESSA Pharma, Ferring, Innocrin Pharmaceuticals, Janssen Cilag, MaxiVAX, Millenium, Nectar, Novartis, Orion, Pfizer, ProteoMediX, Roche, Sanofi, and has reported being the co-inventor for a method for biomarker discovery (on patent application WO 2009138392 A1, granted in China, Europe, Japan and the USA).

Background: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen., Patients and Methods: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors., Results: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively., Conclusions: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP., Competing Interests: Disclosure SH reports other from Bayer, Eisai and Ferring; outside the submitted work. DPP consultant fees: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics (added January 2020), Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen. Grant support: Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; Ownership interest/investment: Bellicum, Tyme (sold October 2019). KC reports grants and personal fees from Janssen, Astellas, Sanofi, Bayer, Roche and AstraZeneca, outside the submitted work. JDB has served on advisory boards and received fees from many companies including AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Cellcentric, Daiichi, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals. He is an employee of the Institute of Cancer Research, which have received funding or other support for his research work from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, poly (ADP-ribose) polymerase inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. He has been the CI/PI of many industry sponsored clinical trials. JDB is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. CL reports honoraria and consultant fees from Sanofi, Bayer, Janssen, Astellas Pharma. In addition, he reports research grants from Sanofi, Bayer, Janssen, Astellas Pharma and Pfizer. DIQ reports compensated consultant: Astellas, Bayer, BMS, Advanced Accelerator Applications, Roche/Genentech, Janssen, Merck, Novartis, Pfizer. Travel: Astellas, Bayer, Bristol Myers Squibb, Genentech, Merck, Pfizer. Research to institution: Bayer, Bristol Myers Squibb, Roche/Genentech, Merck, Pfizer. KF: participation to advisory boards/honorarium for: Astellas, Bayer, Curevac, Janssen, MSD, Orion, Sanofi. MJM reports consultant fees from Bayer, Endocyte, Advanced Accelerator Applications, Blue Earth Diagnostics, Tokai Pharmaceuticals, Tolmar Pharmaceuticals, ORIC Pharmaceutical. Travel: Bayer, Endocyte. In addition he reports research funding to the institution from Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech. CSH reports other from Aptevo, Aragon Pharma, Astellas, AstraZeneca, Bayer, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hoffman-La Roche, Medivation and Pfizer. She reports personal fees from Aptevo, Asana, Astellas, Bayer, Blue Earth Diagnostics, Pharma, fees from Clovis, Dendreon, Endocyte, Ferring, Hinova, Janssen, Merck, Myriad, Orion, Pfizer, Tolmar, Carrick Therapeutics, Novartis, outside the submitted work. IFT reports other from Sanofi, during the conduct of the study; other from Janssen, Bayer, Roche-Genentech, outside the submitted work. EJS reports consultant fees and honoraria from Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals. Travel from Janssen. In addition, he reports research grants to institution from Janssen, Merck. The remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Metastatic testicular germ cell tumors are rare entities with a high cure rate owing to their major chemosensitivity. Current guidelines should be strictly followed to ensure maximal cure rate. Germ cell tumor treatment requires multidisciplinary skills and is based on cisplatin-based chemotherapy. The current challenge for these patients with favorable prognosis is to limit over- or under-treatment. Centralization of care for patients with these rare cancers is a key point to achieve the best chance of cure., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination., Patients and Methods: We conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study., Results: A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination., Conclusion: The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide., Patients and Methods: Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2 : 1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set., Results: Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups., Conclusions: Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design., Trial Registration: ClinicalTrials.gov: NCT01212991.

Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths among men. Androgen receptor (AR) signaling plays a key role in PC tumor growth and progression, with androgens stimulating PC proliferation and survival. Castration-resistant PC (CRPC) is characterized by increasing levels of prostate-specific antigen or radiographic progression despite androgen-deprivation therapy (ADT). In most patients, castration resistance results from aberrations in AR or the AR signaling pathway. Up to one-third of patients with localized high-risk PC will have disease progression on local therapy and develop CRPC. This review summarizes the key clinical data, including ongoing trials, for hormonal therapies in CRPC and provides an overview of the clinical development of darolutamide, a novel, nonsteroidal AR antagonist currently in phase III development for the treatment of nonmetastatic CRPC and metastatic hormone-sensitive PC. In phase I/II trials, darolutamide has demonstrated a favorable safety profile, antitumor activity, and significant decreases in prostate-specific antigen in patients with metastatic CRPC. In the phase III ARAMIS (NCT02200614; A Multinational, Randomized, Double-Blind, Placebo-Controlled, Phase III Efficacy and Safety Study of Darolutamide [ODM-201] in Men With High-Risk Non-metastatic Castration-Resistant Prostate Cancer) study, metastasis-free survival is being evaluated in men with nonmetastatic CRPC who will receive ADT in combination with darolutamide or placebo. The ARASENS (NCT02799602; A Randomized, Double-Blind, Placebo Controlled Phase III Study of Darolutamide [ODM-201] Versus Placebo in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer) study is a placebo-controlled trial assessing whether the addition of darolutamide to ADT and docetaxel significantly prolongs overall survival in men with metastatic hormone-sensitive PC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies., Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed., Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability)., Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Background: Abiraterone acetate (AA), an androgen biosynthesis inhibitor, is now a standard of care for men with metastatic, castration-sensitive and castration-resistant prostate cancer (mCRPC). Data exploring real-world toxicity and outcomes are scarce., Methods: Retrospective study on unselected patients with mCRPC on AA plus steroids., Results: 93 patients were included in the study. Median duration of treatment by AA was 7.5 months (95% CI 5.7-12) among the 58 patients pretreated with chemotherapy, versus 12.7 months ( 95% CI 8.2-35.9) among the 33 chemo-naive patients. Median survivals would reach 13.4 months (95% CI 10.2-19.1) and 36.4 months (95% CI 24.7-41.5) respectively. Rates of hypokalemia, peripheral edema, hypertension, cardiac failure, and overall survival assessments in patients with and without prior chemotherapy were similar to that previously reported in phase 3 randomized trials. The median survival time without adverse event of special interest was 7.5 months for hypokalemia and hypertension, and 5.3 months for liver-function test abnormalities (it was not reached for cardiac disorders)., Conclusion: Our findings provide further evidence for the survival benefits of AA with a low frequency of additional adverse events among unselected patients. In patients who have not developed hypokalemia or a transaminase increase within 7.5 and 5.3 months respectively, a lighter systematic monitoring may be considered., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Everolimus (E) and axitinib (A) have been standard treatments for patients with metastatic renal cell carcinoma after failure of first-line therapy (1L) with vascular endothelial growth factor-targeted therapy. This study aims to compare both drugs in a large comprehensive cancer center., Methods: Patient characteristics and outcome data from all patients with metastatic renal cell carcinoma who received E or A as second-line therapy at Gustave Roussy from April 2007 to May 2015 have been recorded., Results: A total of 81 patients were treated with E and 45 patients with A. There were no major differences between the 2 groups. The most common 1L was sunitinib (79% in the E group and 82.2% in the A group). The median follow-up was 29 months; 26 months for A and 33 months for E (P = .046). The median overall survival (OS) was 21.5 months for E and 14.9 months for A (P = .23). The median progression-free survival (PFS) was 5.3 and 7.7 months for E and A, respectively (P = .39). Partial response was achieved in 4% and in 24% of patients (P = .002) in the E and A cohort, respectively. In the A group, the median PFS and OS were statistically different according to response, tumor burden, and 1L duration. No differences were found in the E arm., Conclusion: In this series, there are no significant differences for PFS and OS with E and A. A appears to provide more objective response. A appears to be more effective in patients with small tumor burden, responders to 1L, and 1L therapy > 12 months., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy., Patients and Methods: Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded., Results: A total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%)., Conclusions: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%., Clinicaltrials: gov identifier NCT01732549., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Background: The objective of this study was to present a statistical method to define an optimal duration of follow-up for patients in remission after treatment for cancer, for detection of recurrences., Patients and Methods: Surveillance duration was estimated using the 2-step approach proposed by Mould et al. Relapse-free interval was modeled using the parametric cure model proposed by Boag. The optimal length of follow-up was then estimated as the minimal elapsed time after which the probability of a patient to relapse and to be cured with success is below a given threshold value. The method is applied to 2 real data sets of patients treated for metastatic non seminomatous germ-cell tumors: T93BP and T93MP., Results: For the T93BP, cure rate was estimated at 91.3% and proportions of patients who relapsed after 3 and 5 years were estimated at 0.5% and 0.2%. With a probability of success of salvage treatment equal to 80% and 50%, numbers of delayed cases after 5 years were 2 and 1. For T93MP, the proportion of patients who presented relapse after 5 and 10 years were estimated at 5.2% and 2.6%. Considering a probability of salvage treatment equal to 20%, the number of delayed cases after 5 and 10 years were 10 and 5., Conclusion: Using this methodology, duration of post-therapeutic follow-up might be tailored according to an objective criteria: the number of patients who present relapse after the end of follow-up and who could have been treated with success in case of early detection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536)., Patients and Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II)., Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors., Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively., Patients and Methods: Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model., Results: Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups., Conclusion: OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis., Clinical Trials Number: COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198)., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC., Patients and Methods: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort., Results: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286)., Conclusion: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design., Trial Registration Numbers: NCT00638690., (© Janssen R&D 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Following the results of the TAX-327 study, questions have been raised as to whether administering chemotherapy to men with prostate cancer before symptomatic disease progression when receiving standard hormonal treatment can improve the duration and quality of patient survival. The GETUG-AFU-15 and CHAARTED studies both assessed the efficacy and tolerability of androgen deprivation therapy (ADT) with or without docetaxel in men with metastatic hormone-naive prostate cancer. Both studies included a mix of patients with de novo metastatic disease (∼75%) and patients who developed metastases following treatment of localized disease. A short course of ADT was allowed in both trials prior to accrual. Key differences between the two studies include the number of patients with high-volume metastases (GETUG-AFU-15: 52%; CHAARTED: 65%) and number of docetaxel cycles (GETUG-AFU-15: up to nine cycles; CHAARTED six cycles). Both studies reported an improvement in progression-free survival with docetaxel plus ADT versus ADT alone. The GETUG-AFU-15 did not find a significant difference in the primary end point of overall survival (OS) {hazard ratio (HR) 0.9 [95% confidence interval (CI) 0.7-1.2]; P = 0.44} for ADT plus docetaxel versus ADT alone. The CHAARTED study met the primary end point of OS [HR 0.61 (95% CI 0.47-0.80); P = 0.0003], and in a subset analysis reported the greatest improvement in OS for patients with high-volume disease [HR 0.60 (95% CI 0.45-0.81); P = 0.0006]. The following article debates the results from the GETUG-AFU-15 and CHAARTED studies and asks whether medical practice should be changed for patients with metastatic hormone-naive prostate cancer based on the results of one positive study., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer-specific morbidity and mortality, time to castration resistance, and overall survival (OS)., Methods: We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-à-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups., Results: The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis., Conclusion: The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients' immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm., Design: References for this review were identified through searches of PubMed with the search terms "prostate cancer," "immune system," "vaccine," "immunotherapy," and "T cells." Articles were also identified through searches of the authors' own files. The final reference list was generated based on originality and relevance., Results: The immune system can recognize and respond to prostate tumor antigens, effected through tumor-associated antigens and tumor infiltration of immune effector cells. However, evidence also suggests that prostate tumors are adept at escaping immunological recognition, thus hypothesizing multiple therapeutic strategies. Therapeutic approaches could include vaccination and modulation of T-cell function via the blockade of checkpoint receptors such as cytotoxic T-lymphocyte antigen-4 and programmed death 1. In phase III trials, sipuleucel-T improved overall survival for an M1 patient population with castration-resistant prostate cancer and ipilimumab also did so when given after radiotherapy in a subset of better risk patients. In randomized phase II trials, prostate-specific antigen-TRICOM improved overall survival and tasquinimod improved progression-free survival., Conclusion: Although immunotherapy has the potential to affect advanced prostate cancer, additional research is needed to (1) identify predictive or surrogate markers of activity, (2) understand which agents are clinically effective alone or in combination with other therapies, and (3) define the optimal timing for an immunotherapy to achieve maximal benefit., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To improve the early detection of responders to salvage external beam radiotherapy (RT) after radical prostatectomy (RP)., Methods: Between 2002 and 2007, in a single institution, 136 consecutive patients received salvage RT to a dose of 66 Gy without androgen-deprivation therapy after RP for a rising prostate-specific antigen (PSA) level. PSA measurements were systematically performed before RT (PSART), at the fifth week of RT (PSA5), and in the follow-up at least twice a year (every 6 mo). The PSA level decline during RT was expressed as PSA ratio (PSA5/PSART). Two different definitions of biochemical failure after salvage RT were considered: PSA level>0.4 ng/ml and PSA>PSA nadir post-RT +0.4 ng/ml. Statistical analyses included univariate and multivariate Cox regression models., Results: The median follow-up was 60 months. The 5-year freedom from biochemical and clinical failure rates were 57% (95% CI: 48%-66%) and 92% (95% CI: 87%-97%), respectively. The mean PSA5 was 0.61 ng/ml (range: 0-7) and the mean PSA ratio was 0.67 (0-1.7). A PSA ratio<1 was a significant prognostic factor in multivariate analysis for both definitions of biochemical failure (P = 0.01 for both) and for clinical failure (P = 0.005)., Conclusions: For patients undergoing salvage RT after RP for a rising PSA level, the absence of PSA level decline during RT is predictive of biochemical and clinical failure and may be used to rapidly identify poor responders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point., Patients and Methods: Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form., Results: Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE., Conclusion: In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: To present longitudinal changes in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores during 25-week treatment with enzalutamide or placebo in men with progressive metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy in the AFFIRM trial., Patients and Methods: Patients were randomly assigned to enzalutamide 160 mg/day or placebo. FACT-P was completed before randomization, at weeks 13, 17, 21, and 25, and every 12 weeks thereafter while on study treatment. Longitudinal changes in FACT-P scores from baseline to 25 weeks were analyzed using a mixed effects model for repeated measures (MMRM), with a pattern mixture model (PMM) applied as secondary analysis to address non-ignorable missing data. Cumulative distribution function (CDF) plots were generated and different methodological approaches and models for handling missing data were applied. Due to the exploratory nature of the analyses, adjustments for multiple comparisons were not made. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311., Results: The intention-to-treat FACT-P population included 938 patients (enzalutamide, n = 674; placebo n = 264) with evaluable FACT-P assessments at baseline and ≥1 post-baseline assessment. After 25 weeks, the mean FACT-P total score decreased by 1.52 points with enzalutamide compared with 13.73 points with placebo (P < 0.001). In addition, significant treatment differences at week 25 favoring enzalutamide were evident for all FACT-P subscales and indices, whether analyzed by MMRM or PMM. CDF plots revealed differences favoring enzalutamide compared with placebo across the full range of possible response levels for FACT-P total and all disease- and symptom-specific subscales/indices., Conclusion: In men with progressive mCRPC after docetaxel-based chemotherapy, enzalutamide is superior to placebo in health-related quality-of-life outcomes, regardless of analysis model or threshold selected for meaningful response., Clinical Trial Number: NCT00974311., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: High-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT., Patients and Methods: This phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen. The main objective was to determine the complete response rate., Results: Forty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4-51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2-not reached] and 32 months (95% CI 4-49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32-67) and the 2-year OS was 66% (95% CI 44-81)., Conclusion: The TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens., Trial Registration Number: NCT00231582., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)