Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.05.011
Philip Sutera , Yang Song , Amol C. Shetty , Keara English , Kim Van der Eecken , Ozan Cem Guler , Jarey Wang , Yufeng Cao , Soha Bazyar , Sofie Verbeke , Jo Van Dorpe , Valérie Fonteyne , Bram De Laere , Mark Mishra , Zaker Rana , Jason Molitoris , Matthew Ferris , Ana Kiess , Daniel Y. Song , Theodore DeWeese , Matthew P. Deek
<div><h3>Background and objective</h3><div>Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC.</div></div><div><h3>Methods</h3><div>We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1–3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included <em>TP53</em>, <em>ATM, RB1, BRCA1/2, SPOP</em>, and WNT (<em>APC, CTNNB1, RNF43)</em>. Genomic associations with MOP/POF were compared using χ<sup>2</sup> tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure.</div></div><div><h3>Key findings and clinical implications</h3><div>We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; <em>p</em> = 0.005). <em>TP53</em> mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; <em>p</em> = 0.04) and <em>RB1</em> mutation was associated with a high rate of polyprogression (50% vs 19.9%; <em>p</em> = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring <em>TP53</em> mutations (44.8% vs25.9%; <em>p</em> = 0.005) and less common with <em>SPOP</em> mutations (7.1% vs 31.4%; <em>p</em> = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, <em>p</em> = 0.05) or <em>SPOP</em> mutations (17.9% vs 6.3%; <em>p</em> = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles.</div></div><div><h3>Conclusions and clinical implications</h3><div>Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with <em>TP53</em> and <em>RB1</em> mutations have a higher likelihood
背景和目的：低转移性阉割敏感性前列腺癌（omCSPC）是转移性疾病进展的早期状态，与疾病负担较重的患者相比，患者的预后较好。尽管前列腺癌一般较为隐匿，但仍存在很大的异质性，一些患者的临床病程更具侵袭性，而临床特征本身无法解释其原因。我们的目的是研究肿瘤基因组学与omCSPC首次治疗（转移导向和/或全身治疗）后的进展模式（MOP）和失败模式（POF）的相关性：我们开展了一项国际多机构回顾性研究，研究对象是接受过转移性omCSPC治疗的男性患者，他们在首次治疗后至少随访1年，并接受了肿瘤新一代测序。报告了相关通路基因组改变的描述性澳门巴黎人娱乐官网和 POF 结果。MOP定义为I级，长期控制（LTC；最后一次随访时无放射学进展）；II级，少进展（1-3个病灶）；或III级，多进展（≥4个病灶）。POF包括首次失败时病变的位置。受关注的基因组通路包括 TP53、ATM、RB1、BRCA1/2、SPOP 和 WNT（APC、CTNNB1、RNF43）。使用χ2检验比较了基因组与MOP/POF的相关性。探索性分析表明，COSMIC突变特征和差异基因表达也与MOP/POF相关。总生存期（OS）采用卡普兰-梅耶法计算，从首次失败时算起：我们在分析中纳入了267名患者；大多数患者在少转移灶有一个（47%）或两个（30%）转移病灶。3年的OS率与MOP显著相关（多发转移为71%，少发转移为91%；P = 0.005）。TP53突变与明显较低的长期生存率相关（27.6% vs 42.3%; p = 0.04），RB1突变与较高的多发性进展率相关（50% vs 19.9%; p = 0.022）。关于POF，骨衰竭在TP53突变的肿瘤中更常见（44.8% vs 25.9%；p = 0.005），而在SPOP突变的肿瘤中较少见（7.1% vs 31.4%；p = 0.007）。内脏衰竭在WNT通路突变（17.2% vs 6.8%，p = 0.05）或SPOP突变（17.9% vs 6.3%；p = 0.04）的肿瘤中更为常见。最后，内脏和骨骼衰竭与不同的基因表达谱有关：结论和临床意义：肿瘤基因组学提供了治疗远期omCSPC后MOP和POF的新见解。TP53和RB1基因突变的患者病情进展的可能性更高，TP53、SPOP和WNT通路突变可能在转移性有机体中发挥作用。患者摘要：我们评估了转移性前列腺癌首次治疗后的癌症进展情况，转移灶多达5个。我们发现，某些基因的突变与这些患者进一步转移的位置和程度有关。
{"title":"Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer","authors":"Philip Sutera , Yang Song , Amol C. Shetty , Keara English , Kim Van der Eecken , Ozan Cem Guler , Jarey Wang , Yufeng Cao , Soha Bazyar , Sofie Verbeke , Jo Van Dorpe , Valérie Fonteyne , Bram De Laere , Mark Mishra , Zaker Rana , Jason Molitoris , Matthew Ferris , Ana Kiess , Daniel Y. Song , Theodore DeWeese , Matthew P. Deek","doi":"10.1016/j.euo.2024.05.011","DOIUrl":"10.1016/j.euo.2024.05.011","url":null,"abstract":"<div><h3>Background and objective</h3><div>Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC.</div></div><div><h3>Methods</h3><div>We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1–3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included <em>TP53</em>, <em>ATM, RB1, BRCA1/2, SPOP</em>, and WNT (<em>APC, CTNNB1, RNF43)</em>. Genomic associations with MOP/POF were compared using χ<sup>2</sup> tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure.</div></div><div><h3>Key findings and clinical implications</h3><div>We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; <em>p</em> = 0.005). <em>TP53</em> mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; <em>p</em> = 0.04) and <em>RB1</em> mutation was associated with a high rate of polyprogression (50% vs 19.9%; <em>p</em> = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring <em>TP53</em> mutations (44.8% vs25.9%; <em>p</em> = 0.005) and less common with <em>SPOP</em> mutations (7.1% vs 31.4%; <em>p</em> = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, <em>p</em> = 0.05) or <em>SPOP</em> mutations (17.9% vs 6.3%; <em>p</em> = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles.</div></div><div><h3>Conclusions and clinical implications</h3><div>Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with <em>TP53</em> and <em>RB1</em> mutations have a higher likelihood","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 111-118"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.05.009
Neal D. Shore , Michael S. Broder , Pedro C. Barata , Tony Crispino , André P. Fay , Jennifer Lloyd , Begoña Mellado , Nobuaki Matsubara , Nicklas Pfanzelter , Katrin Schlack , Paul Sieber , Andrey Soares , Hannah Dalglish , Alexander Niyazov , Saif Shaman , Michael A. Zielinski , Jane Chang , Neeraj Agarwal
Background and objective
Recent clinical trials have shown improvement in progression-free survival in men with metastatic prostate cancer (mPC) treated with combination poly-ADP ribose polymerase (PARP) inhibitors (PARPi) and novel hormonal therapy (NHT). Regulatory bodies in the USA, Canada, Europe, and Japan have recently approved this combination therapy for mPC. Common adverse events (AEs) include fatigue, nausea and vomiting, and anemia. Nuanced AE management guidance for these combinations is lacking. The panel objective was to develop expert consensus on AE management in patients with mPC treated with the combination PARPi + NHT.
Methods
The RAND/University of California Los Angeles modified Delphi Panel method was used. AEs were defined using the Common Terminology Criteria for Adverse Events. Twelve experts (seven medical oncologists, one advanced practice registered nurse, three urologists, and one patient advocate) reviewed the relevant literature; independently rated initial AE management options for the agent suspected of causing the AE for 419 patient scenarios on a 1–9 scale; discussed areas of agreement (AoAs) and disagreement (AoDs) at a March 2023 meeting; and repeated these ratings following the meeting. Second-round ratings formed the basis of guidelines.
Key findings and limitations
AoDs decreased from 41% to 21% between the first and second round ratings, with agreement on at least one management strategy for every AE. AoAs included the following: (1) continue therapy with symptomatic treatment for patients with mild AEs; (2) for moderate fatigue, recommend nonpharmacologic treatment, hold treatment temporarily, and restart at a reduced dose when symptoms resolve; (3) for severe nausea or any degree of vomiting where symptomatic treatment fails, hold treatment temporarily and restart at a reduced dose when symptoms resolve; and (4) for hemoglobin 7.1–8.0 g/dl and symptoms of anemia, hold treatment temporarily and restart at a reduced dose after red blood cell transfusion.
Conclusions and clinical implications
This expert guidance can support management of AEs in patients with mPC receiving combination PARPi + NHT therapy.
Patient summary
A panel of experts developed guidelines for adverse event (AE) management in patients with metastatic prostate cancer treated with a combination of poly-ADP ribose polymerase inhibitors and novel hormonal therapy. For mild AEs, continuation of cancer therapy along with symptomatic treatment is recommended. For moderate or severe AEs, cancer therapy should be stopped temporarily and restarted at the same or a reduced dose when AE resolves.
{"title":"Expert Consensus Recommendations on the Management of Treatment-emergent Adverse Events Among Men with Prostate Cancer Taking Poly-ADP Ribose Polymerase Inhibitor + Novel Hormonal Therapy Combination Therapy","authors":"Neal D. Shore , Michael S. Broder , Pedro C. Barata , Tony Crispino , André P. Fay , Jennifer Lloyd , Begoña Mellado , Nobuaki Matsubara , Nicklas Pfanzelter , Katrin Schlack , Paul Sieber , Andrey Soares , Hannah Dalglish , Alexander Niyazov , Saif Shaman , Michael A. Zielinski , Jane Chang , Neeraj Agarwal","doi":"10.1016/j.euo.2024.05.009","DOIUrl":"10.1016/j.euo.2024.05.009","url":null,"abstract":"<div><h3>Background and objective</h3><div>Recent clinical trials have shown improvement in progression-free survival in men with metastatic prostate cancer (mPC) treated with combination poly-ADP ribose polymerase (PARP) inhibitors (PARPi) and novel hormonal therapy (NHT). Regulatory bodies in the USA, Canada, Europe, and Japan have recently approved this combination therapy for mPC. Common adverse events (AEs) include fatigue, nausea and vomiting, and anemia. Nuanced AE management guidance for these combinations is lacking. The panel objective was to develop expert consensus on AE management in patients with mPC treated with the combination PARPi + NHT.</div></div><div><h3>Methods</h3><div>The RAND/University of California Los Angeles modified Delphi Panel method was used. AEs were defined using the Common Terminology Criteria for Adverse Events. Twelve experts (seven medical oncologists, one advanced practice registered nurse, three urologists, and one patient advocate) reviewed the relevant literature; independently rated initial AE management options for the agent suspected of causing the AE for 419 patient scenarios on a 1–9 scale; discussed areas of agreement (AoAs) and disagreement (AoDs) at a March 2023 meeting; and repeated these ratings following the meeting. Second-round ratings formed the basis of guidelines.</div></div><div><h3>Key findings and limitations</h3><div>AoDs decreased from 41% to 21% between the first and second round ratings, with agreement on at least one management strategy for every AE. AoAs included the following: (1) continue therapy with symptomatic treatment for patients with mild AEs; (2) for moderate fatigue, recommend nonpharmacologic treatment, hold treatment temporarily, and restart at a reduced dose when symptoms resolve; (3) for severe nausea or any degree of vomiting where symptomatic treatment fails, hold treatment temporarily and restart at a reduced dose when symptoms resolve; and (4) for hemoglobin 7.1–8.0 g/dl and symptoms of anemia, hold treatment temporarily and restart at a reduced dose after red blood cell transfusion.</div></div><div><h3>Conclusions and clinical implications</h3><div>This expert guidance can support management of AEs in patients with mPC receiving combination PARPi + NHT therapy.</div></div><div><h3>Patient summary</h3><div>A panel of experts developed guidelines for adverse event (AE) management in patients with metastatic prostate cancer treated with a combination of poly-ADP ribose polymerase inhibitors and novel hormonal therapy. For mild AEs, continuation of cancer therapy along with symptomatic treatment is recommended. For moderate or severe AEs, cancer therapy should be stopped temporarily and restarted at the same or a reduced dose when AE resolves.</div></div>","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 94-104"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.08.006
Maria Ruiz-Vico , Daniel Wetterskog , Francesco Orlando , Suparna Thakali , Anna Wingate , Anuradha Jayaram , Paolo Cremaschi , Osvaldas Vainauskas , Nicole Brighi , Daniel Castellano-Gauna , Lennart Åström , Vsevolod B. Matveev , Sergio Bracarda , Adil Esen , Susan Feyerabend , Elżbieta Senkus , Marta López-Brea Piqueras , Santosh Gupta , Rick Wenstrup , Gunther Boysen , Gerhardt Attard
<div><h3>Background and objective</h3><div>The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [<em>AR</em>] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo.</div></div><div><h3>Methods</h3><div>Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (<em>N</em> = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated.</div></div><div><h3>Key findings and limitations</h3><div>There was a significant association of worse PFS with pre-docetaxel ctDNA detection (<em>N</em> = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, <em>p</em> = 0.004) or persistence/rise of ctDNA at C2D1 (<em>N</em> = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15–3.30, <em>p</em> = 0.019). LBRB-positive patients (<em>N</em> = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41–1.48, <em>p</em> = 0.44; RMST: 7.9 vs 7.1 mo, <em>p</em> = 0.50). Conversely, resistance biomarker–negative patients (<em>N</em> = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29–0.82, <em>p</em> = 0.006; RMST: 11.5 vs 8.9 mo, <em>p</em> = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (<em>CDK6</em>/<em>CDK4</em>) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required.</div></div><div><h3>Conclusions and clinical implications</h3><div>Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.</div></div><div><h3>Patient summary</h3><div>In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (<em>AR</em>) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in
背景和目的：PRESIDE（NCT02288247）随机试验证明，对于开始接受多西他赛治疗的转移性耐药前列腺癌（mCRPC）患者，在病情进展后继续服用恩杂鲁胺可延长无进展生存期（PFS）。本研究旨在检验多西他赛一个周期（第2周期第1天[C2D1]）之前和之后的PFS与循环肿瘤DNA（ctDNA）的关系，以及在继续服用恩杂鲁胺/安慰剂之前与液体活检抗性生物标记物（LBRB；血浆雄激素受体[AR]增量和/或表达AR剪接变体7[CTC-AR-V7]的循环肿瘤细胞[CTC]）的关系：纳入同意生物标志物子研究并在开始多西他赛与恩杂鲁胺/安慰剂治疗前献血的患者（N = 157）。使用前列腺癌定制的新一代测序捕获面板（PCF_SELECT）对连续血浆 DNA 样品进行定性，并对 CTC 进行 AR-V7 评估（Epic Sciences，San Diego，CA，USA）。计算了Cox模型、Kaplan-Meier和18个月时的限制性平均生存时间（RMST）：多西他赛前检测到ctDNA（86例（55%），8.1个月 vs 10.8个月，危险比[HR] = 1.78，P = 0.004）或C2D1时ctDNA持续/上升（35/134例，5.5个月 vs 10.9个月，HR = 1.95，95%置信区间[CI] = 1.15-3.30，P = 0.019）会导致PFS恶化。LBRB阳性患者（N = 62）继续服用恩杂鲁胺与多西他赛无益（HR = 0.78，95% CI = 0.41-1.48，p = 0.44；RMST：7.9 月 vs 7.1 月，p = 0.50）。相反，耐药性生物标志物阴性患者（N = 87）的 PFS 明显延长（HR = 0.49，95% CI = 0.29-0.82，p = 0.006；RMST：11.5 月 vs 8.9 月，p = 0.005）。有八名患者无法进行评估。一项探索性分析发现，多西他赛治疗进展期拷贝数增殖（CDK6/CDK4）增加。局限性包括CTC-AR-V7的检出率相对较低。结论和临床意义：患者总结：在PRESIDE生物标志物研究中，我们发现在开始使用多西他赛（化疗）治疗对雄激素剥夺疗法耐药的转移性前列腺癌后，检测血浆中的循环肿瘤DNA可以及早预测患者对治疗的反应时间。液体活检耐药性生物标志物（基于循环肿瘤细胞中雄激素受体（AR）基因和AR剪接变体7的状态）阴性的患者可从继续恩杂鲁胺联合多西他赛中获益，而耐药性生物标志物阳性的患者则不能获益。此外，我们还发现细胞周期基因CDK6和CDK4的改变是导致多西他赛耐药的潜在遗传学原因，这可能有助于测试针对这些改变的特定药物。
{"title":"Liquid Biopsy in Progressing Prostate Cancer Patients Starting Docetaxel with or Without Enzalutamide: A Biomarker Study of the PRESIDE Phase 3b Trial","authors":"Maria Ruiz-Vico , Daniel Wetterskog , Francesco Orlando , Suparna Thakali , Anna Wingate , Anuradha Jayaram , Paolo Cremaschi , Osvaldas Vainauskas , Nicole Brighi , Daniel Castellano-Gauna , Lennart Åström , Vsevolod B. Matveev , Sergio Bracarda , Adil Esen , Susan Feyerabend , Elżbieta Senkus , Marta López-Brea Piqueras , Santosh Gupta , Rick Wenstrup , Gunther Boysen , Gerhardt Attard","doi":"10.1016/j.euo.2024.08.006","DOIUrl":"10.1016/j.euo.2024.08.006","url":null,"abstract":"<div><h3>Background and objective</h3><div>The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [<em>AR</em>] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo.</div></div><div><h3>Methods</h3><div>Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (<em>N</em> = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated.</div></div><div><h3>Key findings and limitations</h3><div>There was a significant association of worse PFS with pre-docetaxel ctDNA detection (<em>N</em> = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, <em>p</em> = 0.004) or persistence/rise of ctDNA at C2D1 (<em>N</em> = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15–3.30, <em>p</em> = 0.019). LBRB-positive patients (<em>N</em> = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41–1.48, <em>p</em> = 0.44; RMST: 7.9 vs 7.1 mo, <em>p</em> = 0.50). Conversely, resistance biomarker–negative patients (<em>N</em> = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29–0.82, <em>p</em> = 0.006; RMST: 11.5 vs 8.9 mo, <em>p</em> = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (<em>CDK6</em>/<em>CDK4</em>) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required.</div></div><div><h3>Conclusions and clinical implications</h3><div>Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.</div></div><div><h3>Patient summary</h3><div>In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (<em>AR</em>) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in ","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 135-144"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.09.001
Alessio Pecoraro , Giuseppe Dario Testa , Laura Marandino , Laurence Albiges , Axel Bex , Umberto Capitanio , Ilaria Cappiello , Lorenzo Masieri , Carme Mir , Morgan Roupret , Sergio Serni , Andrea Ungar , Giulia Rivasi , Riccardo Campi
Context
Frailty, a geriatric syndrome characterized by decreased resilience and physiological reserve, impacts the prognosis and management of older adults significantly, particularly in the context of surgical and oncological care.
Objective
To provide an overview of frailty assessment in the management of older patients with a renal mass/renal cell carcinoma (RCC), focusing on its implications for diagnostic workup, treatment decisions, and clinical outcomes.
Evidence acquisition
A narrative review of the literature was conducted, focusing on frailty definitions, assessment tools, and their application in geriatric oncology, applied to the field of RCC. Relevant studies addressing the prognostic value of frailty, its impact on treatment outcomes, and potential interventions were summarized.
Evidence synthesis
Frailty is a poor prognostic factor and can influence decision-making in the management of both localized and metastatic RCC. Screening tools such as the Geriatric Screening Tool 8 (G8) and the Mini-COG test can aid clinicians to select older patients (ie, aged ≥65 yr) for a further comprehensive geriatric assessment (CGA) performed by dedicated geriatricians. The CGA provides insights to risk stratify patients and guide subsequent treatment pathways. As such, the involvement of geriatricians in multidisciplinary tumor boards emerges as an essential priority to address the complex needs of frail patients and optimize clinical outcomes. Herein, we propose a dedicated care pathway as a first key step to implement frailty assessment in clinical practice and research for RCC.
Conclusions
Frailty has emerged as a crucial factor influencing the management and outcomes of older patients with RCC. Involvement of geriatricians in diagnostic and therapeutic pathways represents a pragmatic approach to screen and assess frailty, fostering individualized treatment decisions according to holistic patient risk stratification.
Patient summary
Frailty, a decline in resilience and physiological reserve, influences treatment decisions and outcomes in elderly patients with renal cell carcinoma, guiding personalized care. In this review, we focused on pragmatic strategies to screen patients with a renal mass suspected for renal cell carcinoma, who are older than 65 yr, for frailty and on personalized management algorithms integrating geriatric input beyond patient- and tumor-related factors.
{"title":"Frailty and Renal Cell Carcinoma: Integration of Comprehensive Geriatric Assessment into Shared Decision-making","authors":"Alessio Pecoraro , Giuseppe Dario Testa , Laura Marandino , Laurence Albiges , Axel Bex , Umberto Capitanio , Ilaria Cappiello , Lorenzo Masieri , Carme Mir , Morgan Roupret , Sergio Serni , Andrea Ungar , Giulia Rivasi , Riccardo Campi","doi":"10.1016/j.euo.2024.09.001","DOIUrl":"10.1016/j.euo.2024.09.001","url":null,"abstract":"<div><h3>Context</h3><div>Frailty, a geriatric syndrome characterized by decreased resilience and physiological reserve, impacts the prognosis and management of older adults significantly, particularly in the context of surgical and oncological care.</div></div><div><h3>Objective</h3><div>To provide an overview of frailty assessment in the management of older patients with a renal mass/renal cell carcinoma (RCC), focusing on its implications for diagnostic workup, treatment decisions, and clinical outcomes.</div></div><div><h3>Evidence acquisition</h3><div>A narrative review of the literature was conducted, focusing on frailty definitions, assessment tools, and their application in geriatric oncology, applied to the field of RCC. Relevant studies addressing the prognostic value of frailty, its impact on treatment outcomes, and potential interventions were summarized.</div></div><div><h3>Evidence synthesis</h3><div>Frailty is a poor prognostic factor and can influence decision-making in the management of both localized and metastatic RCC. Screening tools such as the Geriatric Screening Tool 8 (G8) and the Mini-COG test can aid clinicians to select older patients (ie, aged ≥65 yr) for a further comprehensive geriatric assessment (CGA) performed by dedicated geriatricians. The CGA provides insights to risk stratify patients and guide subsequent treatment pathways. As such, the involvement of geriatricians in multidisciplinary tumor boards emerges as an essential priority to address the complex needs of frail patients and optimize clinical outcomes. Herein, we propose a dedicated care pathway as a first key step to implement frailty assessment in clinical practice and research for RCC.</div></div><div><h3>Conclusions</h3><div>Frailty has emerged as a crucial factor influencing the management and outcomes of older patients with RCC. Involvement of geriatricians in diagnostic and therapeutic pathways represents a pragmatic approach to screen and assess frailty, fostering individualized treatment decisions according to holistic patient risk stratification.</div></div><div><h3>Patient summary</h3><div>Frailty, a decline in resilience and physiological reserve, influences treatment decisions and outcomes in elderly patients with renal cell carcinoma, guiding personalized care. In this review, we focused on pragmatic strategies to screen patients with a renal mass suspected for renal cell carcinoma, who are older than 65 yr, for frailty and on personalized management algorithms integrating geriatric input beyond patient- and tumor-related factors.</div></div>","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 190-200"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.12.001
Julien Anract , Clément Klein , Ugo Pinar , Morgan Rouprêt , Nicolas Barry Delongchamps , Grégoire Robert
{"title":"Reply to Riccardo Leni, Andreas Roder, and Hein V. Stroomberg’s Letter to the Editor re: Julien Anract, Clément Klein, Ugo Pinar, Morgan Rouprêt, Nicolas Barry Delongchamps, Grégoire Robert. Incidental Prostate Cancer in Patients Undergoing Surgery for Benign Prostatic Hyperplasia: A Predictive Model. Eur Urol Oncol. 2025;8:145–51","authors":"Julien Anract , Clément Klein , Ugo Pinar , Morgan Rouprêt , Nicolas Barry Delongchamps , Grégoire Robert","doi":"10.1016/j.euo.2024.12.001","DOIUrl":"10.1016/j.euo.2024.12.001","url":null,"abstract":"","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 213-214"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.04.023
Paul Sargos , Carine Bellera , Rita Bentahila , Marie Guerni , Nicolas Benziane-Ouaritini , Diego Teyssonneau , Nam-Son Vuong , Guillaume Ploussard , Morgan Roupret , Guilhem Roubaud
Background
Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction.
Objective
To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa.
Design, setting, and participants
The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa.
Outcome measurements and statistical analysis
The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence–free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included.
Results and limitations
In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study.
Conclusions
Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa.
Patient summary
The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.
{"title":"Short-term Darolutamide (ODM-201) Concomitant to Radiation Therapy for Patients with Unfavorable Intermediate-risk Prostate Cancer: The Darius (AFU-GETUG P15) Phase 2 Trial Protocol","authors":"Paul Sargos , Carine Bellera , Rita Bentahila , Marie Guerni , Nicolas Benziane-Ouaritini , Diego Teyssonneau , Nam-Son Vuong , Guillaume Ploussard , Morgan Roupret , Guilhem Roubaud","doi":"10.1016/j.euo.2024.04.023","DOIUrl":"10.1016/j.euo.2024.04.023","url":null,"abstract":"<div><h3>Background</h3><div>Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction.</div></div><div><h3>Objective</h3><div>To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa.</div></div><div><h3>Design, setting, and participants</h3><div>The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa.</div></div><div><h3>Outcome measurements and statistical analysis</h3><div>The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence–free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included.</div></div><div><h3>Results and limitations</h3><div>In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study.</div></div><div><h3>Conclusions</h3><div>Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa.</div></div><div><h3>Patient summary</h3><div>The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.</div></div>","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 73-79"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.12.002
Kang Liu , Hongda Zhao , Xuan Chen , Hongwei Wu , Chris Ho-Ming Wong , Ivan Ching-Ho Ko , Rossella Nicoletti , Peter Ka-Fung Chiu , Chi-Fai Ng , Jeremy Yuen-Chun Teoh
<div><h3>Background and objective</h3><div>There is a lack of data on the impact of hypoglycemia agents, especially metformin, on prognosis for non–muscle-invasive bladder cancer (NMIBC). Our aim was to investigate the association between hypoglycemia agents, especially metformin, and long-term survival outcomes for patients with NMIBC treated with bacillus Calmette-Guérin.</div></div><div><h3>Methods</h3><div>All patients with NMIBC treated with intravesical BCG therapy from 2001 to 2020 were identified in a territory-wide database in Hong Kong. Patients were stratified into two groups according to whether or not they were taking a hypoglycemia agent at BCG treatment initiation. We analyzed data for overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS) using the Kaplan-Meier method. Multivariable Cox regression analysis was used to adjust for potential confounding factors and estimate hazard ratio (HRs) and 95% confidence intervals (CIs). Subgroup analyses were conducted to assess the specific influence of metformin on survival outcomes.</div></div><div><h3>Key findings and limitations</h3><div>Of 2602 patients with NMIBC treated with intravesical BCG, 19.5% (<em>n</em> = 507) were taking a hypoglycemia agent at BCG initiation (treatment group) and 80.5% (<em>n</em> = 2095) were not (control group). At median follow-up of 11 yr, Kaplan-Meier analysis revealed a significant difference in OS between the groups (<em>p</em> < 0.01), but not in CSS (<em>p</em> = 0.36), RFS (<em>p</em> = 0.19), or PFS (<em>p</em> = 0.05). Subgroup analysis comparing outcomes for patients taking metformin, patients taking a hypoglycemia agent other than metformin, and control subjects revealed significant differences in OS (<em>p</em> < 0.01) and RFS (<em>p</em> = 0.02), but not in CSS (<em>p</em> = 0.59) or PFS (<em>p</em> = 0.08). Multivariable Cox regression analysis identified metformin-based treatment for hypoglycemia as an independent risk factor for RFS (HR 1.22, 95% CI 1.02–1.46), whereas hypoglycemia agents other than metformin were not significantly associated with RFS (HR 0.71, 95% CI 0.47–1.06).</div></div><div><h3>Conclusions and clinical implications</h3><div>Metformin-based hypoglycemia treatment was an independent risk factor for RFS in BCG-treated NMIBC. Hypoglycemia treatment with an agent other than metformin was not related to long-term survival outcomes.</div></div><div><h3>Patient summary</h3><div>We investigated the relationship between treatment for high blood sugar and long-term survival for patients with intermediate-risk or high-risk non–muscle-invasive bladder cancer. The patients had received BCG (bacillus Calmette-Guérin) treatment in Hong Kong for their bladder cancer over the past two decades. Our results show that metformin, but not other drugs used to treat high blood sugar, was associated with poorer survival free from bladder cancer recurrence for these patien
{"title":"Association Between Hypoglycemia Agents and Long-term Survival Outcomes for Patients with Non–muscle-invasive Bladder Cancer Treated with Intravesical Bacillus Calmette-Guérin Immunotherapy","authors":"Kang Liu , Hongda Zhao , Xuan Chen , Hongwei Wu , Chris Ho-Ming Wong , Ivan Ching-Ho Ko , Rossella Nicoletti , Peter Ka-Fung Chiu , Chi-Fai Ng , Jeremy Yuen-Chun Teoh","doi":"10.1016/j.euo.2024.12.002","DOIUrl":"10.1016/j.euo.2024.12.002","url":null,"abstract":"<div><h3>Background and objective</h3><div>There is a lack of data on the impact of hypoglycemia agents, especially metformin, on prognosis for non–muscle-invasive bladder cancer (NMIBC). Our aim was to investigate the association between hypoglycemia agents, especially metformin, and long-term survival outcomes for patients with NMIBC treated with bacillus Calmette-Guérin.</div></div><div><h3>Methods</h3><div>All patients with NMIBC treated with intravesical BCG therapy from 2001 to 2020 were identified in a territory-wide database in Hong Kong. Patients were stratified into two groups according to whether or not they were taking a hypoglycemia agent at BCG treatment initiation. We analyzed data for overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS) using the Kaplan-Meier method. Multivariable Cox regression analysis was used to adjust for potential confounding factors and estimate hazard ratio (HRs) and 95% confidence intervals (CIs). Subgroup analyses were conducted to assess the specific influence of metformin on survival outcomes.</div></div><div><h3>Key findings and limitations</h3><div>Of 2602 patients with NMIBC treated with intravesical BCG, 19.5% (<em>n</em> = 507) were taking a hypoglycemia agent at BCG initiation (treatment group) and 80.5% (<em>n</em> = 2095) were not (control group). At median follow-up of 11 yr, Kaplan-Meier analysis revealed a significant difference in OS between the groups (<em>p</em> < 0.01), but not in CSS (<em>p</em> = 0.36), RFS (<em>p</em> = 0.19), or PFS (<em>p</em> = 0.05). Subgroup analysis comparing outcomes for patients taking metformin, patients taking a hypoglycemia agent other than metformin, and control subjects revealed significant differences in OS (<em>p</em> < 0.01) and RFS (<em>p</em> = 0.02), but not in CSS (<em>p</em> = 0.59) or PFS (<em>p</em> = 0.08). Multivariable Cox regression analysis identified metformin-based treatment for hypoglycemia as an independent risk factor for RFS (HR 1.22, 95% CI 1.02–1.46), whereas hypoglycemia agents other than metformin were not significantly associated with RFS (HR 0.71, 95% CI 0.47–1.06).</div></div><div><h3>Conclusions and clinical implications</h3><div>Metformin-based hypoglycemia treatment was an independent risk factor for RFS in BCG-treated NMIBC. Hypoglycemia treatment with an agent other than metformin was not related to long-term survival outcomes.</div></div><div><h3>Patient summary</h3><div>We investigated the relationship between treatment for high blood sugar and long-term survival for patients with intermediate-risk or high-risk non–muscle-invasive bladder cancer. The patients had received BCG (bacillus Calmette-Guérin) treatment in Hong Kong for their bladder cancer over the past two decades. Our results show that metformin, but not other drugs used to treat high blood sugar, was associated with poorer survival free from bladder cancer recurrence for these patien","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 164-170"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.03.009
Andrei Gafita , Andrew J. Martin , Louise Emmett , Matthias Eiber , Amir Iravani , Wolfgang P. Fendler , James Buteau , Shahneen Sandhu , Arun A. Azad , Ken Herrmann , Martin R. Stockler , Ian D. Davis , Michael S. Hofman
<div><h3>Background</h3><div>Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [<sup>177</sup>Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [<sup>177</sup>Lu]Lu-PSMA compared with standard chemotherapy has not been established.</div></div><div><h3>Objective</h3><div>To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective).</div></div><div><h3>Design, setting, and participants</h3><div>All 200 patients were randomised in the TheraP trial to receive [<sup>177</sup>Lu]Lu-PSMA-617 (<em>n</em> = 99) or cabazitaxel (<em>n</em> = 101) between February 2018 and September 2019.</div></div><div><h3>Outcome measurements and statistical analysis</h3><div>Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [<sup>177</sup>Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis.</div></div><div><h3>Results and limitations</h3><div>The probability of PSA50 in patients classified as having a favourable outcome was greater in the [<sup>177</sup>Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69–30.80] vs 0.96 [95% CI 0.32–3.05]; <em>p</em> = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [<sup>177</sup>Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: <em>p</em> = 0.36 and <em>p</em> = 0.41, respectively).</div></div><div><h3>Conclusions</h3><div>A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [<sup>177</sup>Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [<sup>177</sup>Lu]Lu-PSMA-617 and cabazitaxel.</div></div><div><h3>Patient summary</h3><div>In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA ra
{"title":"Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial","authors":"Andrei Gafita , Andrew J. Martin , Louise Emmett , Matthias Eiber , Amir Iravani , Wolfgang P. Fendler , James Buteau , Shahneen Sandhu , Arun A. Azad , Ken Herrmann , Martin R. Stockler , Ian D. Davis , Michael S. Hofman","doi":"10.1016/j.euo.2024.03.009","DOIUrl":"10.1016/j.euo.2024.03.009","url":null,"abstract":"<div><h3>Background</h3><div>Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [<sup>177</sup>Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [<sup>177</sup>Lu]Lu-PSMA compared with standard chemotherapy has not been established.</div></div><div><h3>Objective</h3><div>To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective).</div></div><div><h3>Design, setting, and participants</h3><div>All 200 patients were randomised in the TheraP trial to receive [<sup>177</sup>Lu]Lu-PSMA-617 (<em>n</em> = 99) or cabazitaxel (<em>n</em> = 101) between February 2018 and September 2019.</div></div><div><h3>Outcome measurements and statistical analysis</h3><div>Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [<sup>177</sup>Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis.</div></div><div><h3>Results and limitations</h3><div>The probability of PSA50 in patients classified as having a favourable outcome was greater in the [<sup>177</sup>Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69–30.80] vs 0.96 [95% CI 0.32–3.05]; <em>p</em> = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [<sup>177</sup>Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: <em>p</em> = 0.36 and <em>p</em> = 0.41, respectively).</div></div><div><h3>Conclusions</h3><div>A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [<sup>177</sup>Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [<sup>177</sup>Lu]Lu-PSMA-617 and cabazitaxel.</div></div><div><h3>Patient summary</h3><div>In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA ra","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 21-28"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140735439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.euo.2024.10.012
David D’Andrea , Hugh Mostafid , Paolo Gontero , Shahrokh Shariat , Ashish Kamat , Alexandra Masson-Lecomte , Maximilian Burger , Morgan Rouprêt
<div><h3>Background and objective</h3><div>Non–muscle-invasive bladder cancer (NMIBC) poses a significant clinical challenge, particularly when failing bacillus Calmette-Guérin (BCG) therapy, necessitating alternative treatments. Despite radical cystectomy being the recommended treatment, many patients are unfit or unwilling to undergo this invasive procedure, highlighting the need for effective bladder-sparing therapies. This review aims to summarize and report the evidence on the efficacy and to estimate the costs of bladder-preserving strategies used in NMIBC recurrence after failure of intravesical BCG therapy.</div></div><div><h3>Methods</h3><div>We systematically searched online databases for prospective studies investigating intravesical therapy, systemic therapy, or combination of both in patients treated previously with BCG. Owing to significant heterogeneity across the studies, a meta-analysis was inappropriate. A sensitivity analysis was performed in an exploratory manner. We used a decision-analytic Markov model to compare novel U.S. Food and Drug Administration–approved treatments with a 2-yr time horizon.</div></div><div><h3>Key findings and limitations</h3><div>A total of 57 studies published between 1998 and 2024, with 68 unique study arms and consisting of 2589 patients, were identified. The 3-mo overall response rate (ORR) across all studies, complete response rate (CRR) in concomitant carcinoma in situ (CIS) or CIS only disease, and recurrence-free rate (RFR) in papillary disease were estimated to be 52.4% (95% confidence interval [CI]: 45.4–59.2), 52.8% (95% CI: 42.9–62.6), and 26.4% (95% CI: 13.3–45.6), respectively. The 12-mo ORR, CRR, and RFR were estimated to be 78% (95% CI: 52.9–91.8), 27.8% (95% CI: 21.3–35.4), and 25.4% (95% CI: 18.2–34.2), respectively. The progression rate was estimated to be 13% (95% CI: 9–18.2). The mean proportion of patients treated with radical cystectomy was estimated to be 24.7 (range 0–85.7). The reported toxicity grades were overall mild, with a median of 3.4% (range 0–33.3%) participants experiencing a dose limiting toxicity. Compared with using radical cystectomy to treat patients failing BCG therapy, at a willingness-to-pay threshold of 100 000 USD, nadofaragene firadenovec was cost effective, with an incremental cost-effectiveness ratio (ICER) of 10 014 USD per quality-adjusted life year (QALY), while nogapendekin alfa inbakicept was less cost effective than nadofaragene firadenovec (ICER of 44 602 USD per QALY). Pembrolizumab, which dominated, was both less costly and more effective than the other strategies.</div></div><div><h3>Conclusions and clinical implications</h3><div>Salvage bladder-sparing therapies show a response rate of around 50% at 3 mo in patients with NMIBC failing BCG. However, long-term data are heterogeneous. Nevertheless, recently developed agents show promising tumor control activity. In the rapidly evolving landscape of urothelial cancer, some of these treatment str
{"title":"Unmet Need in Non–muscle-invasive Bladder Cancer Failing Bacillus Calmette-Guérin Therapy: A Systematic Review and Cost-effectiveness Analyses from the International Bladder Cancer Group","authors":"David D’Andrea , Hugh Mostafid , Paolo Gontero , Shahrokh Shariat , Ashish Kamat , Alexandra Masson-Lecomte , Maximilian Burger , Morgan Rouprêt","doi":"10.1016/j.euo.2024.10.012","DOIUrl":"10.1016/j.euo.2024.10.012","url":null,"abstract":"<div><h3>Background and objective</h3><div>Non–muscle-invasive bladder cancer (NMIBC) poses a significant clinical challenge, particularly when failing bacillus Calmette-Guérin (BCG) therapy, necessitating alternative treatments. Despite radical cystectomy being the recommended treatment, many patients are unfit or unwilling to undergo this invasive procedure, highlighting the need for effective bladder-sparing therapies. This review aims to summarize and report the evidence on the efficacy and to estimate the costs of bladder-preserving strategies used in NMIBC recurrence after failure of intravesical BCG therapy.</div></div><div><h3>Methods</h3><div>We systematically searched online databases for prospective studies investigating intravesical therapy, systemic therapy, or combination of both in patients treated previously with BCG. Owing to significant heterogeneity across the studies, a meta-analysis was inappropriate. A sensitivity analysis was performed in an exploratory manner. We used a decision-analytic Markov model to compare novel U.S. Food and Drug Administration–approved treatments with a 2-yr time horizon.</div></div><div><h3>Key findings and limitations</h3><div>A total of 57 studies published between 1998 and 2024, with 68 unique study arms and consisting of 2589 patients, were identified. The 3-mo overall response rate (ORR) across all studies, complete response rate (CRR) in concomitant carcinoma in situ (CIS) or CIS only disease, and recurrence-free rate (RFR) in papillary disease were estimated to be 52.4% (95% confidence interval [CI]: 45.4–59.2), 52.8% (95% CI: 42.9–62.6), and 26.4% (95% CI: 13.3–45.6), respectively. The 12-mo ORR, CRR, and RFR were estimated to be 78% (95% CI: 52.9–91.8), 27.8% (95% CI: 21.3–35.4), and 25.4% (95% CI: 18.2–34.2), respectively. The progression rate was estimated to be 13% (95% CI: 9–18.2). The mean proportion of patients treated with radical cystectomy was estimated to be 24.7 (range 0–85.7). The reported toxicity grades were overall mild, with a median of 3.4% (range 0–33.3%) participants experiencing a dose limiting toxicity. Compared with using radical cystectomy to treat patients failing BCG therapy, at a willingness-to-pay threshold of 100 000 USD, nadofaragene firadenovec was cost effective, with an incremental cost-effectiveness ratio (ICER) of 10 014 USD per quality-adjusted life year (QALY), while nogapendekin alfa inbakicept was less cost effective than nadofaragene firadenovec (ICER of 44 602 USD per QALY). Pembrolizumab, which dominated, was both less costly and more effective than the other strategies.</div></div><div><h3>Conclusions and clinical implications</h3><div>Salvage bladder-sparing therapies show a response rate of around 50% at 3 mo in patients with NMIBC failing BCG. However, long-term data are heterogeneous. Nevertheless, recently developed agents show promising tumor control activity. In the rapidly evolving landscape of urothelial cancer, some of these treatment str","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":"8 1","pages":"Pages 216-229"},"PeriodicalIF":8.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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