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Importance: The presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC). Objective: To compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis. Design, Setting, and Participants: This post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis. Interventions: In the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal. Main Outcomes and Measures: Overall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level. Results: Of the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P = .02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P < .001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P < .001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P < .001). Conclusions and Relevance: In this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.
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Antagonistas de Andrógenos , Neoplasias Óseas , Neoplasias de la Próstata , Humanos , Masculino , Anciano , Antagonistas de Andrógenos/uso terapéutico , Persona de Mediana Edad , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/patología , Neoplasias Óseas/secundario , Neoplasias Óseas/mortalidad , Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Nitrilos/uso terapéutico , Estudios Prospectivos , Dolor en Cáncer/tratamiento farmacológico , Anilidas/uso terapéutico , Compuestos de Tosilo/uso terapéutico , Compuestos de Tosilo/efectos adversos , Androstenos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiologíaRESUMEN
The treatment landscape for patients with advanced urothelial carcinoma continues to evolve. Enfortumab vedotin plus pembrolizumab has received Food and Drug Administration approval based on recent phase 3 trial data showing superior efficacy compared with first-line platinum-based chemotherapy; however, its distinct toxicity profile may make it less suitable for some patients, and availability in some countries may be limited by cost considerations. Consequently, platinum-based chemotherapy is expected to remain an important first-line treatment option. Choice of platinum regimen (cisplatin- or carboplatin-based) is informed by assessment of clinical characteristics, including performance status, kidney function, and presence of peripheral neuropathy or heart failure. For patients without disease progression after completing platinum-based chemotherapy, avelumab first-line maintenance treatment is recommended by international guidelines. For patients who have disease progression, pembrolizumab is the preferred approach. Additionally, following results from a recent phase 3 trial, nivolumab plus cisplatin-based chemotherapy has also received Food and Drug Administration approval and is an additional first-line treatment option for cisplatin-eligible patients. Later-line options for patients with advanced urothelial carcinoma, depending on prior treatment, may include enfortumab vedotin, erdafitinib (for patients with FGFR2/3 mutations or fusions/rearrangements), sacituzumab govitecan, and platinum rechallenge. For the small proportion of patients ineligible for any platinum-based chemotherapy (i.e., unsuitable for cisplatin or carboplatin), immune checkpoint inhibitor monotherapy with pembrolizumab or atezolizumab is a first-line treatment option, although approved agents vary between countries. In summary, this podcast discusses recent developments in the treatment landscape for advanced urothelial carcinoma, eligibility for platinum-based chemotherapy, potential first-line treatment options, and treatment sequencing. Supplementary file1 (MP4 246907 KB).
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Carcinoma de Células Transicionales , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Metástasis de la Neoplasia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológicoRESUMEN
CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities. OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors. EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs). EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender. CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.
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Neoplasias Urogenitales , Humanos , Neoplasias Urogenitales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Factores de Riesgo , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/terapia , Erupciones por Medicamentos/epidemiología , Erupciones por Medicamentos/diagnóstico , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/etiología , Enfermedades de la Piel/epidemiología , Antagonistas de Receptores Androgénicos/efectos adversos , Antagonistas de Receptores Androgénicos/uso terapéutico , Anticuerpos MonoclonalesRESUMEN
BACKGROUND: The application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). MATERIALS AND METHODS: A modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. RESULTS: Nine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. CONCLUSION: This consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.
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Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Técnica Delphi , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/terapia , Medicina de Precisión/métodos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias Urológicas/genética , Neoplasias Urológicas/terapia , ConsensoRESUMEN
The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.
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Neoplasias Primarias Secundarias , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapia , Medición de RiesgoRESUMEN
BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) herald a transformative era in metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) treatment, amid acknowledged sex-based disparities in these cancers. We conducted a systematic review and network meta-analysis (NMA) to identify sex-specific differences in the efficacy of ICI/ADC monotherapy or combination therapies for RCC and TCC survival, in metastatic and adjuvant settings. METHODS: A systematic search was conducted up to October 2023 for English articles on ICIs and ADCs as systemic therapies (ICIs in first-line and adjuvant treatment for RCC, ICIs and ADCs in first- and second-line treatment for TCC). Randomised clinical trials were considered. The primary objective was overall survival (OS) of ICIs and ADCs between males and females. The secondary outcomes included progression-free survival, overall response rate, disease-free survival, and recurrence-free survival. Treatment efficacy was evaluated by sex via odds ratios (ORs) and confidence intervals compared with controls. Log ORs were used for creating a frequentist NMA. This meta-analysis was registered on PROSPERO (CRD42023468632). KEY FINDINGS AND LIMITATIONS: Eighteen articles met the inclusion criteria. Females had an advantage for RCC-adjuvant treatment for atezolizumab (log OR [SE] = -0.57 ± 0.25, p = 0.024) in OS. Males showed a survival advantage in TCC second-line treatment for ADC-Nectin 4 (log OR [SE] = 0.65 ± 0.28, p = 0.02). No other significant results were shown. CONCLUSIONS AND CLINICAL IMPLICATIONS: The NMA revealed gender-specific variations in ICI and ADC responses for RCC and TCC, offering insights for personalised cancer care and addressing disparities in cancer care and outcomes. PATIENT SUMMARY: In this systematic review, we looked at the sex differences for metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) for antibody-drug conjugates and immune checkpoint inhibitors. In our analysis, female and male sex has better overall survival for adjuvant and second-line therapies for RCC and TCC, respectively. Urgent research on gender-specific cancer therapies is imperative.
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BACKGROUND: Combinations of immune checkpoint inhibitors (ICI) with platinum-based chemotherapy (PlatinumCT) or with another ICI in the first-line setting for patients with metastatic urothelial carcinoma (mUC) have mixed results. METHODS: Records were searched electronically from January 2019 to January 2024. A meta-analysis was performed to evaluate OS, progression-free survival (PFS), and overall response rate (ORR). RESULTS: Immune-based combinations were associated with an OS (HR: 0.75; 95% CI: 0.61-0.92; p < 0.001; I2= 84.1%) and PFS benefit in the intention-to-treat population (HR: 0.67; 95%CI: 0.51-0.89; p < 0.001; I2 = 89.7%). There was no ORR improvement with immune-based combinations (HR: 1.36; 95% CI:0.84-2.20; p < 0.001; I2 = 92.6%). CONCLUSION: This systematic review and study-level meta-analysis demonstrated that the immune-based combinations in first-line treatment for patients with mUC are associated with survival benefit.
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Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metaanálisis en Red , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/inmunología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/mortalidad , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Resultado del TratamientoRESUMEN
PURPOSE: It is estimated that the PTEN tumor suppressor gene is functionally lost in 40%-50% of patients with metastatic castration-resistant prostate cancer (mCRPC). There is limited information on the prognostic significance of PTEN status identified with genomic testing. This real-world cohort study assessed PTEN as a genetic biomarker using data from US-based oncology practices. METHODS: This retrospective real-world cohort study used a deidentified US-based metastatic prostate cancer clinicogenomic database linked to longitudinal clinical data derived from electronic health records. Patients were aged 18 years and older and diagnosed with mCRPC between January 1, 2018, and June 30, 2021. Comprehensive genomic profiling (CGP) of tumor specimens was performed using next-generation sequencing. First-line (1L) and second-line (2L) treatment patterns were assessed and stratified by PTEN status. Kaplan-Meier methods and a multivariable Cox model were used to compare the real-world overall survival by PTEN status among patients who received 1L novel hormone therapy or taxanes. RESULTS: In patients with mCRPC who underwent CGP, PTEN loss of function (LOF) was associated with decreased survival compared with intact PTEN (hazard ratio, 1.61 [95% CI, 1.07 to 2.42]; P = .024). The results were not influenced by 1L treatment type. 1L treatment patterns were similar between intact PTEN and PTEN LOF subgroups, with abiraterone and enzalutamide being the two most common treatments in both groups. Patients with PTEN LOF were less likely to receive 2L treatments than patients with intact PTEN. CONCLUSION: PTEN LOF, identified with genomic testing, was associated with decreased survival and negative prognoses in patients with mCRPC.
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Fosfohidrolasa PTEN , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Estudios de Cohortes , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Fosfohidrolasa PTEN/genética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).
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Anticuerpos Monoclonales , Antineoplásicos , Carcinoma de Células Transicionales , Neoplasias Urológicas , Humanos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/secundario , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Neoplasias de la Vejiga Urinaria , Gemcitabina/administración & dosificación , Gemcitabina/efectos adversos , Gemcitabina/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Análisis de Supervivencia , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/secundarioRESUMEN
BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.
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BACKGROUND: Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216. METHODS: Bone resorption [C-telopeptide (CTx); Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP); bone alkaline phosphatase (BAP)] were assessed in blood from men with bone metastatic HSPC. Patients were randomly divided into training (n = 238) and validation (n = 475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics. RESULTS: Of 1279 men, 713 had both baseline bone metastases and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone metastases. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP-1.31 (0.93, 1.84), p = 0.12; CICP-1.58 (1.09, 2.29), p < 0.02; CTx - 1.55 (1.12, 2.15), p = 0.008; and PYD-1.66 (1.27, 2.217), p = 0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p > 0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group). CONCLUSIONS: In this planned S1216 subset analysis of men with HSPC and bone metastases, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes. GOV IDENTIFIER: NCT01809691.
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Antagonistas de Andrógenos , Biomarcadores de Tumor , Neoplasias Óseas , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias Óseas/secundario , Neoplasias Óseas/mortalidad , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/metabolismo , Anciano , Biomarcadores de Tumor/sangre , Antagonistas de Andrógenos/uso terapéutico , Persona de Mediana Edad , Pronóstico , Huesos/metabolismo , Huesos/patología , Péptidos , Colágeno Tipo IRESUMEN
INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.
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Antineoplásicos Inmunológicos , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Interrupción del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inducido químicamente , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Immuno-oncology (IO) has made monumental gains in the past decade in the genitourinary space. In this review, we highlight advances with IO in renal cell carcinoma where it now has become standard-of-care frontline therapy in the metastatic setting but also discuss challenges with the initial approach. In urothelial carcinoma, we discuss the growing use of IO including exciting recent updates with IO-based regimens that may soon become the new standard of care. We further discuss difficulties with IO in prostate cancer, germ cell tumors, and penile squamous cell carcinoma. Finally, we highlight advances in IO approaches beyond checkpoint inhibition including the role of the gut microbiome and T-cell redirecting therapies.
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Carcinoma de Células Transicionales , Inmunoterapia , Neoplasias Renales , Neoplasias de la Próstata , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Oncología MédicaRESUMEN
BACKGROUND: Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC). OBJECTIVE: Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel. DESIGN, SETTING, AND PARTICIPANTS: Patients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera. RESULTS AND LIMITATIONS: Of 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set. CONCLUSIONS: In men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state. PATIENT SUMMARY: In men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan.
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Imidazoles , Naftalenos , Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/efectos adversos , Andrógenos/uso terapéutico , Biomarcadores , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Biomarcadores de TumorRESUMEN
BACKGROUND: Most patients with treatment-naïve metastatic renal cell carcinoma (mRCC) receive combination-based immunotherapy with either 2 immune-oncology checkpoint inhibitors (IO/IO) or an IO agent in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (IO/TKI). The rates of thromboembolism (TE) in these cohorts are not clearly described and can potentially impact decision-making between IO/IO and IO/TKI. METHODS: We conducted a retrospective investigation of patients with treatment-naïve mRCC treated with IO-based combinations between January 2015 and April 2021 at the Cleveland Clinic. TE events, including venous and arterial, were identified in each group. Competing risk regression was done to identify factors associated with the development of TE following therapy, with all-cause mortality treated as a competing event. RESULTS: Of 180 patients identified, 77 (43%) received IO/TKI and 103 (57%) received IO/IO. Median age was 65 years, 75% were male, and 80% had clear cell histology. Baseline characteristics were similar between the 2 groups. At a median follow-up of 22.0 months, 10.0% of all patients had a TE. The one-year incidence of TE was 8.1% (95% CI: 3.3%-15.8%) with IO/TKI and 9.8% (95% CI: 5.0%-16.5%) with IO/IO and was not significantly different between the 2 groups (HR 0.89, 95% CI: 0.35%-2.28%). Occurrence of TE was associated with decreased overall survival regardless of IO/IO or IO/TKI therapy (HR 2.80, 95% CI: 1.57-5.02). There was no difference in incidence of TE based on patient age, gender, prior history of TE, International Metastatic Renal Cell Carcinoma (IMDC) risk group, or Khorana score. CONCLUSIONS: Incidence of TE is similar between IO/IO and IO/TKI regimens in treatment-naïve mRCC and is also associated with decreased overall survival. While risk of TE may not guide decision-making in choice of front-line mRCC therapy, careful attention should be given to the high risk of TE in this population.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Anciano , Femenino , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Factor A de Crecimiento Endotelial Vascular , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Inmunoterapia/efectos adversosRESUMEN
BACKGROUND: The treatment landscape for locally advanced/metastatic urothelial carcinoma (la/mUC) has evolved. This study examined US prescribing patterns and clinical decision-making for first-line (1L) and first-line maintenance (1LM) treatment. MATERIALS AND METHODS: US-based oncologists (Nâ =â 150) completed an online survey on patient demographics, practice patterns, and important factors considered in 1L/1LM selection. Multivariable logistic regression was used to assess factors associated with more vs less frequent 1L/1LM prescribing. RESULTS: Physician reports estimated that 23% of patients with la/mUC had not received any systemic therapy in the previous 6 months; however, 46% received 1L, 32% received second-line, and 22% received subsequent-line systemic treatments. Of patients who were receiving 1L treatment, 72% were estimated to be receiving 1L platinum-based chemotherapy. Around 69% of patients eligible for 1LM received the treatment. Physicians categorized as frequent prescribers reported overall survival (OS), disease control rate (DCR), and rate of grade 3/4 adverse events (AEs) as factors associated with 1L treatment selection (all Pâ <â .05). OS, rate of grade 3/4 immune-mediated AEs, and inclusion in institutional guidelines were reported as attributes used in 1LM treatment selection (all Pâ <â .05). Multivariable analysis revealed OS, DCR, and rate of grade 3/4 AEs as important factors in oncologists' 1L treatment selection; academic practice setting and use of Response Evaluation Criteria in Solid Tumors version 1.1 were associated with 1LM use (all Pâ <â .05). CONCLUSION: OS and AEs were found to be relevant factors associated with offering 1L and 1LM treatment. Variability exists in physicians' decision-making in the real-world setting for la/mUC.
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Carcinoma de Células Transicionales , Oncólogos , Médicos , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint), PFS, and safety were assessed. RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Vejiga Urinaria , Estudios Prospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This summary provides the results of a study of two treatments for cancer, enfortumab vedotin and pembrolizumab, that were studied together against locally advanced or metastatic urothelial cancer (la/mUC), a cancer that occurs most commonly in the bladder. WHAT WERE THE RESULTS?: In the 45 patients studied, around 16% did have serious side effects, but most side effects were manageable. Twenty-four percent of patients, however, stopped the study treatment because of their side effects. Within about 2 months of starting treatment, most patients' (73%) tumors were smaller and stayed smaller, on average, for more than 2 years. WHAT DO THE RESULTS MEAN?: The combination of enfortumab vedotin plus pembrolizumab is a new treatment option for patients with locally advanced or metastatic urothelial cancer when they cannot receive the typical treatment, cisplatin. Advanced or metastatic urothelial cancer is a type of cancer where the cancer has already spread outside of the bladder or urinary tract.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: This study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting. METHODS: This retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record-derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan-Meier method. RESULTS: The overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type. CONCLUSION: This real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options.