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Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed. Herein we summarize what is known to date regarding coorelative findings and subgroup analysis and EV response, including novel biopsy data in patients with tumor progression post EV.

Background The value of a complete response to immune checkpoint inhibitor treatment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation. Objective To determine clinical outcomes in patients with a partial response or stable disease on atezolizumab therapy for advanced urinary tract carcinoma (UTC). Design, setting, and participants Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease). Intervention Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211. Outcome measurements and statistical analysis Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately. Results and limitations The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on ≥5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up. Conclusions Stable disease and partial response are meaningful clinical outcomes in atezolizumab-treated patients with advanced UTC. Patient summary In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment.

Objective To better understand the physical and psychosocial components of female sexual dysfunction (FSD) among women undergoing radical cystectomy (RC) for bladder cancer (BCa). Methods We conducted semistructured individual interviews and a focus group with pre- and post-RC female patients and their partners regarding the impact of RC on sexual health and psychosocial wellbeing. Themes were inductively identified by 2 independent coders and subsequently organized into themes and subthemes using qualitative description and constant comparison. Results In the preoperative cohort, 6 women and 1 partner participated (50% contact rate, 75% participation rate). In the postoperative cohort, 16 women and 2 partners participated (61% contact rate, 64% participation rate). Major themes that emerged in interviews with both cohorts included concerns about changes to body image, the psychological impact of BCa diagnosis and treatment, concerns about the impact of RC on sexual function, and inadequacies in provider-led sexual health counseling. Participants varied in the importance they placed on sexual function, with factors such as age, relationship status, and oncologic concerns impacting prioritization, although both younger and older patients expressed a desire to retain the option of sexual function. Conclusion Female patients with BCa undergoing RC experience changes in body image, psychological distress, physical disruptions in sexual function, and inadequacies in sexual health counseling and education. Future efforts should be directed towards improving sexual health counseling and psychosocial support resources for women with BCa.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. Patient summary Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

Background: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic mutations in specific gene pathways including DNA damage response genes. Objective: To evaluate the ability of post-NAC clinical restaging, with or without tumor sequencing, to predict final RC pathologic staging. Design, setting, and participants: We reviewed our institutional review board–approved institutional database to identify patients with MIBC who underwent NAC followed by RC from 2003 to 2016. Following NAC prior to RC, cystoscopy was performed routinely, with resection of residual visible tumor and/or tumor base (transurethral resection [TUR]). For patients with pre-NAC tumor tissue available, tumor sequencing was performed. Outcome measurements and statistical analysis: Clinical restaging and tumor sequencing were evaluated for their ability to predict the final pathologic stage accurately at RC using chi-square or Fisher’s exact test. Results and limitations: A total of 114 patients underwent restaging TUR following NAC and prior to RC. The diagnostic accuracy of post-NAC clinical restaging including TUR was poor, with 32% of patients being downstaged falsely when compared with their final RC pathology. Forty-nine patients had sequencing of pre-NAC tumor tissue, of whom 32 showed at least one mutation of interest. However, NAC responses and rates of false downstaging did not differ significantly according to tumor mutation status. Conclusions: This study highlights the inaccuracy of post-NAC clinical restaging TUR with or without adjunctive tumor mutation analysis, to assess pathologic residual disease accurately. Caution must be taken when performing post-NAC restaging, especially when considering conservative management strategies such as active surveillance on this basis. Patient summary: Several groups are evaluating whether certain patients, whose bladder cancer responds well to upfront chemotherapy, may be able to forego cystectomy safely. We demonstrate that currently available staging tools and tumor DNA sequencing cannot identify such patients reliably and accurately.

Immunohistochemical stains have been suggested to aid in diagnostically challenging cases of urothelial carcinoma in-situ (CIS). Although full thickness immunostaining for CK20 is supportive of CIS, a subset of CIS cases is CK20(-), the clinical significance of which was unknown. This study included 43 patients with primary diagnosis of bladder CIS including 32 with only CIS, 5 with CIS and separate noninvasive high-grade papillary urothelial carcinoma, and 6 with CIS and separate high-grade urothelial carcinoma with lamina propria invasion. Digital morphometric image analysis showed that the average nuclear areas of enlarged nuclei were similar in CK20(+) and CK20(-) CIS (26.9 vs. 24.5 µM2; P=0.31). Average Ki67 index for CK20(+) CIS was higher than CK20(-) CIS (31.1% vs. 18.3%; P=0.03). Patients with CK20(+) CIS [28 (65%)] and patients with CK20(-) CIS [15 (35%)] had the same rates of Bacillus Calmete-Guerin (BCG) failure but patients with CK20(-) CIS had higher stage progression [3 CK20(+) (11%) vs. 6 CK20(-) (40%); P=0.02]. Given recent approval of immune checkpoint inhibitors in patients with CIS refractory to BCG, programmed death ligand-1 expression and colocalization with CD8(+) lymphocytes was investigated as signature of adaptive immune response and was seen in 8 patients regardless of CK20 status and exclusively among patients who failed BCG. Our results confirm that negative CK20 IHC does not exclude CIS and that those patients have similar clinical outcomes as patients with CK20(+) CIS. Programmed death ligand-1 and CD8 colocalization seen among patients who failed BCG therapy is an easy assay to perform to identify patients who could potentially benefit from combined BCG therapy and immune checkpoint inhibition.

Background, context and purpose In spite of the mixed evidence for their impact, survivorship Care Plans (SCPs) are recommended to enhance quality of care for cancer survivors. Data on the feasibility of SCPs in bladder cancer (BC) is sparse. Using a mixed-methods approach, this study describes the iterative development, acceptability and feasibility of BC specific SCP (BC-SCP) in clinical settings. Methods In Phase I, we developed the BC-SCP. In Phase II, we conducted four focus groups with 19 patients and 15 providers to examine its acceptability and usability challenges. Data analyses using the Atlas.ti program, informed refinement of the BC-SCP. In Phase III, we conducted feasibility testing of the refined BC-SCP with 18 providers from 12 health-centers. An encounter survey was completed after each assessment to examine the feasibility of the BC-SCP. Chi-square and Fisher Exact tests were used for comparative analyses. Results During phase I, we observed high patient and provider acceptability of the BC-SCP and substantial engagement in improving its content, design, and structure. In Phase II, providers completed 59 BC-SCPs. Mean time for BC-SCP completion was 12.3 min. Providers reported that BC-SCP content was clear, did not hamper clinic flow and was readily completed with easy-to-access information. Comparative analyses to examine differences in SCP completion time by patient clinico-demographic characteristics and provider type revealed no significant differences. Conclusions Our BC-SCP has clinical relevance, and can be used in an active practice setting. However, considerable progress will be necessary to achieve implementation of and sharing the BC-SCP with patients and care providers, particularly within the electronic medical record. In summary, BC-SCPs are essential to improve the follow up care of BC survivors. Clinical resources are required to ensure appropriate implementation of BC-SCPs. Trial registration Study HUM00056082.

Purpose Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer. Methods and Materials Twenty men were enrolled in this institutuional review board–approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. Results With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain. Conclusions This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed.

Objectives There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors. Materials and methods mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Results Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). Conclusion Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

Summary Background Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. Method In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Findings Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. Interpretation To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. Funding F Hoffmann-La Roche/Genentech.

Introduction Small cell subtype is a rare and aggressive variant of bladder and upper tract cancers. Due to poor prognosis, patients with any component of this variant are often excluded from clinical trials, thus activity of novel agents in this population is unknown. Patients and Methods We retrospectively reviewed the Johns Hopkins Greenberg Bladder Cancer Center’s database of patients with small cell variant bladder and upper tract cancer treated with checkpoint inhibitors in the second line and beyond between 2014 – 2019. Results Out of 5 identified patients, 3 demonstrated radiographic response. Toxicity of checkpoint inhibitor therapy post platinum was similar to that described in conventional urothelial cancer. Incidence of TP53 and RB alterations were high in this group, as has been previously reported with this subtype. Conclusion Our series indicates small cell variant bladder cancers are sensitive to checkpoint inhibitor immunotherapy. Inclusion, rather than exclusion of patients with variant subtype histology to clinical trials with novel agents, will better serve patients with historically poorer prognosis than those with conventional urothelial cancer.

Background Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the “on-target” class effect of FGFR1 inhibition. Objective To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. Intervention Oral infigratinib 125 mg/d for 21 d every 28 d. Design, setting, and participants Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. Outcome measurements and statistical analysis Clinical outcomes were compared in groups with/without hyperphosphatemia. Results and limitations Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4–48.4) versus 5.3% (95% CI 0.1–26.0); disease control rate 75.0% (95% CI 60.4–86.4) versus 36.8% (95% CI 16.3–61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. Conclusions This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. Patient summary Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.

Purpose: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. Experimental Design: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. Results: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. Conclusions: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven. See related commentary by Jiang and Greenberg, p. 1833

BackgroundAtezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not well characterized.ObjectiveTo report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP).Design, setting, and participantsA total of 218 patients were enrolled at 36 US study sites (November 2015–August 2016), and the trial ended following the approval of atezolizumab by the US Food and Drug Administration. This post hoc analysis investigated outcomes in specific study subgroups.InterventionAtezolizumab 1200 mg was administered intravenously every 3 weeks until loss of clinical benefit, unacceptable toxicity, death, consent withdrawal, decision to discontinue, commercial availability, or study closure.Outcome measurements and statistical analysisResponse Evaluation Criteria in Solid Tumors V.1.1 responses and safety were evaluated by baseline renal function and histology.Results and limitationsObjective responses occurred in 0/6 (0%), 4/19 (21%), 1/27 (3.7%), and 12/62 (19%) of evaluable patients with creatinine clearance (CrCl) ConclusionsIn this EAP mUC subgroup analysis, clinical benefit of atezolizumab occurred in patients with compromised renal function or MVH UC tumors. Safety was comparable across subgroups.Patient summaryWe examined the efficacy and safety of atezolizumab for UC in certain patients participating in an EAP. We found that responses to atezolizumab occurred, and safety was similar, in most patient subgroups with varying levels of kidney functioning or less common types of tumor tissue histology.

Cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in muscle invasive bladder cancer (MIBC). However, only a subset of patients (25–50%) have pathologic complete response at cystectomy. Using a cohort of patients (n = 58) from two phase II trials, our group previously reported that mutations in the ATM, RB1, and FANCC genes correlate with complete response to cisplatin-based NAC, and consequently improved overall and disease specific survival. These trials enrolled patients with T2-T4 (N0 or N1) MIBC and treated them with dose dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or Gem/Cis (gemcitabine and cisplatin) with plan for curative cystectomy. Updated long-term follow up (median follow-up = 74 months) shows that patients with mutations in ATM, RB1 or FANCC maintained significantly greater OS and DSS. The 5-year-survival rate for patients with at least one mutation was 85% compared to 45% for patients without a mutation. Based on the association with response, long-term OS and DSS, we propose that these alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients who are most likely to benefit from NAC prior to radical cystectomy. PATIENT SUMMARY: (2–3 short sentences in plain English to describe your findings to a non-medical audience. For example: “In this report we looked at the outcomes from invasive bladder cancer in a large European population. We found that outcomes varied with patient age and treating centre. We conclude that the best outcomes are seen in younger patients treated at high volume hospitals.”): In this report we looked at the outcomes for patients with muscle-invasive bladder cancer treated with cisplatin-based chemotherapy before surgery (neoadjuvant) who had mutations in a set of DNA damage repair genes (ATM, RB1, FANCC) compared to those who did not. We found that patients who had at least one mutation in one of these genes survived longer after receiving cisplatin chemotherapy before surgery than patients who did not.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781

Atezolizumab (anti-programmed death-ligand 1) was approved in the USA, Europe, and elsewhere for treatment-naive and platinum-treated locally advanced/metastatic urothelial carcinoma (mUC).To report efficacy and safety from an atezolizumab expanded access study.This single-arm, open-label study enrolled 218 patients at 36 US sites. Key eligibility criteria included progression during/following ≥1 platinum-based chemotherapy for mUC or in perioperative setting (progression within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2.Patients received atezolizumab1200mg intravenously every 3 wk until loss of clinical benefit, unacceptable toxicity, consent withdrawal, decision to discontinue, death, atezolizumab commercial availability, or study closure.Key end points reported herein included Response Evaluation Criteria in Solid Tumors v1.1 objective response rate and duration, disease control rate (DCR; response or stable disease), and safety.All patients received prior systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57% of 214 treated patients had ECOG PS ≥1, 19% had hemoglobin10g/dl, and 25% had liver metastases. Median treatment duration was 9 wk (interquartile range [IQR], 6-12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6-3.4 mo) overall and 2.7 mo (IQR, 2.0-3.5 mo) in patients not known to have died. Seventeen of 114 evaluable patients (15%) had objective responses (16 ongoing at study termination). DCR was 49%. Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients.The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1-3 studies.In this expanded access study, atezolizumab was active and tolerable in a range of patients with platinum-treated metastatic urothelial carcinoma.

Urothelial carcinoma of the bladder is a common malignancy which has historically been difficult to treat in its advanced stages. Clinically effective treatment options for locally advanced/inoperable or metastatic urothelial carcinoma (mUC) consisted of cisplatin-based chemotherapy regimens, with few other impactful therapeutic options. The past 2 years have seen a remarkable shift in the therapeutic landscape of mUC, with 5 novel immunotherapy agents receiving FDA approval for mUC, including first-line and second-line postplatinum settings. There are now many important clinical trials ongoing seeking to answer how best to use chemotherapy, immunotherapy, and targeted therapy agents in patients with mUC. Here we review the current standard of care for patients with mUC based on published data from the past 2 years, and look forward toward future research directions.

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies., The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.

Background Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator’s discretion: this analysis assessed post-progression outcomes in these patients. Patients and methods Patients were treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. Results In total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for ≥ 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. Conclusion In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma. ClinicalTrials.gov ID NCT02108652.

Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies for toxicity management. Additionally, we summarize the studies that address cabazitaxel treatment sequencing and optimal dosing schedule.

Background Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings. Methods Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized. Results A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%). Conclusions Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.

INTRODUCTION AND OBJECTIVES:We sought to assess if pembrolizumab (pembro) improves the pathologic response rate in locally advanced urothelial carcinoma (UC) when combined with gemcitabine (G) and ...

397 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT have potential short and long-term toxicity and QOL implications. Mutations in DNA damage repair/response genes are associated with pathologic downstaging after NAC. Methods: We conducted a phase II, multi-institutional clinical trial (NCT02710734) to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Pre-NAC TURBT specimens were sequenced (Caris Life Sciences) for mutations (pathogenic or VUS) in ATM, ERCC2, FANCC or RB1. Pts with at least one mutation and no clinical evidence of disease by restaging TUR and imaging post-NAC began pre-defined active surveillance (AS). Remaining pts underwent bladder-directed therapy: intravesical therapy ( < cT2 post-NAC), CRT or Cx. The primary endpoint was metastasis-free survival (MFS) at 2 years which is not mature. We herein report key interim results of clinically-meaningful intermediate endpoints. Results: Seventy-one (ITT) pts were enrolled over 33 months at four academic centers. Median age was 70 years (47-83), 74% were male, 92% Caucasian, 81% ECOG PS 0 and 79% cT2. 90% completed 3 cycles of NAC and with 17% grade 3-4 TRAEs and one death during AMVAC. At the time of data cut-off (September 11, 2020), for the ITT pts, 32 pts have had a Cx, 5 underwent CRT and 7 underwent intravesical therapy, at some point during the trial. Thirty-three pts (46%) had a mutation of interest and 28 pts (39%) started AS (2 of the 28 pts on AS did not have a mutation but elected to start AS after achieving cT0 post AMVAC). 76% of those with a mutation were cT0 at post-NAC TURBT. With a median follow-up of 14.9 mo (range: 3.1-35.3 mo), 14 AS pts recurred (50%). Of the 14 recurrences, 2 recurred with locally advanced or metastatic disease and have died, 5 had MIBC with one eventual metastatic recurrence, and 7 had NMIBC. Six (14%) non-AS pts have died. Out of the 40 pts who did not go to upfront Cx [AS (N = 28), CRT (N = 5), intravesical tx (N = 7)], 3 (7.5%) (all in the AS group) went on to Cx later. The bladder preservation rate is 55% for ITT pts and 89% for the AS group. In the AS cohort, mutations were seen in RB1 (50%), ATM (42%), ERCC2 (31%), FANCC (4%) with lowest rate for recurrence in ERCC2 (25% recurrence) vs RB1 (62% recurrence). Conclusions: Interim results of a phase II trial of risk enabled therapy utilizing a selection of clinical and genomic factors in pts with cT2-T3 MIBC demonstrates a 50% rate of any UC recurrence and a 11% rate of locally advanced/metastatic disease in the AS group. 89% of AS pts have retained their bladder. Follow-up continues for the primary endpoint of 2-year MFS. Clinical trial information: NCT02710734.

Purpose Metastatic recurrence occurs in over 25% of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. While metastatic recurrence suggests poor prognosis, the impact of the specific site of recurrence on prognosis is not well documented. Materials and methods We retrospectively analyzed 188 patients who underwent radical nephroureterectomy for high-grade, node-negative upper tract urothelial carcinoma at our institution from 2003 to 2018 without receiving neoadjuvant or adjuvant chemotherapy. Competing-risks survival analysis was performed to evaluate the cumulative incidence and predictors of metastatic recurrence. The Kaplan-Meier method and log-rank test were used to estimate and compare recurrence site-specific survival probabilities following metastatic recurrence. Cox regression analyses were performed to assess site-specific prognoses. Results Of the 188 patients, 47 (25%) developed metastatic recurrence over a median follow-up of 30 months (interquartile range: 10.5–58.5 months). The 1- and 2-year cumulative incidences of metastatic recurrence were 13.6% and 23.6%, respectively. On multivariable analysis, lymphovascular invasion was significantly predictive of metastatic recurrence (subhazard ratio: 2.6, P = 0.01). Of the 47 patients who developed recurrence, 38 (80.9%) died over a median follow-up of 10 months (interquartile range: 5–20 months). Metastatic recurrence was most common in the lungs (n= 13, 28%) and at multiple sites (n= 14, 30%). Median time to recurrence was shorter for recurrences at multiple sites (6.5 months) and those in the liver (13 months) and bone (18 months) compared to other sites. Patients who recurred in the liver (hazard ratio: 6.3, P = 0.007), bone (hazard ratio: 4.9, P = 0.02), and multiple sites (hazard ratio: 4.6, P = 0.01) had significantly worse prognosis compared to those who recurred in lymph nodes. Statistical significance persisted after adjusting for treatment with salvage therapy. Conclusions A significant proportion of high-grade upper tract urothelial carcinoma patients recur systemically after radical nephroureterectomy. Lymphovascular invasion is a predictor of metastatic recurrence and may inform decisions regarding perioperative chemotherapy. Hepatic and osseous recurrences have relatively quicker onset and less favorable prognosis compared to other sites. These findings may benefit future efforts to develop recurrence site-specific treatment plans and highlight the necessity of subsequent endeavors to explore the genetic associations of recurrence in upper tract urothelial carcinoma.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

5038 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), previously reported to be effective and well tolerated in patients with locally advanced/unresectable or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al. Cancer Discovery 2018]. However, this previous study did not examine differences in infigratinib activity based on number of prior lines of treatment (LOT). TKIs studied in other indications (e.g. VEGFRis in renal cell carcinoma) have shown consistent activity in both the first and later LOT. Given the effect seen with other TKIs, we sought to determine if infigratinib showed consistent treatment responses in patients with mUC according to LOT. Methods: Eligible patients had mUC and prior platinum-based chemotherapy unless contraindicated and activating FGFR3 mutations/fusions. Infigratinib was dosed at 125 mg orally daily (3 weeks on/1 week off). The primary endpoint of objective response rate (ORR: partial response [PR] and complete response [CR]) was assessed, as well as disease control rate (DCR: CR + PR + stable disease [SD]). After classification of LOT for each patient, subgroup analysis of response by LOT was performed. Results: 67 patients were enrolled; 81% received ≥1 prior LOT for mUC. 13 patients (19.4%) received infigratinib as 1st LOT for mUC due to ineligibility to receive platinum-based chemotherapy. ORR for the 67 patients was 25% (95% CI 15.5–37.5) and DCR was 64% (95% CI 51.5–75.5). The ORR with 1st-line infigratinib was 31% (95% CI 9.1–61.4) compared with 24% (95% CI 13.5–37.6) for 2nd and later (salvage) LOT. DCR was 46% (95% CI 19.2–74.9) for 1st-line and 69% (95% CI 54.4–80.5) for ≥2 LOT. 13 of the 59 patients with urothelial bladder carcinoma (UBC) received 1st-line treatment with an ORR of 31% (95% CI 9.1–61.4) and 46 patients in ≥2 LOT had an ORR of 20% (95% CI 9.4–33.9). All 8 patients with upper tract urothelial carcinoma (UTUC) received salvage therapy, with an ORR of 50% and a DCR of 100%. An analysis of other outcome measures (e.g. PFS, OS) will be presented. Conclusions: These results indicate that infigratinib has activity in patients with mUC regardless of LOT. Additionally, patients with UTUC showed a trend for better ORR and DCR. Taken together, these results support the ongoing adjuvant PROOF 302 study comparing infigratinib with placebo in patients with resected disease, assessing infigratinib in an even earlier setting in a UTUC-enriched population (NCT04197986). Clinical trial information: NCT01004224 .

5047 Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, ≤pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% > cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766 .

5000 Background: Radical surgery ± cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti–PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled ≤ 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 < 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 ≥ 5%; n = 392). 16% of atezo-treated pts had a tx-related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331 . [Table: see text]

576 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant clinical activity in aUC bearing FGFR3 alterations. A common adverse event is hyperphosphatemia, a class effect associated with FGFR1 inhibition. We sought to better understand the relationship between hyperphosphatemia and response to infigratinib in patients with aUC. Methods: Eligible patients had aUC with activating FGFR3 mutations/fusions and had received prior platinum-based chemotherapy, unless contraindicated. Patients received infigratinib 125 mg orally daily (3w on/1w off) until disease progression or unacceptable toxicity. Calcium and phosphate levels within normal limits were required at enrollment. Efficacy was assessed by overall response rate (ORR) and disease control rate (DCR) based on RECIST 1.0 criteria. All patients received prophylaxis with the oral phosphate binder sevelamer. Hyperphosphatemia was defined as serum phosphorous >5.5 mg/dL, consistent with the threshold for action in the protocol. Results: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on ≥1 post-baseline lab test. Efficacy findings in patients with vs without hyperphosphatemia were: ORR 33.3% (95% CI 20.4–48.4) vs 5.3% (95% CI 0.1–26.0), mPFS 4.9 months (95% CI 3.65–5.98) vs 1.84 months (95% CI 1.28–3.48), and mOS 8.74 months (95% CI 5.72–13.67) vs 7.62 months (95% CI 2.53–15.57). Median treatment length was 4.1 vs 1.4 months and mDOR was 5.0 vs 3.7 months for patients with vs without hyperphosphatemia, respectively. A landmark analysis at the 1-month mark was performed, and hyperphosphatemia (Y/N) was determined based on lab tests within the first month. The differences in efficacy outcomes were still observed. Conclusions: Hyperphosphatemia is a well-described class effect and pharmacodynamic biomarker of FGFR inhibitors, including infigratinib, and is generally reversible/easily managed with diet and phosphate binders. Our data support prior observations with FGFR inhibitors, suggesting that hyperphosphatemia is associated with treatment response and is not negatively associated with treatment length. Clinical trial information: NCT01004224.

BACKGROUND: Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. OBJECTIVE: To determine the safety and efficacy of neoadjuvant DDGC in MIBC. DESIGN, SETTING, AND PARTICIPANTS: Patients with cT2–4a, N0–1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. RESULTS AND LIMITATIONS: Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16–49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1–25%) were downstaged to non–muscle-invasive (

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA—a clinically heterogeneous disease.

Background Multidisciplinary clinics integrate the expertise of several specialties to provide effective treatment to patients. This exposure is especially relevant in the management of muscle-invasive bladder cancer (MIBC), which requires critical input from urology, radiation oncology, and medical oncology, among other supportive specialties. Materials and Methods In the present study, we sought to catalog the different styles of multidisciplinary care models used in the management of MIBC and to identify barriers to their implementation. We surveyed providers from academic and community practices regarding their currently implemented multidisciplinary care models, available resources, and perceived barriers using the Bladder Cancer Advocacy Network and the Genitourinary Medical Oncologists of Canada e-mail databases. Results Of the 101 responding providers, most practiced at academic institutions in the United States (61%) or Canada (29%), and only 7% were from community practices. The most frequently used model was sequential visits on different days (57%), followed by sequential same-day (39%) and concurrent (1 visit with all providers; 22%) models. However, most practitioners preferred a multidisciplinary clinic involving sequential same-day (41%) or concurrent (26%) visits. The lack of clinic space (58%), funding (41%), staff (40%), and time (32%) were the most common barriers to implementing a multidisciplinary clinic. Conclusion Most surveyed practitioners at academic centers use some form of a multidisciplinary care model for patients with MIBC. The major barriers to more integrated multidisciplinary clinics were limited time and resources rather than a lack of provider enthusiasm. Future studies should incorporate patient preferences, further evaluate practice patterns in community settings, and assess their effects on patient outcomes.

Background A randomised study to assess the addition of apatorsen, an antisense oligonucleotide that inhibits Hsp27 expression, to docetaxel in patients with metastatic urothelial carcinoma (mUC) relapsed after prior platinum-based chemotherapy. Methods Multicentre, phase II study with 1:1 randomisation to apatorsen (three loading doses at 600 mg intravenous followed by weekly doses) plus docetaxel (75 mg/m2 intravenous every 21 days) (A/D) or docetaxel alone. Overall survival (OS) was the primary end point with a P value 20.5% increase. Conclusions A/D met its predefined OS end point in patients with platinum-refractory mUC in this phase II trial. This trial is hypothesis generating requiring further study before informing practice.

Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone.In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6).Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×10/L in patients receiving Radium alone, versus 2.3×10/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×10 cells/L in patients receiving Radium alone versus 70.6×10 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24).Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.

SummaryMuscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

4510 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant activity in patients (pts) with advanced or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al 2018]. Given the distinct biologic characteristics of upper tract UC (UTUC) and urothelial carcinoma of the bladder (UCB), we sought to determine if infigratinib had varying activity in these settings. Methods: Eligible pts had mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy, unless contraindicated. Pts received infigratinib 125 mg orally daily (3 wks on/1 wk off). Overall response rate (ORR: CR+PR) and disease control rate (DCR; CR+PR+SD) were characterized in UCB and UTUC pts. Comprehensive genomic profiling was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA). Blood was collected for cell-free (cf)DNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer. Results: 67 pts were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. ORR was 25.4% and DCR was 64.2%. In the 8 pts with UTUC, 1 CR and 3 PRs were observed (ORR 50%); the remainder had a best response of SD (DCR 100%). UTUC pts were predominantly 2nd line (62.5%), with only 2 (25%) showing response to previous treatment. In pts with UCB, 13 PRs were observed (ORR 22%), and 22 pts had a best response of SD (DCR 59.3%). Notable differences in genomic alterations between cohorts included a higher frequency of FGFR3-TACC3 fusions (12.5% vs 5.8%) and FGFR3 R248C mutations (50% vs 11.5%), and a lower frequency of FGFR3 S249C mutations (25% vs 59.6%) in UTUC vs UCB. Consistent with previous reports [Sfakianos et al 2016], UTUC pts had a differential frequency of alterations in HRAS, CDKN2B and ARID1A. Sufficient cfDNA yield was obtained in UTUC and UCB pts and a comprehensive comparison of these data will be presented. Conclusions: Differences in cumulative genomic profile were observed between UCB and UTUC in this FGFR3-restricted experience, underscoring the distinct biology of these diseases. Results with infigratinib in UTUC support a planned phase III adjuvant study predominantly in this population. Clinical trial information: NCT01004224.

394 Background: Cisplatin-based chemotherapy is currently the standard 1L treatment for mUC, but many pts are ineligible and progression is common. Atezo (anti–PD-L1) is approved for certain types of mUC, and long-term efficacy and safety have been shown (Balar, ASCO 2018). Elderly pts in particular tend to have poor outcomes and may be chemotherapy intolerant, so this analysis sought to evaluate clinical outcomes in pts aged ≥ 65 and ≥ 75 y from the Phase II IMvigor210 study. Methods: This 2-cohort, single-arm study enrolled pts ineligible for 1L cisplatin and previously platinum-treated pts. Atezo 1200 mg IV q3w was given until PD (Cohort 1) or loss of clinical benefit (Cohort 2). RECIST v1.1 ORR (independent review; primary endpoint) and DOR and OS (secondary) were evaluated in pt subgroups based on PD-L1 status and age. Results: Evaluable pts as of July 12, 2018, are shown in the Table. In Cohort 1 pts ≥ 75 y, ORR was 29% overall, CR rate was 8%, DOR was NE and median OS was 21.4 mo. In Cohort 2 pts ≥ 75 y, ORR was 23%, CR rate was 7%, mDOR was 20.9 mo and mOS was 9.2 mo. Updated safety analyses in elderly pts will be presented. Conclusions: Efficacy outcomes in IMvigor210 elderly pts with mUC, and PD-L1 subgroup analysis appear generally consistent with those in the overall population in this long-term analysis. (Cohort 1; Balar Lancet 2017; NCT02951767). (Cohort 2; Rosenberg Lancet 2016; NCT02108652). Clinical trial information: NCT02951767 and NCT02108652. [Table: see text]

Purpose of review Combination immunotherapy has already shown promise in several tumor types, such as melanoma and nonsmall cell lung cancer, and studies are ongoing to evaluate this approach in other malignancies. Trials such as these will only continue to expand as additional immune therapies are shown to have efficacy as single agents in cancer. The purpose of this review is to outline the current landscape of immunotherapy in genitourinary cancer, and to highlight ongoing and pending combination immunotherapy trials in bladder, kidney, and prostate cancers. Recent findings Immunotherapy agents have long been a part of the treatment armamentarium for patients with bladder, kidney, and prostate cancers, contributing to responses with variable toxicities.In the last year, checkpoint blockade immunotherapy has been Food and Drug Administration approved for renal and bladder cancer, whereas novel vaccines continue to be tested in prostate cancer. The efficacy coupled with mostly mild toxicity of modern immunotherapy make these agents perfect vehicles for combination, sequence, or priming studies to maximize benefit. Published and recently presented combination immunotherapy studies in genitourinary malignancies are summarized. Summary Immune therapy strategies are integral to the treatment of bladder, kidney, and prostate cancers. Though the current experience with combination immunotherapy in these cancers is limited, ongoing and maturing studies of combination immunotherapy discussed herein may lead to improved outcomes for patients and change in standard of care. What is learned from correlative data on tumor microenvironment and systemic immune response before, during and following immunotherapy will be integral to the future design of combination immunotherapy trials.

Lessons Learned Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone. There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 3+3 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

Background Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

Background Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. Methods For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged >= 18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an a level of 0.05. This study is registered with ClinicalTrials.gov, number NCT02108652. Findings Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (= 1% but < 5%), and IC2/3 (>= 5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p< 0.0001; IC1/2/3: 18% [13-24], p= 0.0004) and in all patients (15% [11-20], p= 0.0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95% CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. Interpretation Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.

4523Background: Platinum-based chemotherapy is a standard first-line approach for mUC, but many pts are ineligible for cisplatin, and progression is common. Atezo (anti–PD-L1) was approved for firs...

TPS384 Background: Current data suggests RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). Recent findings identified perturbations of the RB tumor suppressor as a major mechanism of androgen receptor (AR) deregulation and castration-resistant prostate cancer (CRPC) formation. Our preclinical studies indicate RB+ tumors are exquisitely responsive to CDK4/6 inhibitors, revealing tumor-specific cytostatic and cytotoxic effects. These analyses strongly support the use of CDK4/6 inhibitors to activate the RB pathway, and impede the transition to CRPC. We hypothesize the CDK4/6 inhibitor ribociclib (ribo) in combination with enzalutamide (enz) in patients (pts) with progressive metastatic CRPC (mCRPC) that retains RB expression will significantly increase the efficacy of enz. Methods: This is a phase IB/II study of pts with mCRPC with RB+ tumors who have not received chemotherapy. Since ribo and enz have not been combined together in pts, the standard doses of enz and a traditional 3x3 dose escalation schema will be used in phase I to establish the safe dose of the combination; this dose will be used in phase II. Since both drugs are metabolized via the liver, plasma concentrations of ribo and enz will be monitored. To determine if ribo will improve the clinical activity in pts treated with enz, a randomized (1:1) phase II study using enz as the control arm vs. the combination will follow. This study will evaluate an early clinical activity readout, thus the primary phase II endpoint will be a proportion of pts with ≥ 50% PSA decline at 12 weeks. Secondary endpoints are rPFS, PSA PFS, OS and safety. If there is clinical activity noted, further randomized testing will be required to establish ribo clinical benefit in combination with enz. 5 sites are participating, managed by the Prostate Cancer Clinical Trials Consortium. Dose Levels 1 and 2 have been completed without any DLTs in the phase I portion of the study. A review of Dose Level 3 is planned for October 2017. Clinical trial information: NCT02555189.