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In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Background Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy. Methods We queried two institutional clinical databases (Dana-Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan-Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors. Results Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57-1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69-1.16, P = 0.38) in the statin users versus non-users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57-1.10). Conclusions Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide- and docetaxel-naive JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.

Purpose: The use of large-field external beam reirradiation (re-RT) after pelvic radiation therapy (RT) for genitourinary (GU) cancers has not been reported. We report the results of such treatment in patients with either symptomatic GU second malignant neoplasms or locally recurrent pelvic tumors after initial RT for whom surgery or further systemic therapy was not an option. Methods and materials: The records of 28 consecutive patients with advanced, bulky GU malignancies treated with high-dose, large-field re-RT with palliative intent between 2008 and 2014 were retrospectively reviewed. Descriptive outcome analyses focused on toxicities and symptom control, and responses were evaluated by 2 independent observers. Results: Twenty-seven male patients (96%) were included. Median initial external beam RT dose was 64 Gy (range, 30-75.6 Gy). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At the time of re-RT, there were 16 local recurrences and 12 second malignant neoplasms together comprising 16 bladder, 10 prostate, 1 ureteral, and 1 penile cancer. Indications for re-RT were pain and bleeding/hemorrhage. The median equivalent sphere diameter planning target volume for re-RT was 8.6 cm (range, 4.7-16.3 cm). Given the severity of the symptoms and the bulk of the disease at the time of re-RT, a higher dose of RT was administered. The median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received

PURPOSE In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation. PATIENTS AND METHODS Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory. RESULTS Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1–positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1–negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy. CONCLUSION In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1–positive tumors.

PURPOSE Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer. PATIENTS AND METHODS Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored. RESULTS Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. CONCLUSION Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2–4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p = 0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3–4 or pN1 disease who received AC (75% vs 54%; p < 0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p = 0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

Background Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis. Objective To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents. Design, setting, and participants We analyzed two cohorts: an institutional cohort (n = 146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n = 4144) receiving interferon-α (n = 510), mammalian target of rapamycin (mTOR) inhibitors (n = 660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n = 2974) on phase II/III clinical trials. Outcomes measurements and statistical analysis The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors. Results and limitations Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n = 31, 21%) had a lower ORR (12.9% vs 34.8%, p = 0.026) and shorter PFS (adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.20–3.20, p = 0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n = 709, 17%) adversely impacted OS in patients treated with interferon (HR = 1.62, 95% CI 1.13–2.31, p = 0.008) or with VEGF-TT and prior cytokines (HR = 1.65, 95% CI 1.04–2.62, p = 0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration. Conclusions Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs. Patient summary We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use.

Adjuvant therapy for non-metastatic renal cell carcinoma (RCC) remains controversial. Of the four reported randomized controlled trials evaluating adjuvant vascular endothelial growth factor (VEGF) inhibition, only one met its primary endpoint. The S-TRAC study demonstrated a statistically significant improvement in disease-free survival (DFS) of greater than 1 year with adjuvant sunitinib compared to placebo in patients with high-risk localized RCC and earned it FDA approval. However, the larger ASSURE study which reported first did not find a difference in DFS or overall survival between 1 year of adjuvant sunitinib or sorafenib compared to placebo. Given the discordant results of the two sunitinib studies, two other negative studies of adjuvant targeted therapy with pazopanib and axitinib, the lack of definite overall survival benefit in any study, and the high incidence of treatment-related adverse events with sunitinib, we do not recommend the routine use of adjuvant sunitinib. The decision to offer adjuvant sunitinib should be considered on an individual basis after an informed discussion of the potential toxicities and the risk/benefit ratio. Despite numerous efforts and recently published works, there is a paucity of prognostic and predictive molecular biomarkers in RCC. Further investigation is needed to discover new tools that can enhance the identification of patients who are most likely to benefit from adjuvant treatment beyond pathologic stage. Immune checkpoint inhibitors have great potential to significantly improve outcomes in high-risk localized RCC. Building on their established efficacy in the metastatic setting, several ongoing clinical trials are evaluating their value as single agents or in combination in the neoadjuvant and adjuvant settings. At this time, we recommend participation in clinical trials as the preferred therapeutic option for patients with high-risk, non-metastatic RCC planned for nephrectomy.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. Design, setting, and participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic. ±. RP) only, first-line platinum-based chemotherapy given. Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. Outcome measures and statistical analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. Results and limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p = 0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p = 0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. Patient summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies. In contemporary cohorts of patients with metastatic pelvic or retroperitoneal lymph nodes from bladder cancer, we found no survival benefit from postchemotherapy surgery versus observation in a retrospective study. Performing postchemotherapy lymphadenectomy remains investigational in patients with metastatic bladder cancer.

Background The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. Materials and Methods A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. Results Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1–38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7–93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8–17.6) and 49.3% (95% CI: 28.2–67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. Conclusion Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. Implications for Practice Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

Background: Little is known about the outcomes of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) combined with perioperative chemotherapy for muscle-invasive urothelial bladder cancer (UBC). Objective: To evaluate surgical and oncological outcomes for RARC and ORC in multimodal treatment. Design, setting, and participants: Data from 28 centres were collected for cystectomies performed between January 2000 and July 2013. Intervention: RARC or ORC combined with perioperative chemotherapy for UBC. Outcome measures and statistical analysis: Fisher's exact tests, χ2 tests, and Wilcoxon rank-sum tests were used to compare the RARC and ORC groups. Logistic and Cox regression analyses were performed to evaluate potential prognostic factors. Results and limitations: A total of 688 patients (n = 603 ORC and n = 85 RARC) were analysed; 60.6% received neoadjuvant chemotherapy, and 45.1% adjuvant chemotherapy. No significant differences in baseline characteristics were found between the groups. The median time from surgery to adjuvant chemotherapy was 1.9 mo for both RARC and ORC groups. The median number of lymph nodes removed was 21 (interquartile range [IQR] 14-35) for RARC and 13 (IQR 8-21) for ORC (p< 0.001); the results were confirmed in subgroup analyses. Multivariable analyses revealed no difference in the rate of positive surgical margins (p = 0.54 and p = 0.78), rate of neobladder diversion (p = 0.33 and p = 0.51), relapse-free survival (p = 0.31 and p = 0.23), and overall survival (p = 0.63 and p = 0.69). The retrospective nature of the data is the major limitation. Conclusions: In this study, no differences in efficacy outcomes or ability to deliver adjuvant chemotherapy were observed between RARC and ORC. The increasing use of RARC is justifiable from an oncological viewpoint. Patient summary: In a retrospective study of patients who received perioperative chemotherapy for urothelial bladder cancer, we found no difference in key outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy. Performing RARC seems to be justifiable in the multidisciplinary setting. In contemporary cohorts of patients who have received perioperative chemotherapy for muscle-invasive bladder cancer, no substantial differences were found between robot-assited radical cystectomy (RARC) and open radical cystectomy, and the number of lymph nodes removed was higher with RARC.

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes > 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.

310 Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. [Table: see text]

459 Background: First-line platinum-based combination chemotherapy (fPBC) is standard of care for fit patients with mUC. Further lines of therapy include immuno-oncology agents, erdafitinib, and enfortumab vedotin, but patients ineligible for these therapies or who subsequently progress may be considered for further chemotherapy. As the choice of chemotherapy regimen is unclear for these patients, we compared the efficacy of subsequent platinum-based chemotherapy (sPBC) and subsequent non-platinum-based chemotherapy (sNPBC) in patients with mUC. Methods: Data was analyzed from the Retrospective International Study of Cancers of the Urothelium (RISC), comprising patients from 28 international centers treated 2005-2012. Inclusion criteria were diagnosis of mUC, receipt of fPBC for mUC, and receipt of ≥2 cycles of subsequent chemotherapy. Patients who had received prior platinum-based chemotherapy in the non-metastatic setting were excluded. A multivariate Cox proportional hazards model was used to compare overall survival (OS), while χ2 and student’s t-test were used for univariate analyses. A two-sided p value of

BACKGROUND: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start within 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome.METHODS: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Univariate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed using Kruskal-Wallis testing and Fisher's exact test. Analysis of progression-free (PFS) and overall survival (OS) (follow-up time beginning with the start date of adjuvant chemotherapy) was analyzed in relation to S-AC-interval (continuous and dichotomous with a cut-off at 90 days) using Kaplan-Meier method and COX regression analysis.RESULTS: We identified 238 eligible patients (83.5% male, mean age: 63.4 years, 76.1% T3/T4, 66.4% pN+, 14.7% R+, 70.6% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). The majority of patients (n = 207, 87%) started chemotherapy within 90 days after surgery. Median S-AC-interval was 57 days (interquartile range 32.8). S-AC-interval did not have consistent association with any patient/tumor characteristics or surgery related factors (type of surgery, urinary diversion). Survival analysis using continuous S-AC-interval revealed a trend toward an impact of S-AC-interval on OS (hazard ratio 1.004, 95% confidence ratio 0.9997-1.0084, P = 0.071). With regards to PFS, that impact was shown to be statistically significant (hazard ratio 1.004, 95% confidence ratio 1.0003-1.0075, P = 0.032). In multivariate analysis, however, S-AC-interval was negated by tumor and patient related factors (pathological T-stage, N-stage, ECOG performance status). Accounting for eligibility criteria defined in some clinical trials, we extended our analysis dividing S-AC-interval in ≤90 and >90 days. Although we could confirm the trend toward better outcome in patients with a shorter S-AC interval in dichotomous analysis, neither differences in OS nor in PFS reached statistical significance (P = 0.438 and P = 0.056).CONCLUSIONS: In a large multi-institutional experience, 87% of patients who received adjuvant chemotherapy received it within the guideline recommended window of 90 days. While it was not possible to determine whether this is the optimal cut-off, early start of adjuvant chemotherapy seems to be reasonable. Regarding prognosis, tumor-related pathological factors abrogated the importance of the S-AC-interval in our analysis.

Background: Trimodality bladder preservation therapy (BPT) in muscle invasive bladder cancer (MIBC) includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to radical cystectomy (RC) in appropriately selected patients, or as a treatment option in non-cystectomy candidates. Several chemotherapy regimens can be used in BPT, but little is known about current practice patterns. Objective: To describe utilization patterns of BPT and associated survival outcomes in MIBC. Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3,024 consecutive patients from 29 international academic centers from 2005 to 2013. Patients with clinical T2-T4aN0M0 urothelial cancer of the bladder were included. Results: 265 patients received BPT. Compared with the 1,447 patients who received RC, BPT patients were older, had poorer performance status, and had more comorbidities (p

We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer.We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA]20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (2 years).The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending ≥ 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score 8 (AHR = 5.66), and PSA 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P .05 for all).In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.

Background The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity. Methods This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort. Results Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received ≥2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively. Conclusions Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. © 2016 American Cancer Society.

In 2014, more than 74,000 new cases and 15,000 deaths from bladder cancer were estimated to occur. The most reliable prognostic factors for survival are pathologic stage and histologic grade. Accordingly, a good understanding of the pathologic features of these cancers is essential to guide optimal clinical treatment, which requires a multidisciplinary team of pathologists, urologists, radiation oncologists, and medical oncologists. This review highlights several clinical scenarios in which detailed pathologic evaluation and accurate reporting impact clinical management.

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

5005 Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]

e17005 Background: The optimal choice of first-line chemotherapy for urothelial carcinoma (UC) patients who recur after previous cisplatin-based chemotherapy for locally-advanced disease is unclear. Our objective is to compare the efficacy of platinum (PBC) versus non-platinum (NPBC) based first-line chemotherapy regimens for such patients after metastatic recurrence. Methods: Data was collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database consisting of patients with muscle-invasive or advanced UC from 28 centers between 2005 and 2012. Patient inclusion criteria included: 1) UC with no initial metastases (cT2-4, cN0-N3, and cM0), 3) receipt of cisplatin in the locally advanced setting, and 4) receipt of chemotherapy in the first-line metastatic setting. Overall survival (OS) was the primary endpoint. Secondary endpoints included progression-free survival (PFS) and response to chemotherapy. Kaplan-Meier and Cox regression models estimated OS, PFS, and response, adjusting for age, gender, Eastern Cooperative Oncology Group (ECOG-PS), Charlson comorbidity index (CCI), surgery, T and N stage, albumin, creatinine clearance, number of initial cisplatin cycles, and time from last chemotherapy. Results: 152 patients with metastatic UC (88 PBC and 64 NPBC) were analyzed. Twelve (7.9%) patients received local definitive radiation and 7 of these 12 also underwent cystectomy. The most common NPBC regimens included taxanes, gemcitabine, or pemetrexed. The median OS was 8.70 (95% CI: 7.53 to 11.16) and 10.27 months (95% CI: 7.37 to 13.10) for PBC and NPBC (HR: 1.04, 95% CI: .67 – 1.61, p = 0.86), respectively. Multivariable analysis showed an independent prognostic effect on OS for number of previous chemotherapy cycles (3-4 vs. 1-2) (HR: 0.44, 95% CI 0.20 – 0.96, P = 0.03) and whether surgery was performed (HR: 0.44, 95% CI 0.26 – 0.75, P = 0.003). Time from last chemotherapy was not prognostic for OS (HR: 0.99, 95% CI: 0.99 – 1.00, p = 0.19). There were no significant differences for both investigator-designated PFS (HR: 0.84, 95% CI: 0.57 – 1.24, p = .39) and response to chemotherapy between PBC and NPBC (p = 0.57). Conclusions: There is no significant outcome difference between PBC vs. NPBC in patients with metastatic-recurrent urothelial carcinoma who previously received cisplatin-based chemotherapy for locally advanced disease. Those who previously underwent radical surgery or who received 3-4 cycles of cisplatin had better OS with PBC.

5542 Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ≥6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles. Clinical trial information: NCT02141438 . [Table: see text]

BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (pConclusionsThis study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.

698 Background: Several ICIs are approved for use in first and subsequent lines of therapy in mRCC, either alone or in combination with another ICI or targeted therapy. There is limited data on whether patients who receive an ICI derive benefit from a subsequent line of ICI-based therapy. Methods: We reviewed mRCC patients at our institution who were treated with an ICI between 2009 and 2018 having previously received ICI-based therapy. The primary outcomes of interest were radiologic response and time to treatment failure (TTF) on ICI retreatment. Immune-related adverse events (irAEs) were graded using CTCAE v5.0. Results: A total of 31 patients were retreated with an ICI, either alone (n=15) or in combination with another ICI (n=8), tyrosine kinase inhibitor (n=2) or investigational agent (n=6); reasons for discontinuation of prior ICI were disease progression (n=23), toxicity (n=7) and study completion (n=1). Median age at the start of first-line therapy was 62 years and the majority of patients (n=30, 90%) had International Metastatic RCC Database Consortium intermediate- or poor-risk disease; median follow-up was 3.4 years (95% CI 2.5-4.6). The median number of lines of therapy received prior to ICI retreatment was 3 (range 1-7). Of 27 evaluable patients, 3 (11%) had a partial response (PR) to ICI retreatment (2 with ICI-ICI combination therapy and 1 with single-agent ICI), 13 (48%) had stable disease, and 11 (41%) had progressive disease (PD) as their best response; of the 3 with a PR, 2 had a PR and 1 had SD to prior ICI therapy. In comparison, 13 of 31 patients (42%) had a PR or better to first ICI-based therapy, with 4 (13%) having PD. Median TTF on ICI retreatment was 3.2 months (95% CI 1.8-5.2), compared to 8.2 months (3.3-10.0) on prior ICI. 19 patients experienced an irAE with ICI retreatment, with 8 (26%) suffering a grade 3 or higher irAE. Conclusions: Retreatment with ICIs after prior therapy with an ICI was relatively safe but demonstrated limited efficacy. Additional data, ideally from prospective studies, assessing outcomes of retreating patients with ICIs are needed to determine whether using different ICIs in sequence has a role in treatment of mRCC.

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

171 Background: IL-8 (CXCL-8) is a cytokine produced by leukocytes and tumor cells, which promotes inflammation, angiogenesis, anti-apoptosis, and metastasis. Our published training set identified serum IL-8 levels drawn within 28 days of androgen deprivation therapy (ADT) initiation as prognostic for shorter overall survival (OS). We sought to validate this finding using samples from CHAARTED patients treated with ADT +/- docetaxel for mHSPC. Methods: We assayed serum samples drawn ≤28 days from ADT initiation from 233 patients using the same Mesoscale multiplex ELISA assay as the training set. Multivariable Cox proportional hazards models adjusted for ECOG performance status, disease volume, and prior local therapy (radiation/prostatectomy vs. none) with IL-8 as continuous and binary variables. The training median 9.3 pg/mL was the a priori binary cutpoint. Fixed-effects meta-analysis of the training and validation sets was performed. Results: Higher IL-8 levels were prognostic for shorter OS and time to CRPC for ADT alone and ADT + docetaxel (Table) and were independent of disease volume or docetaxel use. Meta-analysis of binary IL-8 levels >9.3pg/mL from patients treated with ADT alone (training + validation cohorts) was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p= 0.007) and shorter time to CRPC (HR: 1.4, 95%CI: 0.99-1.9, p=0.057). The validation cohort’s baseline median IL-8 level was similar at 10 pg/mL. Conclusions: Higher IL-8 is prognostic for shorter time to CRPC and OS independent of docetaxel use, disease volume and presentation with metachronous or de novo metastatic disease. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.[Table: see text]

740 Background: Metastatic vRCC are aggressive tumors with poor prognosis. Our phase 2 trial of AB in vRCC showed a response rate of 33%. We investigated on-therapy changes in circulating immune cells and cytokines and their association with outcomes. Methods: Blood was collected at baseline (C1D1) and on-therapy (C3D1). Peripheral blood mononuclear cells were analyzed for cell type, expression of immune checkpoints, markers of activation, proliferation and function using flow cytometry; circulating cytokines by multiplex immunoassay. Relationship with progression-free (PFS) and overall survival (OS) was assessed by cox regression models. Results: Baseline and on-therapy samples were collected from all 60 patients. High baseline levels of immunosuppressive cytokines IL1α, IL6, CCL4 and IL13, as well as high baseline levels of CD4+ lymphocytes expressing CD69, were associated with inferior PFS and OS (Table). However, a decline in these markers on-therapy was not predictive of outcomes. On-therapy assessments showed an increase in the IFN-γ inducible cytokine CXCL10 (p

Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described.CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy.TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P0.0001) and with visceral metastases (P0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic.TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response.Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135.Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Purpose Data revealed the benefit of high-volume care in many complex disease processes. Among patients undergoing nephrectomy, those receiving cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) constitute a unique subset. They often have a greater medical and surgical complexity. Against this backdrop, we sought to investigate the effect of hospital volume on overall survival among patients undergoing CN for mRCC. Material and methods We identified 11,089 patients who received CN for mRCC in the National Cancer Database from 1998 to 2012. We ranked hospitals based on annual CN volume. Patients who received surgery in hospitals in the top vs. bottom deciles were compared. Inverse Probability of Treatment Weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses were used to compare the primary endpoint of overall survival between balanced cohorts of patients. Secondary endpoints were 30-day mortality, 30-day readmissions, and receipt of subsequent systemic therapy. Results Median follow-up was 60.39 months (interquartile range [IQR] 35.09–95.95). Median overall survival was 17.61 months (IQR 7.16–44.58). Following propensity score weighting, surgery at a high-volume hospital was associated with a decreased risk of mortality (IPTW-adjusted Cox proportional Hazard Ratio = 0.91; 95% confidence interval: 0.86–0.96). On our IPTW-adjusted Kaplan-Meier analysis, the median survival was 19.94 months (IQR 7.98–50.27) at high-volume hospitals vs. 15.97 months (IQR 6.6–41.56) at low-volume hospitals. With regard to secondary endpoints, the data did not reveal a significant advantage for treatment at a high-volume hospital. Conclusion We found a significant association between receipt of CN at high-volume hospitals and prolonged overall survival, demonstrated by a nearly 4 month survival benefit.

Background: Currently, there is no universally accepted prognostic classification for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT). Subgroup analyses demonstrated that pts with low volume (LV), per CHAARTED trial definition, mHSPC, and those who relapse after prior local therapy (PLT) have longer overall survival (OS) compared to high volume (HV) and de-novo (DN), respectively. Using a hospital-based registry, we aimed to assess whether a classification based on time of metastatic disease (PLT vs DN) and disease volume (LV vs HV) are prognostic for mHSPC pts treated with ADT. Methods: A retrospective cohort of consecutive patients with mHSPC treated with ADT between 1990 and 2013 was selected from the prospectively collected Dana-Farber Cancer Institute database and categorized as DN or PLT and HV or LV, at time of ADT start. Primary and secondary endpoints were OS and time to castration-resistant prostate cancer (CRPC), respectively, which were measured from date of ADT start using Kaplan-Meier method. Multivariable Cox proportional hazards models using known prognostic factors was used. Results: The analytical cohort consisted of 436 patients. The median OS and time to CRPC for PLT/LV were 92.4 (95%CI: 80.4-127.2) and 25.6 (95%CI: 21-35.7) months and 43.2 (95%CI: 37.2-56.4) and 12.2 (95%CI: 9.8-14.8) months for DN/HV, respectively, whereas intermediate values were observed for PLT/HV and DN/LV. A robust gradient for both outcomes was observed (Trend test P < 0.0001) in the four groups. In a multivariable analysis, DN presentation, HV, and cancer-related pain were independent prognostic factors. Conclusions: In our hospital-based registry, time of metastatic presentation and disease volume were prognostic for mHSPC pts treated with ADT. This simple prognostic classification system can aid patient counseling and future trial design.

CONTEXT: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC). OBJECTIVE: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3–4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC. EVIDENCE ACQUISITION: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated. EVIDENCE SYNTHESIS: The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n = 1943), sunitinib versus placebo (S-TRAC, n = 615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n = 1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR(random)]: 0.92, 95% confidence interval [CI]: 0.82–1.03, p = 0.16) or OS (HR(random): 0.98, 95% CI: 0.84–1.15, p = 0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3–4 AEs (OR(random): 5.89, 95% CI: 4.85–7.15, p < 0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR(random): 0.83, 95% CI: 0.73–0.95, p = 0.005). CONCLUSIONS: This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs. PATIENT SUMMARY: Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects.

Patients with relapsed or refractory urothelial carcinoma (UC) face a poor prognosis and a dearth of available treatment options that improve their survival. End-organ function and performance status play a vital role in the choice of second-line therapies. Evidence supporting the use of cytotoxic chemotherapy, as single agents or in combination, arises from small phase 2 studies with modest responses. With the evolution of genomic testing in UC, several pathways amenable to available targeted therapies have emerged. Encouraging patient participation in clinical trials is critical to improve patient outcomes and to advance the current modest treatment armamentarium.

The past several years have witnessed a resurgence of interest in cancer immunotherapy. The development of blocking antibodies against the inhibitory programmed death-1 (PD-1) pathway represents a clinical breakthrough in the treatment of solid tumors such as melanoma, and these agents show great promise in renal cell carcinoma (RCC). The early data have been surprising in that they demonstrate that blockade of a single immune checkpoint can elicit objective responses in patients with RCC, despite the recognized complexity of the immunosuppressive tumor microenvironment. Reinvigorating the patient's own immune cells to reactivate and to target the tumor has the potential advantages of more selective killing and thus decreased toxicity. In addition, checkpoint blockade immunotherapy has the advantage of inducing a memory response that is unattainable with our current cytotoxic and targeted therapies. This Crossroads overview will highlight the emerging investigation of PD-1 blockade in RCC and how this T cell–targeted strategy may thwart the tumor's escape mechanisms and shift the immune system/tumor balance back to a state of equilibrium and even to tumor elimination. Cancer Immunol Res; 2(12); 1132–41. ©2014 AACR.

Programmed cell death-1 (PD-1) is a recognized immune checkpoint. It is frequently upregulated on the T cells that infiltrate tumors, providing an inhibitory signal, which may facilitate immune escape. Blocking antibodies have been developed to interrupt the interaction of PD-1 with its ligands PD-L1/PD-L2, with the goal of increasing the host antitumor immune response. Initial results have been encouraging, with durable responses in both treatment-naive and pretreated patients, along with an acceptable toxicity profile. This tolerability makes PD-1 blockade an excellent potential partner for combination strategies with the approved targeted agents, such as tyrosine kinase inhibitors (TKIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies, as well as other investigational immune checkpoint inhibitors or agonist antibodies that may costimulate an immune response. PD-L1 expression on tumor cells and tumor-infiltrating immune cells is also being evaluated as a predictive biomarker of response to treatment. This review summarizes the biological basis, preclinical studies, ongoing trials, and future challenges associated with targeting the PD-1 pathway in renal cell carcinoma.

Worldwide, patients with urothelial carcinoma characterized by a bone-exclusive metastatic spread usually present with poor performance status, have limited access to active therapy, and have a poor outcome. Consequently, treatments offered and outcomes should be improved in this rare subgroup. BACKGROUND: Patients with exclusive bone metastatic spread from urothelial carcinoma (UC) throughout their disease course represent a rare subgroup with unique clinical features. These patients deserved special consideration in a retrospective multicenter study. PATIENTS AND METHODS: Analyses were made from a pool of 1911 patients with a diagnosis of metastatic UC, from 23 centers. Baseline characteristics, access to treatment, and outcomes were analyzed according to metastatic spread. Univariable and multivariable Cox analyses were performed. RESULTS: A total of 128 evaluable patients (6.7%), diagnosed between February 1997 and April 2013, were identified. Eastern Cooperative Oncology Group performance status (PS) was ≥ 2 in 33.3% versus 17.7% of the remaining patients. Seventy-three (57%) received first-line chemotherapy, that was platinum-based in 50 patients (69%). Twenty-eight (21.9%) received second-line chemotherapy (vs. 75.9% and 32.2%, respectively, of the remaining patients). In multivariable analyses, no clinical factor was significantly associated with overall survival (OS). Among platinum chemotherapy-treated patients (total evaluable n = 972), significantly different relapse-free survival (RFS) and OS were observed according to bone metastases status (no bone metastases vs. bone metastases only vs. bone and other sites, P < .001). In these groups, 2-year RFS was 37.4%, 28.8%, and 25.9%, respectively. Two-year OS was 35.5%, 15.8%, and 23%, respectively. CONCLUSION: Patients with metastatic UC and bone-only metastases are less likely to receive systemic therapy than those with other metastases, likely because of their lower PS. The prognostic effect of having exclusive bone metastases or additional sites seems to be equally poor. These patients deserve new effective and tolerable agents, and improvements in the knowledge of their disease.

Overall survival (OS) is a critical endpoint in adjuvant trials but requires long durations to events and significant patient resources. In the current study, the authors assessed whether disease-free survival (DFS) can be an early clinical surrogate for OS in the adjuvant setting for localized renal cell carcinoma (RCC).Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors performed a systematic literature review of PubMed and the American Society of Clinical Oncology, European Society for Medical Oncology, and ClinicalTrial.gov Web sites (1996-2016). Inclusion in the current study required randomized controlled trials (RCTs) of adjuvant systemic therapy for localized RCC after nephrectomy with ≥3 years of outcomes data. Data regarding hazard ratios (HRs) and 5-year event-free rates from Kaplan-Meier estimates were extracted. A trial-level meta-analysis correlated estimates of 5-year DFS and 5-year OS as well as treatment effects (HRs) on these endpoints, weighted by the number of DFS events. R-squared ≥ 0.7 was prespecified as being indicative of a strong correlation and the potential for surrogacy.Thirteen RCTs encompassing 6473 patients who were treated with a variety of systemic therapies met eligibility. Only a modest correlation was observed between 5-year DFS and 5-year OS rates (R-squared, 0.48; 95% confidence interval, 0.14-0.67) and between treatment effects as measured by DFS and OS HRs (R-squared, 0.44; 95% confidence interval, 0.00-0.69).Across RCTs of adjuvant systemic therapy for localized RCC, there was no strong correlation noted between 5-year DFS and 5-year OS rates or between treatment effects on these endpoints. These results highlight the need to identify alternative and more rapid clinical or biologic endpoints to hasten drug development and improve clinical outcomes. Cancer 2018;124:925-33. © 2017 American Cancer Society.

IF 3.156; International audience; Background: Radical cystectomy (RC) and radiochemotherapy (RCT) are curative options for muscle-invasive bladder cancer (MIBC). Optimal treatment strategy remains unclear in elderly patients.Material and methods: Patients aged 80 years old and above with T2-T4aN0-2M0-Mx MIBC were identified in the Retrospective International Study of Cancers of the Urothelial Tract (RISC) database. Patients treated with RC were compared with those treated with RCT. The impact of surgery on overall survival (OS) was assessed using a Cox proportional hazard model. Progression included locoregional and metastatic relapse and was considered a time-dependent variable.Results: Between 1988 and 2015, 92 patients underwent RC and 72 patients had RCT. Median age was 82.5 years (range 80–100) and median follow-up was 2.90 years (range 0.04–11.10). Median OS was 1.99 years (95%CI 1.17–2.76) after RC and 1.97 years (95%CI 1.35–2.64) after RCT (p = .73). Median progression-free survival (PFS) after RC and RCT were 1.25 years (95%CI 0.80–1.75) and 1.52 years (95%CI 1.01–2.04), respectively (p = .54). In multivariate analyses, only disease progression was significantly associated with worse OS (HR = 10.27 (95%CI 6.63–15.91), p

Background Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. Case presentation In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. Conclusions Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor.

Data de publicació electrónica: 24-08-2017 BACKGROUND: Venous thromboembolism (VTE) is common in cancer patients, but there is limited data on patients with urothelial tract tumors (UTT). We previously identified several associative factors for increased VTE rates in patients with metastatic UTT. In this study, we assessed the frequency, associative factors, and impact on survival of VTE in patients with locoregional UTT. METHODS: Patients with locoregional bladder, upper urinary tract, or urethral cancer were included in this multi-center study from 29 academic institutions. Patients with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients with incomplete clinical staging or miscoded/missing data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis of muscle-invasive disease, excluding VTEs diagnosed in the metastatic setting. χ2 statistics tested differences in VTE rates across baseline and treatment-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Overall survival stratified by VTE was estimated using Kaplan-Meier methods and evaluated using the log-rank test. RESULTS: A total of 1732 patients were eligible. There were 132 (7.6%) VTEs. On multivariate analysis, non-urothelial histology (P < .001), clinical Nx stage (P < .001), cardiovascular disease (P = .01), and renal dysfunction (P = .04) were statistically significant baseline factors associated with VTE. Using surgery alone as reference, surgery with perioperative chemotherapy (P = .04) and radiation with concurrent chemotherapy (P = .04) also were significant. CONCLUSIONS: The VTE incidence of 7.6% in locoregional disease is comparable with our previously reported rate in the metastatic setting (8.2%). Similar to our findings in metastatic UTT, non-urothelial histology, renal dysfunction, and CVD was associated with increased VTE risk.

The incidence of localized renal cell carcinoma (RCC) has been steadily increasing, in large part because of the increased use of imaging. Optimizing the management of localized RCC has become one of the leading priorities and foremost challenges within the urologic-oncologic community. Adequate risk stratification of patients following the diagnosis of localized RCC has become meaningful in deciding whether to treat, how to treat, and how intensively to treat. This article characterizes the existing risk assessment models that can be useful as treatment decision aids for patients with localized RCC.

Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6-month VTE incidence rates were determined. The association of first-line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing-risk regression model. VTE patients were matched to non-VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non-urotheilal histology (SHR: 2.67; 95% CI: 1.72–4.16, P P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49–3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P