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Background: Radium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use., Objective: To assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223-treated mCRPC patients., Design, Setting, and Participants: A prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted., Outcome Measurements and Statistical Analysis: The main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated., Results and Limitations: A total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0-1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10-14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3-2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89-2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28-2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003)., Conclusions: Biomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials., Patient Summary: In this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Immuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied., Objective: To describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy., Design, Setting, and Participants: A retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation., Intervention: Patients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs)., Outcome Measurements and Statistical Analysis: Outcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group., Results and Limitations: Among 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30-0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs., Conclusions: Targeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy., Patient Summary: Patients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Introduction of additional new agents targeting the vascular endothelial growth factor receptor (VEGFR) and immune checkpoint inhibitors (ICIs) has completely modified the systemic treatment of metastatic renal cell carcinoma (mRCC) during the last years., Objective: A comprehensive (nonsystematic) review to determine the suggested sequence or combinations for the systemic treatment of mRCC., Evidence Acquisition: PubMed and abstracts from main conferences up to December 2018 were reviewed to retrieve the current evidence for treatment of mRCC. Search terms included renal cell carcinoma, systemic therapy, targeted therapy (TT), and immunotherapy., Evidence Synthesis: Marked advances in the treatment of mRCC have been made with novel VEGFR tyrosine kinase inhibitors and multiple ICIs that have been included in the current treatment paradigm of mRCC. Remarkable advance has been made with the combination of double checkpoint blockade. The combination of ipilimumab and nivolumab compared with sunitinib has shown to increase the overall survival in the intermediate- and poor-risk patients based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model., Conclusions: Double checkpoint blockade with ipilimumab and nivolumab has reported overall survival benefit in IMDC intermediate- and poor-risk patients, providing a durable response for a subset of patients. VEGF inhibitors remain the standard of care for favorable-risk patients in the first line. In the immediate future, more consolidated data on combination of VEGF-TT plus ICIs may show similar robust benefit with different safety profiles., Patient Summary: Multiple drugs and sequences are now accepted as effective treatment for metastatic renal cell carcinoma (mRCC). Combination of immune checkpoint inhibitors has shown to increase the overall survival in treatment-naïve mRCC patients. Combinations of immunotherapy and antiangiogenics may be another option in the near future. Outcomes of the first line will determine the sequence, although the best sequence has yet to be defined., (Copyright © 2019. Published by Elsevier B.V.)

Background: The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last 2 decades., Objective: To define incidence trends according to patient and clinical characteristics, to identify risk factors, and to describe outcomes of patients with BM for RCC., Design, Setting, and Participants: Patients diagnosed with RCC between the years 2010 and 2013 within the Surveillance, Epidemiology, and End Results database. An external validation was also considered using patients diagnosed with RCC between 2010 and 2012 within the National Cancer Database., Outcome Measurements and Statistical Analysis: Incidence proportions of BM were calculated. Risk factors correlated with BM at diagnosis were identified via a 1000-bootstrap corrected multivariable logistic regression model. A risk model was then developed and evaluated using measures of predictive accuracy. Overall survival was examined using Cox regression analyses., Results and Limitations: The overall incidence proportions of BM at RCC diagnosis was 1.51% (95% confidence interval: 1.39-1.64%). White/other race, clear cell histology, and sarcomatoid differentiation, T2-4 disease, tumor dimension >10 cm, and N+ disease were significantly associated with BM at RCC diagnosis, and retained within the final prediction model. A risk score was created based on these variables (c-index: 0.803). BM at RCC diagnosis occurred in 0.5%, 3.6%, and 7.7% of patients categorized as low risk, intermediate risk, and high risk. Patients with BM were more likely to succumb to any death than those without BM at diagnosis (median overall survival: 6.4 mo vs not reached, respectively, adjusted hazard ratio: 1.87, 95% confidence interval: 1.67-2.08, p < 0.001). The real incidence of BM at RCC diagnosis is likely underestimated given that the observed rate likely reflects patients who presented with symptoms., Conclusions: Patients with BM at RCC have poor oncological outcomes. We have characterized the epidemiology of BM at RCC diagnosis and developed a clinical risk model for the purpose of predicting the development of BMs in patients diagnosed with a cortical renal mass., Patient Summary: In this report we examined recent proportions of patients with brain metastases at kidney cancer diagnosis in a large community database originating from the US. We developed a model that may be used during routine clinical practice to predict brain metastases. The urologic-oncological community may consider baseline imaging for brain metastases in patients without any symptoms but at high risk of having brain metastases according to the risk model. However, the proposed model certainly needs further testing and validation in the clinical setting. Future studies on brain metastases survival and treatment options are also needed., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity., Objective: To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs)., Design, Setting, and Participants: Germline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n=159) or mTOR inhibitors (n=62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed., Outcome Measurements and Statistical Analysis: Primary endpoints were grade ≥3 AEs for all patients; grade ≥3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors., Results and Limitations: In total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08-0.88; p=0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with analyzed toxicities., Conclusions: We observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed., Patient Summary: We found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)