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Context Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations. Objective To maintain living evidence for contemporary first-line treatment for previously untreated mRCC. Evidence acquisition We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence–assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner. Evidence synthesis As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps. Conclusions This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons. Patient summary It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.

Background Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment. Methods We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan–Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ2 test and Kruskal–Wallis rank sum test. Cox regression was used for univariate and multivariable analyses. Results We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3–26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8–10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8–13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1–not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7–12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8–24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42–3.96; P Conclusions The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.

Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel–Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. Experimental Design: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. Results: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. Conclusions: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

Purpose CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A). Methods We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study. Results The ratios of the geometric means of the maximum azacitidine plasma concentration (Cmax) and of the area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC∞) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of Cmax was significantly decreased by ~ 21% in the fed state. Median Tmax was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P Cmax and Tmax are not expected to have a clinical impact. Conclusion The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.

Objectives Previous studies noted discordance of programmed death‐1 (PD‐1) and one of its ligands (PD‐L1) across patient‐matched primary and metastatic clear cell renal cell carcinoma (ccRCC). There are inconsistencies if the primary or metastatic tumor has higher expression, and whether metastatic tumor expression is associated with patient outcome. Thus, we examined PD‐1 and PD‐L1 in patient‐matched tumors using a large number of ccRCC patients with long follow‐up. Materials and Methods We analyzed PD‐1 and PD‐L1 using immunohistochemistry in patient‐matched primary and metastatic tumors from 110 ccRCC patients. Concordance was assessed among longitudinal metastatic tumors, as well as across patient‐matched primary and metastatic tumors. Cox proportional hazards regression was used to evaluate the associations of metastatic tumor expression with cancer‐specific survival. Results We observed inter‐metastatic tumor heterogeneity of PD‐1 in 25 (69%) of the 36 patients and of PD‐L1 in seven (19%) patients. Concordance between patient‐matched primary and metastatic tumors was 73% (Kappa = 0.16, 95% CI: −0.003‐0.32). Similarly, concordance of PD‐L1 between metastatic and patient‐matched primary tumors was 78% (Kappa = 0.27, 95% CI: 0.09‐0.46). Both markers demonstrated higher expression in primary vs metastatic tumors. Metastatic tumor expression of PD‐1 was significantly associated with metastatic location (P, We examined PD‐1 and PD‐L1 in patient‐matched tumors in a large cohort of ccRCC with long‐term follow‐up. The expression of PD‐1 and PD‐L1 was discordant across patient‐matched ccRCC tumors, with higher expression in primary tumors. Higher PD‐1 expression was associated with metastatic location and lower cancer‐specific survival.

Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

Background Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis. Results To address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as ‘low risk’ by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0–3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score. Conclusions This study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0–3).

Introduction The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Materials and Methods A retrospective review of 472 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within six months of death were included. A total of 164 patients were eligible for analysis. Results Overall rates of visceral and distant metastases, including the lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p-value = 0.07). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusion The emergence of new systemic therapies for mPC is changing the natural history of the disease. Visceral metastases are being seen with increasing frequency than in the past. This observation is important for clinicians who are monitoring patients with prostate cancer to maintain a high suspicion for visceral disease.

Background The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown. Methods We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. Results The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. Conclusions These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

Renal cell carcinoma (RCC) is a malignancy that has been found to be responsive to various immune therapies and immunomodulation. Historic agents such as interleukin-2 and interferon alfa demonstrated some benefit in select patients with advanced disease; however, their use has become limited due to the introduction of targeted novel immunomodulators, such as the checkpoint inhibitors. This chapter reviews the historical development and indications of immune therapies for advanced RCC. Early agents such as interleukin and interferon will be discussed, as well as the newer contemporary checkpoint inhibitors, which are becoming first-line therapies for this patient population.

CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A).We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study.The ratios of the geometric means of the maximum azacitidine plasma concentration (CThe single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.

Context The role of antiangiogenic agents in advanced renal cell carcinoma (RCC) is well established. However, it is still not clear whether this benefit can be extrapolated to the adjuvant setting. Objective To determine the efficacy and safety of antiangiogenic agents in patients with RCC and a high risk of relapse after nephrectomy. Evidence acquisition We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) evaluating the use of any oral antiangiogenic agent compared to placebo in post-nephrectomy RCC patients. Prespecified data elements were extracted from each trial. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). The overall effect was pooled using the DerSimonian and Laird random-effects models. Evidence synthesis Three RCTs comparing antiangiogenics to placebo among 3693 patients met our inclusion criteria and were used in meta-analyses. Overall, antiangiogenics did not improve DFS (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.78–1.07) or OS (HR 0.99, 95% CI 0.79–1.25). These results persisted when restricting the analysis to patients with clear cell carcinoma and patients with highest risk of relapse. Similarly, sunitinib did not show any improvement in the entire cohort for either DFS (HR 0.89, 95% CI 0.67–1.19) or OS (HR 1.11, 95% CI 0.90–1.37). Conclusions In this meta-analysis, antiangiogenics did not improve OS and DFS over placebo in high-risk RCC after nephrectomy. Further studies are needed to identify the patient population that might derive a benefit from antiangiogenics in the adjuvant setting. Patient summary In this article, we found that there is currently insufficient evidence to support the use of oral antiangiogenics in nonmetastatic renal cell carcinoma after nephrectomy. In addition, the use of oral antiangiogenics was associated with a 2.7-fold higher rate of significant side effects compared to placebo.

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745

Background Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher‘s exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4–24.1). Genes in the Wnt/s-catenin pathway were more frequently mutated and negative regulators of Wnt/s-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17–3.80; P = 0.01). Conclusions Wnt/s-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Background Radium-223 ( 223 Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival. Materials and Methods Sixty-four patients with mCRPC who received 223 Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method. Results The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP) 12 g/dL, ALP response after 223 Ra treatment, PSA decrease during 223 Ra treatment, and absence of > 25% PSA increase during 223 Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP 223 Ra treatment. Conclusion When 223 Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after 223 Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether 223 Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy.

Background: Prostate cancers (PC) are intrinsically complex, with few prognostic biomarkers that differentiate aggressive and indolent disease. Cancer associated macrophage like cells (CAMLs) have shown to be significant independent prognostic indicators for poor survival in tumors if engorged to ≥50μm. However, no group has examined CAMLs' in PC. In this prospective pilot study, we analyzed PSA & ≥50μm CAML presence in (n=51) Stage I-III & (n=41) metastatic PC (mPC) prior to the start of new treatments to examine CAMLs' on outcomes. We found that ≥50μm CAML presence significantly predicted worse patient survival in mPC. These preliminary results suggest that CAMLs may serve as a cheap, non-invasive prognostic biomarker that predicts for worse outcomes in both local & mPC prior to new therapies. Methods: We prospectively recruited (n=92) PC patients in this pilot study to examine CAML's prognostic significance in non-metastatic (stages I-III) and mPC. Of (n=92) total patients, 15% (n=14/92) were stage I, 32% (n=29/92) stage II, 9% (n=8/92) stage III, and 45% (n=41/92) Stage IV. Prior to the induction of new therapy or first line therapy for newly diagnosed patients, 7.5mL peripheral baseline (BL) blood was collected. Blood was filtered via CellSieveTM microfiltration, which excludes cells by size ≥7μm. In parallel, changes in PSA was monitored to compare prognostic significance against ≥50μm CAMLs. Wilcoxon univariate analysis was used to analyze ≥50μm CAMLs and PSA in progression free survival (PFS) and overall survival (OS). Results: CAML's were identified in 78.9% (n=71/90) of available BL samples, with two samples failing from clotting. Stage I-III patients had an average of ~3 CAMLs/7.5mL blood, whereas mPCs contained ~6 CAMLs/7.5mL. Average CAML size increased linearly with advancing stage of disease with stage I patients averaging 23μm, stage II 33μm, stage III 65μm, and stage IV 78μm. Of available BL samples, 41% (n=38/90) patients with ≥50μm CAMLs significantly predicted for worse PFS (HR=10.0, p Conclusions: CAMLs have shown potential as a predictive non-invasive blood based biomarker across multiple solid malignancies, and here we compared this biomarker in PC. While preliminary, these data suggests that engorged CAML presence prior to the start of new treatment may be a statistically significant predictor of survival in both the local and metastatic setting, and a larger validation cohort should be established. Citation Format: Daniel J. Gironda, Raymond Bergan, R K. Alpaugh, Daniel C. Danila, Tuan L. Chuang, Brenda Y. Hurtado, Thai Ho, Cha-Mei Tang, Daniel L. Adams. Cancer associated macrophage like cells predict aggressive disease in local and metastatic prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 357.

In the original version of [this article][1] ([1][2]), the wrong files were supplied for Figs. 5B and C. The figures and related article text have been corrected in the latest online HTML and PDF versions of this article. The authors regret these errors. 1. 1.[↵][3]1. Cowman SJ, 2. Fuja

Purpose Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. Methods We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Results Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001). Conclusion EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.

Background Antineoplastic therapy with the tyrosine kinase inhibitor pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC) has been associated with hypertension (HTN), cardiomyopathy, and cardiac dysrhythmias. We therefore assessed the cardiovascular (CV) risk with pazopanib in a clinical setting. Methods Medical records of 35 antineoplastic-naïve mRCC patients newly started on pazopanib were retrospectively reviewed at a single academic medical center. Assessment of the hypertensive response and adverse cardiac events associated with pazopanib was the primary objective. Outcomes were defined using the National Cancer Institute’s Common Terminology Criteria for Adverse Events v4.0. Potential clinical risk factors were investigated with univariate and multivariable logistic regression. Results Pazopanib-induced HTN was observed in 57% of patients. Median maximal systolic blood pressure (SBP) during pazopanib treatment was 167.5 mmHg with median time to event of 24.5 days. New-onset HTN occurred in 6/14 (43%) patients. Baseline SBP > 130 mmHg (odds ratio [OR]: 5.32; 95% confidence interval [CI]: 0.94-29.99; p = 0.058) and ACEi/ARB use (OR: 4.88; 95% CI: 1.05 22.84; p = 0.044) were risk factors for pazopanib-induced HTN. When HTN was excluded, 34% of patients developed a CV adverse event. Age ≥ 60 years (OR: 8.72; 95% CI: 0.74-513.26; p = 0.105) trended towards being a predictor for a non-HTN CV adverse event. Conclusions Our findings suggest that pazopanib has a broad CV toxicity profile in treatment-naïve mRCC patients headlined by a rapid and striking hypertensive response. More intensive BP control prior to starting pazopanib and standardization of CV surveillance particularly in older patients may optimize oncologic care while minimizing CV risk.

Background The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM):DCN,SLIT2,LUM,LAMA2,ADAMTS12,CEACAM6 andLMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P Conclusions We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

INTRODUCTION AND OBJECTIVES:Sarcomatoid features are present in about 5% of renal cell carcinoma (RCC) cases and have significant clinical implications, as patients are more likely to succumb to me...

3039 Background: Patients with multiple organ metastases have poorer prognoses than those with a single organ metastasis, are frequently associated with drug resistance, and have higher tumor burden. Engorged (≥50um) Cancer Associated Macrophage-Like Cells (CAMLs) are a circulating stromal cell subtype detected in the blood of patients with solid tumors at high risk for recurrence or progression. While numerous studies have shown that ≥50um CAMLs predict poor clinical outcomes, meta-analysis of these studies have also suggested that hyper engorged CAMLs ≥100um (heCAMLs) may be associated with multifocal metastatic disease and even worse outcomes. In this prospective study, we evaluated the presence of heCAMLs in patients with metastatic disease and demonstrated a strong relationship with multi organ spread, which also correlated with shorter Progression Free Survival (PFS) and Overall Survival (OS). Methods: We prospectively recruited 151 patients with metastatic (m) mbreast (n = 58), mlung (n = 34), mprostate (n = 39), and mrenal (n = 20) cancers. Peripheral blood was collected prior to the induction of new treatment for metastatic cancer. Cells were isolated following standard CellSieve techniques, then imaged and measured in ZenBlue. Multi organ metastasis was defined as spread to ≥2 distant organ sites, or any spread to the brain. Single factor ANOVA was conducted to compare heCAML presence in multi organ metastatic patients versus patients with single organ site metastasis. Univariate and multivariate analysis was run to evaluate for PFS and OS against heCAMLs, and all known clinical parameters. Results: 150 viable samples (excluding 1 failed sample) were obtained. Multi organ metastases were present in 55% (n = 83/150) of patients. heCAMLs were found in 59% (n = 49/83) of the multi organ metastatic population, but only in 16% (n = 11/67) of the single site metastatic cohort (p < 0.001). heCAML presence appeared to differentiate multi organ vs single organ metastases in mbreast (85% vs. 52%, p = 0.006), mlung (71% vs. 26%, p = 0.025), mprostate (75% vs. 37%, p = 0.029), and mRCC (88% vs. 36%, p = 0.025). Further, in all n = 150 patients, heCAML presence predicted a significantly shorter median PFS of 4.5 versus 7.2 months, 24 month PFS (HR = 1.67, 95%CI = 1.13-2.45, p = 0.013), and significantly shorter median OS of 13.1 versus 20.4 months, 24 month OS (HR = 2.05, 95%CI = 1.24-3.39, p = 0.008). Conclusions: We examined a non-invasive prognostic blood based assay to determine its relationship to multi organ metastatic spread as well as its prognostic value in several solid cancers. These results showed patients with heCAMLs had higher rates of multi organ metastases, and appear to predict for shorter PFS and OS. Studies of larger cohorts are needed for prospective validation of these initial findings.

335 Background: Systematic reviews are outdated quickly when the evidence is rapidly evolving as the process is laborious and there is little incentive for primary author team of an index SRMA to update the evidence. Consequently, there is an epidemic of redundant SRMAs performed by different teams—sometimes with conflicted results—for treatment of first line mRCC. Methods: We have created a living, interactive systematic review (LISR)and network meta-analysis(LINMA) for the treatment of first line mRCC using an Artificial intelligence (AI) assisted framework for evidence synthesis (Living, Interactive evidence synthesis framework) (LIvE) . The framework is implemented in five-layered architecture (application layer, shared module layer, core service layer, middleware layer, and storage layer) which work together to automate the identification of new studies and analysis and semi-automate the screening and data extraction. Dynamic features such as interactive tables, figures and evidence maps are enabled using Python and JavaScript programming languages. Results: We have maintained a living, interactive evidence profile for the first line treatment mRCC since September 2019 ( LIVING WEBSITE) . Living search strategy identifies new studies as they become available. As of October 13, 2020 LISR, includes data 14 clinical trials ( PRISMA ). Baseline characteristics are summarized in an interactive table ( TABLE) . Cabozantinib& Nivolumab (Cabo-Nivo) is the highest ranked drug for improving Overall Response (OR), Progression Free Survival (PFS) and Overall Survival (OS) whereas Ipilimumab in combination with Nivolumab (Ipi-Nivo) is highest ranked drug for achieving complete response (CR). Ipi-Nivo and Atezolizumab & Bevacizumab (Ate-Bev) ranked highest and Cabo-Nivo ranked lowest for treatment related Adverse events (TRAEs). Results of network meta-analysis are summarized as interactive tables and plots ( NMA ), summary of findings tables ( MULTIPLE COMAPRISONS ) and evidence maps ( MAP ). Conclusions: LISRs can potentially reduce redundancy, increase transparency, reproducibility, enable shared-decision making (at a guideline level, or in a patient-clinician dyad) and support living guidelines.

Objective To predict overall survival, cancer, and metastasis specific survival in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU). Materials and Methods All nonmetastatic UTUC patients who underwent RNU with a curative intent at 1 institution between December 1998 and January 2017 were included. Detailed data were collected. End points for this study included OS, CCS, and MFS. Univariate and multivariate analysis were conducted. Log Rank tests and Kaplan-Meier curves were generated. Backward elimination and boot strapping was used to identify the most parsimonious model with the smallest number of variables in order to predict the outcomes of interest. A separate second institution data base was used for external validation. Results There were 218 patients in the development cohort. Mean follow-up was 42 months (±39.6). There was 99 (45.4%) deaths, 28 (12.8%) cancer related deaths, 72 (33%) recurrences, and 54 (24.8%) metastases. The c-index for our model was 0.71 for OS, 0.72 for MFS and 0.74 for CSS. The nomograms did not show significant deviation from actual observations using our calibration plots. We divided the patient into 3 different groups (low, intermediate and high risk) based on their final total score for each outcome and compared them. On external validation our accuracy was 78.4%, 71.4%, and 75.3% for OS, CSS, and MFS survival respectively. Conclusion We designed a predictive model for survival outcomes following RNU in UTUC. This model uses simple, readily available data for patients without the need for expensive or additional testing.

Purpose We aimed to explore the hypothesis that early subclinical cardiac chamber dysfunction secondary to tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma could be signaled by abnormal cardiac mechanics demonstrated by velocity vector imaging. Methods Echocardiographic images were acquired from the apical views in 23 metastatic renal cell carcinoma patients. All patients had baseline and at least a 3-month follow-up echocardiogram after receiving TKI therapy. Subendocardial borders of all the cardiac chambers were traced to obtain volumetric and deformation indices. Results Mean age was 67 ± 9 years with 92% men. The right ventricle peak systolic global longitudinal strain (GLɛ) and strain rate were significantly lower after TKIs (−23.49 ± 5.1 versus −19.81 ± 5.5, p = 0.002 and −1.52 ± 0.52 versus −1.24 ± 0.35 p = 0.02, respectively). LV GLɛ was not statistically different. Volumetric and deformation indices showed a minimal decrease of the right atrium reservoir and conduit functions, and no significant changes of left atrial function. Conclusions The right heart exhibited greater strain changes than the left heart after TKI treatment. The implications of these findings and their potential significance warrant further work. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound, 2016

3535 Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in >10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities.

Background: Germ cell tumors (GCTs) with malignant somatic transformation (MST) represent an uncommon variant of what is typically a curable malignancy. There is a paucity of data on time of somatic transformation, response to conventional therapy, and survival outcomes of different somatic subtypes. Methods: After obtaining institutional review board (IRB) approval, we searched our institutional database from 1982 to 2017 and identified patients with GCTs with MST. Patient characteristics, pathologic description, treatment, and clinical outcomes were extracted from the medical records. Results: We identified 24 cases of GCTs with MST; the MST was adenocarcinoma in 50% and sarcoma in 50%. Median age at diagnosis was 27. Alpha-fetoprotein and beta-human chorionic gonadotropin were undetectable in 44%, both were elevated in 54%. The majority were advanced stage (71% stage III), and International Germ Cell Cancer Collaborative Group (IGCCCG) risk was classified as ‘good' in 60%. Median follow-up was 41 months (range 10-346 months). Median progression-free survival was 84 months (95% confidence interval (CI) 56-232), and median overall survival was 219 months (95% CI 165-not reported). Conclusion: Patients with GCTs with an MST appear to have poor responses to cisplatin-based chemotherapy, suggesting that somatic component-driven therapies should be considered. Furthermore, resection of residual disease when feasible is an essential component of management.

Renal-cell carcinoma (RCC) is one of the common malignancies in the United States. RCC incidence and mortality have been changing for many reasons. We performed a thorough investigation of incidence and mortality trends of RCC in the United States using the cell Surveillance, Epidemiology, and End Results (SEER) database.The 13 SEER registries were accessed for RCC cases diagnosed between 1992 and 2015. Incidence and mortality were calculated by demographic and tumor characteristics. We calculated annual percentage changes of these rates. Rates were expressed as 100,000 person-years.A total of 104,584 RCC cases were reviewed, with 47,561 deaths. The overall incidence was 11.281 per 100,000 person-years. Incidence increased by 2.421% per year (95% confidence interval, 2.096, 2.747; P .001) but later became stable since 2008. However, the incidence of clear-cell subtype continued to increase (1.449%; 95% confidence interval, 0.216, 2.697; P = .024). RCC overall mortality rates have been declining since 2001. However, mortality associated with distant RCC only started to decrease in 2012, with an annual percentage change of 18.270% (95% confidence interval, -28.775, -6.215; P = .006).Despite an overall increase in the incidence of RCC, there has been a recent plateau in RCC incidence rates with a significant decrease in mortality.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Purpose: PD-1/L1 axis–directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti–PD-1 response. Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti–PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti–PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti–PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250–60. ©2018 AACR.

Background Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and RCC stem cells that is implicated as a mechanism of VEGF resistance. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of VEGF inhibitors in preclinical models and demonstrated a 29% RECIST response rate when combined with AX in patients with mRCC in a Phase 1b trial. Methods TRAXAR was a multicenter, randomized 1:1 (stratified by ECOG, 0 vs. 1), Phase 2 study of TRAX vs AX in patients with mRCC who had progressed following one prior VEGF inhibitor at 33 centers in the US and EU. The primary endpoint was progression-free survival (PFS) assessed by RECIST by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), and safety. PFS and ORR were also assessed by Investigator review (INV) and according to Choi criteria (CC). Results Of 150 pts (TRAX, 75; AX, 75), 106 (71%) were male, 142 (95%) were white; median age was 64 years (range, 38-82). Treatment with TRAX did not prolong PFS compared to AX. ORR was not different based on IRC, INV or CC (Table). Most all-grade common adverse events (AEs) in TRAX vs AX: headache (65.8% vs. 16.2%), epistaxis (63.0% vs. 8.1%), and diarrhea (60.3% vs. 59.5%); most common serious AEs included: anemia (6.9% vs. 1.4%) and dehydration (4.1% vs. 0%). Table . 912PD IRC INV CC TRAX AX TRAX AX TRAX AX Median PFS, mo (95% CI) 6.7 (5.6-13.1) 11.4 (5.8-NE) 7.2 (5.5-9.1) 7.4 (5.5-12.8) 7.2 (5.6-9.4) 7.5 (5.6-20.3) HR (95% CI) p-value 1.42 (0.88-2.30) 0.15 1.41 (0.95-2.10) 0.09 1.30 (0.83-2.03) 0.26 ORR, % 33.8 32.9 34.8 30.6 66.2 67.1 Odds ratio (95% CI) p-value 1.04 (0.50-2.15) 0.92 1.19 (0.58-2.44) 0.63 0.96 (0.47-1.96) 0.91 NE: not estimable; CI: confidence interval; mo: months Conclusions TRC105 did not demonstrate activity when combined with AX in patients with mRCC who had received prior VEGF inhibitor treatment, whether assessed using RECIST or Choi criteria. TRAX was generally well tolerated in pts with advanced or metastatic RCC. Clinical trial identification NCT01806064. Legal entity responsible for the study TRACON Pharmaceuticals. Funding TRACON Pharmaceuticals. Disclosure T.K. Choueiri: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: TRACON; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Cerulean; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche Products Limited; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): GSM; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Peloton; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Prometheus; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Corvus; Honoraria (institution): Calithera. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: Genomic Health; Advisory / Consultancy: Bayer. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array. T.H. Ho: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ipensenlivemeetings; Advisory / Consultancy: cardinal health; Advisory / Consultancy: Exelixis. B.E. Simpson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON Pharmaceuticals. B. Adams: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. L. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. M. Darif: Advisory / Consultancy: TRACON. C. Theuer: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TRACON. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (self): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Nektar; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (self): TRACON. All other authors have declared no conflicts of interest.

Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. Clin Cancer Res; 21(5); 1071–7. ©2014 AACR.

Background Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored. Objective To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors. Design, setting, and participants We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors. Outcome measurements and statistical analysis Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival. Results and limitations Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3–60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10–42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32–55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy. Conclusions Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor. Patient summary Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.

Hereditary forms of renal cell carcinoma (RCC) have yielded clues regarding the molecular pathogenesis of sporadic RCC. The discovery of germline mutations in chromatin-modulating enzymes also defined a new hereditary RCC syndrome. Although histologi cally distinct RCC subtypes exist, emerging themes shared between hereditary and sporadic RCC include dysregulation of the von Hippel-Lindau tumor suppressor protein/hypoxia inducible factor axis, defective ciliogenesis, and aberrant tumor metabolism. This article describes the most common hereditary RCC syndromes and associated extrarenal manifestations. Recent evidence supports developing screening guidelines for early-onset RCC to identify persons with germline mutations in the absence of secondary clinical manifestations. (J Natl Compr Canc Netw 2014;12:1347–1355) tations and incomplete penetrance of RCC, establishing screening guidelines for detecting early-onset RCC may help identify persons with germline mutations who have an increased risk of developing RCC.

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1–3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.

Background BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; however, the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown. Additionally, while intra-tumor heterogeneity has been shown to be common in primary ccRCC, little is known regarding heterogeneity in metastatic ccRCC tumors. Materials and methods We analyzed BAP1 and PBRM1 loss of protein expression in patient-matched primary and metastatic tumors from 97 patients. Expression was determined using a validated immunohistochemistry assay, which has been shown to be correlated with mutation status. Results Of the 97 patients evaluated, 20 and 57% showed loss of BAP1 and PBRM1 in their primary tumors, respectively. Comparing expression across patient-matched primary-metastatic tumor pairs, 98 and 90% had concordant BAP1 and PBRM1 expression, respectively. Both patients who demonstrated discordant BAP1 expression showed loss of BAP1 expression during progression to metastatic ccRCC. Similarly, seven of the ten patients that demonstrated discordant PBRM1 expression showed loss of PBRM1 expression during progression to metastatic ccRCC. We evaluated intra-metastatic tumor heterogeneity using 12 patients who had multiple blocks available from the same tumor with representative pathology; 100 and 92% showed concordant BAP1 and PBRM1 expression, respectively. Amongst 32 patients who had serial metastatic tumors available, both BAP1 and PBRM1 had 97% concordant expression. Conclusions We observed minimal intra- and inter- tumor heterogeneity in metastatic ccRCC tumors. Patients with discordant BAP1 or PBRM1 expression across their matched primary and metastatic tumors usually showed loss of expression during progression to metastatic ccRCC.

Background: The methylthioadenosine phosphorylase (MTAP) gene encodes an essential enzyme for the salvage pathway of adenosine synthesis and is frequently lost in different types of cancer including urothelial bladder carcinoma. Therefore, MTAP-deficient tumors are theoretically very sensitive to anti-folate agents such as pemetrexed that can effectively block the de novo pathway of adenosine synthesis and as a result, create a state of synthetic lethality. We thus hypothesize that tumor MTAP gene deficiency is associated with response to pemetrexed therapy in bladder cancer. Methods: In this study, we investigated MTAP gene deficiency rates in the TCGA database and confirmed MTAP protein loss by immunohistochemistry using a tumor tissue microarray containing bladder tumor tissues from 151 patients. We then performed in vitro and in vivo studies using MTAP-proficient and MTAP-deficient human bladder cancer cell lines. Functional loss of MTAP was verified with mass spectrometry, which detects its substrate methylthioadenosine (MTA) levels. We also correlated these pre-clinical studies with clinical response data on patients with metastatic bladder cancer treated with pemetrexed. Results: We identified that 27.8% bladder cancer patients have MTAP protein deficiency, which is consistent with exome sequencing data from the TCGA database. In vitro data showed MTAP-deficient human bladder cancer cell lines were significantly more sensitive to pemetrexed, with IC50 at least 40 times lower than MTAP-proficient cell lines. Subsequent knockdown of the MTAP gene in MTAP-proficient cell lines increased sensitivities to pemetrexed treatment. Consistent with the in vitro data, pemetrexed significantly inhibited the growth of MTAP-deficient or knockdown xenograft tumors but not MTAP-proficient tumors. Furthermore, 4 of 4 (100%) patients with MTAP-deficient metastatic bladder cancer responded to pemetrexed treatment, whereas only 1 of 11 (9%) patients with MTAP-proficient metastatic bladder cancer responded to pemetrexed. Conclusion: Our data demonstrate that MTAP gene loss in urothelial bladder cancer leads to a metabolic state of synthetic lethality with pemetrexed therapy. Therefore, bladder tumor MTAP loss should be further investigated as a potential biomarker for selection of patients for anti-folate therapy. Citation Format: Jianfeng Chen, Omar Alhalabi, Guangchun Han, Wei-Lien Wang, Xin-Qiao Zhang, Jian H. Song, Lidia P. Lopez, Sumankalai Ramachandran, Anh G. Hoang, Tyrone Garnett, Matthew Campbell, Amishi Y. Shah, Jennifer Wang, Arlene O. Siefker-Radtke, Shi-Ming Tu, Mark Titus, Charles C. Guo, Gary E. Gallick, Eleni Efstathiou, William F. Benedict, Christopher J. Logothetis, Thai H. Ho, Linghua Wang, Jianjun Gao. MTAP gene deficiency creates vulnerability to anti-folate therapy in urothelial bladder carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 385.

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.

5063 Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [Table: see text]

536 Background: The management of malignant mesothelioma of the tunica vaginalis of the testes (MMTVT) is not clearly defined, though retroperitoneal lymph node dissection has been reported as a diagnostic and potentially therapeutic option. Herein we present our experience with robot assisted retroperitoneal lymph node dissection (RARPLND) in a series of patients with MMTVT. Methods: The Mayo Clinic cancer registry was queried from 1972-present for all patients who had a diagnosis of MMTVT. Six patients were identified, five of whom were treated with RPLND, where four underwent RARPLND. Data was collected on pertinent demographic, preoperative, perioperative, postoperative outcomes and follow-up oncological data. Results: In five patients who underwent RPLND, the median age was 50 years (IQR 34-51), median BMI was 26.9 (IQR 26.4-30.6). Four patients originally presented with right sided symptomatic hydroceles, while one presented with right sided chronic epididymitis. Orchiectomy (one simple, two inguinal radical) was performed in three patients and hydrocelectomy in the other two patients prior to presentation. Preoperative cross-sectional imaging, including PET-CT scan in three patients, was negative for lymphadenopathy or metastasis. RARPLND was performed in 4/5 (80%) cases and concomitant hemiscrotectomy in 4/5 (80%) cases. Full bilateral template was performed in three patients and right modified template was performed in the remaining two. Median lymph node yield was 29 (IQR 22-32) and median blood loss was 275 cc (IQR 200-300). Positive retroperitoneal lymph nodes were found in 3/5 (60%) cases. Final margins of hemiscrotectomy were negative in all four cases. All patients who underwent RARPLND were discharged home on postoperative day one. One patient received four cycles of adjuvant Cisplatin and Pemetrexed. Mean follow-up was 27 months (range 2-47). No patients recurred. Conclusions: MMTVT is a very rare malignancy with high potential for retroperitoneal lymph node dissemination. Regardless of the approach, RPLND may provide both a diagnostic and therapeutic benefit, with the robotic approach affording a potentially expedited recovery.

BACKGROUND The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a

Background Prostate tissue expresses 2 estrogen receptor (ER) isoforms, ER-α and ER-β, and estrogen-based therapies have shown activity in preclinical studies. Raloxifene, a selective ER modulator, has inhibited the growth of prostate cancer xenograft models and was tested in a phase II trial of castration-resistant prostate cancer (CRPC), with some patients achieving stable disease. However, no studies have examined the safety of the combination of bicalutamide plus raloxifene for CRPC. Therefore, we investigated the safety of treatment with bicalutamide plus raloxifene in patients with CRPC in an initial study. Materials and Methods We conducted a study to evaluate the toxicity (primary endpoint) of the combination of bicalutamide (50 mg) and raloxifene (60 mg) in 28-day cycles (maximum, 6 cycles) in men with progressive CRPC. The secondary endpoint, quality of life (QOL), was assessed by patients using a 6-item linear analog self-assessment or hormonal domain scale of the Expanded Prostate Cancer Index Composite. Results We enrolled 18 patients with CRPC in the study to evaluate the safety of, and patient assessment of QOL (mental, physical, social, emotional, and spiritual) with, bicalutamide plus raloxifene therapy. No grade 3 or 4 adverse events occurred. None of the 18 patients required dose reductions. The patient assessment of QOL showed no statistically significant changes after 2 treatment cycles. The median progression-free survival with bicalutamide plus raloxifene was 1.9 months (95% confidence interval, 1.8-2.8 months). Conclusion The results of the present study have shown that bicalutamide/raloxifene treatment is well tolerated. However, limited clinical activity occurred in men with CRPC who had previously undergone secondary hormonal therapy or chemotherapy.