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E3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen-deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study.We performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal-Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival.In 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p 0.0001) and poorer baseline QOL on functional assessment of cancer therapy-prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81-1.63, p = 0.44).There was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.

Supplementary Figure 3. Kaplan-Meier OS curves by dichotomized angiokines: VEGF-D, VEGF, VEGF-R1, PDGF-AA, TGF-b1, VEGF-R3, HER-3, BMP-9, CD-73, VEGF-R2, TGF-b2, SDF-1, PDGF-BB, and TGFb-R3

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PDF file - 883K, Patient disposition by treatment group. IP, investigational product; MP, mitoxantrone and prednisone. *Patient had a decrease in hemoglobin prior to administration of IP on day 1 of cycle 1. �Patient had delays to cycles prior to cycle 12.

Supplementary Data from Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

PDF file - 1418K, Forest plot of the treatment effect of rilotumumab compared with placebo on OS by covariate subgroups in the intention-to-treat analysis set. ECOG, Eastern Cooperative Oncology Group; PD, progressive disease.

Supplementary Figure 4A. Kaplan-Meier PFS curves by treatment and dichotomized angiokines groups for following angiokines: TGFb-R3, HGF, TSP-2, OPN, IL-6, SDF-1, Ang-2, ICAM-1, TGF-b2, TIMP-1, BMP-9, PDGF-BB, VCAM-1, PDGF-AA, VEGF-D, TGF-b1, VEGF-R1, HER-3, VEGF, PlGF, CD-73, VEGF-R3, and VEGF-R2

Supplementary Figure 2. Kaplan-Meier PFS curves by dichotomized angiokines: CD-73, BMP-9, VEGF-R1, PDGF-BB, VEGF, IL-6, VCAM-1, OPN, HGF, PDGF-AA, TGFb-R3, TGF-b1, VEGF-R3, and TGF-b2

PDF file - 28K, Kaplan-Meier plot of OS (A) and PFS (B) by tumor MET expression in all treatment arms combined.

CONSORT diagram

Purpose:Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.Patients and Methods:Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m2 on day 1 and day 2 weekly for 3 of 4 weeks (regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTC) and in fresh tumor tissue biopsies.Results:Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose limiting at 260 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients showed an objective or PSA response.Conclusions:Onalespib in combination with AA/P showed mild evidence of some biological effect; however, this effect did not translate into clinical activity, hence further exploration of this combination was not justified.

PDF file - 28K, Waterfall plot of the maximum change in the sum of the longest diameters of tumors from baseline in patients with evaluable tumor response per investigator assessment who received rilotumumab (A) or placebo (B). Fifteen patients in the rilotumumab group and five patients in the placebo group were omitted because post-baseline data were not available. PD, progressive disease; SD, stable disease; UE, unevaluable.

PDF file - 54K, Drug exposure

PDF file - 31K, Waterfall plot of the maximum change of PSA levels from baseline in patients who received rilotumumab (A) or placebo (B) in the intention-to-treat analysis set. A PSA response was defined as ≥50% decline in two consecutive PSA levels ≥3 weeks apart. Six patients in the rilotumumab group were omitted because post-baseline data were not available.

Purpose: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m2 i.v. day 1, 5 mg twice a day orally days 1–21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).Results: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82–1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79–1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Conclusions: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis. Clin Cancer Res; 19(1); 215–24. ©2012 AACR.

Purpose:Biomarkers are needed in patients with non–clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib.Patients and Methods:ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS).Results:We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib.Conclusions:In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

PDF file - 1076K, Kaplan-Meier plot of PFS by tumor MET subgroups in the combined rilotumumab and control arms (A) and forest plot of the biomarker effect of high versus low tumor MET expression on PFS within the combined rilotumumab and control arms (B). MP, mitoxantrone and prednisone; NA, not applicable.

Aim Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). Method This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. Results In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. Conclusions The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. Trial registration ClinicalTrials.gov identifier: NCT01677559 .

Introduction The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. Patients and methods Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. Results Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). Conclusions Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.

Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

448 Background: Immune checkpoint inhibition (ICI) is a standard of care therapy in metastatic urothelial carcinoma (mUC) but its role in the muscle-invasive setting remains unclear. Prior neoadjuvant ICI studies have demonstrated promising antitumor activity. We report results of a multi-institutional phase Ib/II two-stage study investigating chemo-immunotherapy in patients (pts) with cisplatin eligible or ineligible muscle-invasive UC (MIUC) (NCT02365766). Methods: Eligible pts were surgical candidates with clinical stage T2-4aN0M0 UC. Pts were enrolled on either the cisplatin eligible (CE) or cisplatin ineligible (CI) cohort. Both cohorts received 5 doses neoadjuvant pembrolizumab 200 mg every 3 weeks. CE chemo comprised four 21-day cycles of gemcitabine 1000 mg/m2 day (d) 1,8 and cisplatin 70 mg/m2 d 1 or 35 mg/m2 d 1,8. CI chemo comprised three 28-day cycles of gemcitabine 1000 mg/m2 d 1,8,15. Chemo-immunotherapy was followed by definitive surgery (radical cystectomy or nephroureterectomy). Primary endpoint was investigator assessed pathologic muscle-invasive response rate (PaIR, ≤ypT1N0) assessed at definitive surgery. Null hypothesis was PaIR rates of 23% (CE) and 18% (CI) for type I error rate 4% and power 86%. Secondary endpoints were rate of definitive surgery, ypT0 rate, 18 month (mo) relapse free survival (RFS), and 36 mo overall survival (OS). Results: 82 pts (42 CE, 40 CI) enrolled. 1 CI pt withdrew before cycle 1. 88.1% (CE) and 87.2% (CI) pts received definitive surgery, leaving 37 CE and 34 CI pts evaluable for the primary endpoint. 81% CE pts completed all 4 chemo cycles (median 4), and 92% CI pts completed all 3 chemo cycles (median 3). Median pembrolizumab treatments was 5 (range 1-6) in both cohorts. Median follow-up was 54.8 mos (CE) and 29.2 mos (CI). Median age was 64 (CE) and 73 (CI) and stage > T2 at diagnosis was 42.9% (CE) and 60% (CI). PaIR rate for evaluable CE pts was 54% (95% CI 38-69) with 41% pts (95% CI 27-57) down staged to ypT0. 18 mo RFS was 82% (95% CI 66-91) and 36 mo OS was 78.9% (95% CI 65-90). PaIR rate for evaluable CI pts was 53% (95% CI 37-69) with 41% pts (95% CI 26-58) downstaged to ypT0. 18 mo RFS was 65.1% (95% CI 48-78) and 36 mo OS was 65.7% (95% CI 47-79). Most common ≥ grade 3 toxicities were anemia (28.3%), hypertension (28.3%), and neutropenia (22.2%), with cytopenias more common in CE than CI pts. One death from post-operative sepsis occurred in cohort CE. Immune related adverse events (irAEs) ≥ grade 3 include elevated liver enzymes (3.7%), rash (2.5%), pneumonitis (2.5%), and colitis (2.5%). Conclusions: Neoadjuvant chemo-immunotherapy demonstrated significant down staging in CE and CI MIUC pts prior to definitive surgery, meeting the primary endpoint. Survival correlated with pathologic response. Further phase III studies will be necessary to confirm the efficacy and safety of these regimens. Ongoing analysis of biomarkers of response is underway. Clinical trial information: NCT02365766 .

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor-risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Testicular cancer is relatively uncommon and accounts for 50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

The phase II CABOSUN trial compared cabozantinib with sunitinib as initial treatment in patients with advanced renal cell carcinoma of intermediate or poor risk. This article presents subgroup analyses by baseline patient characteristics., Cabozantinib treatment prolonged progression‐free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.

PURPOSE The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

5068 Background: Treatment with immune checkpoint blockade (ICB) alone results in suboptimal response rates in prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self-antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens have been correlated with favorable clinical outcomes. Thus, we hypothesized that the combination of shared antigen and neoantigen vaccines with dual ICB will induce robust immune responses and improve clinical outcomes. Methods: This Phase I clinical trial (NCT03532217) enrolled patients from 2018-2021. Eligible patients had histologically confirmed high risk mHSPC, must have completed a course of docetaxel and received continuous androgen deprivation therapy. Patients were treated with Prostvac-VF in combination with ipilimumab/nivolumab within 60 days of the last docetaxel dose. Then, patients were continued on monthly nivolumab with their personalized neoantigen vaccine administered via intramuscular electroporation. The primary objectives of this study were to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure free survival, milestone overall survival (OS), PSA responses, and radiographic progression free survival. Results: Nineteen patients were enrolled and treated on trial, and feasibility was shown with 15 (79%) receiving neoantigen vaccines. Four patients did not receive neoantigen vaccines (2 for progressive disease, 2 for ICB toxicity). Treatment was well-tolerated with only 2 (2.4%) grade 3 treatment related adverse events (TRAEs) of colitis, and no grade 4+ TRAEs. The common grade 1-2 TRAEs were diarrhea (10%), injection site reactions (10%), rash (7.4%), and fatigue (6%). Median follow-up to date is 22.6 (11.3-39.6) months, with median OS not yet reached and 2 year milestone OS of 75%. Six (31.5%) patients had PSA progression per PCWG2 criteria while on treatment, with the median time to PSA progression not yet reached for the total population. Increases in activation/co-stimulatory/co-inhibitory seen after treatment with Prostvac/ICB, suggest immune priming. Sample collection is complete and immune correlative analyses are ongoing. Final safety/tolerability and preliminary correlative and clinical outcomes will be reported. Conclusions: This is the first clinical trial evaluating the use of personalized neoantigen vaccines in a combination immunotherapeutic approach in mHSPC patients. Clinical trial information: NCT03532217.

5081 Background: To date there is no prospective survival data beyond 5 years for patients treated with ADT with or without docetaxel (D) when analyzed by well-defined baseline prognostic risk groups and treatment arms. In this updated analysis of the CHAARTED trial, we report the 8-year survival rate based on disease volume and metachronous vs. de novo metastatic disease status with ADT without or with docetaxel. Methods: An updated survival sweep was conducted in February 2022. Patients were prospectively identified by the state of metastatic disease as metachronous (prior local therapy) vs. de novo and low volume (LV) vs. high volume (HV; visceral and/or ≥4 bone metastases with one lesion beyond the vertebral bodies or pelvis) disease. Overall survival (OS) was defined as time from randomization to death or date last known alive and calculated using the Kaplan-Meier method. Results: Of the 790 patients randomized (last patient enrolled December 2012), 238 patients were still alive with a median follow up of 9.7 years for patients still alive. Median OS in the overall population was 60.4 and 47.2 mos in the ADT+ D and ADT arms respectively (Table; HR: 0.77; 95% CI: 0.65, 0.92; p=0.004). ADT+ D was associated with significantly higher 8-yr OS rate (28.5%) compared to ADT arm (15.4%; HR: 0.67; 95% CI: 0.53, 0.84; p=0.0005) in the de novo HV group (n=421). Notably, the 8-yr OS rates were almost doubled for patients with HV disease with early docetaxel (16% vs.30.2%, p

5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and > 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses5 mg are often not tolerated when combined with other TKIs

Purpose: Biomarkers are needed in patients with non–clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

PURPOSE Cell-free DNA (cfDNA) and circulating tumor cell (CTC)–based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)–directed therapy in metastatic prostate cancer. However, because of complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (eg, CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in > 80% of patients with metastatic disease and its association with disease resistance presents an opportunity to improve on current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. PATIENTS AND METHODS We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). RESULTS EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS, 30% v 71%; P = .0002; 6-month OS, 59% v 100%; P = .0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay, which was also run on a subset of patients. CONCLUSION cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.

Pemphigus is an autoimmune bullous disease with a number of described associations, including medications, which have been grouped into three structural categories - thiol drugs, phenol drugs, and drugs with neither functional group [1]. Discontinuation of the offending medication is considered a mainstay of therapy. We report a patient in whom the onset of pemphigus foliaceus was associated with initiation of imatinib mesylate adjuvant therapy in a patient with resected gastrointestinal stromal tumor (GIST). Imatinib was continued because of the survival benefit to the patient with a resected, high risk GIST. Treatment with rituximab resulted in near resolution of his blistering rash and follow up enzyme-linked immunosorbent assay (ELISA) demonstrated reference range immunoreactivity for both desmoglein 1 and desmoglein 3. After dose increase of imatinib therapy owing to tumor growth, the patient subsequently again developed a similar eruption. Re-biopsy and ELISA were consistent with recurrence of pemphigus. In conclusion, although the patient's pemphigus was cleared with a single cycle of rituximab infusions while continuing imatinib therapy, the disease returned after imatinib dose was increased a year later, suggesting a dose-response relationship.

Background The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single‐arm, open‐label phase 2 study. Methods Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg). Conclusions To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting., After the genomic‐based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, single‐agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinum‐refractory disease.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23% to 44%) for cabozantinib versus 12% (95% CI, 5.4% to 21%) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

// Nilofer S. Azad 1 , Anthony el-Khoueiry 2 , Jun Yin 3 , Ann L. Oberg 3 , Patrick Flynn 4 , Douglas Adkins 5 , Anup Sharma 1 , Daniel J. Weisenberger 2 , Thomas Brown 1 , Prakriti Medvari 1 , Peter A. Jones 6 , Hariharan Easwaran 1 , Ihab Kamel 1 , Nathan Bahary 7 , George Kim 8 , Joel Picus 9 , Henry C. Pitot 3 , Charles Erlichman 3 , Ross Donehower 1 , Hui Shen 6 , Peter W. Laird 6 , Richard Piekarz 9 , Stephen Baylin 1 and Nita Ahuja 1 1 Johns Hopkins University, Baltimore, MD, USA 2 University of Southern California, Los Angeles, CA, USA 3 Mayo Clinic, Rochestor, MN, USA 4 Metro-Minnesota CCOP, Minneapolis, MN, USA 5 Washington University, St. Louis, MO, USA 6 Van Andel Research Institute, Grand Rapids, MI, USA 7 University of Pittsburgh, Pittsburgh, PA, USA 8 Mayo Clinic, Jacksonville, FL, USA 9 Washington University, St. Louis, MO, USA 10 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA Correspondence to: Nilofer S. Azad, email: // Keywords : epigenetics, colorectal cancer, DNA methyltransferases inhibitors, histone deacetylase inhibitors Received : August 11, 2016 Accepted : October 25, 2016 Published : February 05, 2017 Abstract Purpose: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. Experimental Design: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2 nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and

Background: Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m 2 twice daily administered as 7 days on and 7 days off, intravenous (IV) bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily. The primary end point was progression free survival (PFS) and secondary endpoints included objective response rate (ORR) and tolerability. An exploratory endpoint included correlation of PFS with cytokine levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To examine cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy and to Arm B where levocetirizine was started 7 days prior to chemotherapy. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Results: Forty-seven patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 23 patients and Arm B enrolled 24 patients. Fifty percent of patients had progressive disease and 62% of patients had stable disease in each arm as best response. There was no demonstrable difference in PFS between the two arms (log-rank test P=0.83). Median time to progression was 3.4 months in Arm A and 3.5 months in Arm B. Conclusions: Median PFS in the trial was comparable to and appeared to be better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine measurement with IL-8 levels did not show any correlation with progression free survival but patients with stable disease showed overall lower levels of IL-8 as compared to patients with progressive disease in the cytokine analysis.

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 ...

Purpose: Biomarkers are needed in patients with non–clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomly assigned to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients; 51 received sunitinib and 57 everolimus. Of these, 89 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 87 PFS and 62 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine–treatment outcome interactions were observed for sunitinib or everolimus. OPN, HGF, TIMP-1, VCAM-1, PDGF-AA, and IL6 levels increased with progression on everolimus, while OPN, PlGF, TIMP-1, VEGF, and soluble VEGFR-2 and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

TPS192 Background: Despite robust advances in the use of immune checkpoint blockade (ICB) across multiple cancer types, responses in prostate cancer remain suboptimal. Overall response rates for single-agent ICB in prostate cancer are low, but recent modest gains have been made with ipilimumab and nivolumab combination therapy in metastatic castrate-resistant prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA into the vaccinia (or fowlpox) virus strain. A large randomized phase III clinical trial recently showed no improvement in overall survival (OS) with Prostvac compared with placebo, suggesting that a combinatorial approach is warranted. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens are observed in patients with favorable clinical outcomes, supporting neoantigen vaccination as a promising therapeutic strategy. Improvements in computational genomics and predictive algorithms have allowed the incorporation of MHC class II neoepitopes and those from gene fusion events relevant in prostate cancer. We thus hypothesized that a strategy utilizing both shared antigen (Prostvac) and personalized MHC-I and MHC-II neoantigen vaccines combined with dual ICB would induce robust immune responses and improve clinical outcomes. To maximize tumor burden reduction and minimize tumor-mediated immunoresistence, we are evaluating this novel strategy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who have completed frontline docetaxel chemotherapy. Methods: This ongoing trial (NCT03532217) began accrual in September 2018. Eighteen of 20 planned patients have been enrolled to date. Eligible patients have histologically confirmed high risk/volume mHSPC defined as 4 or more sites of metastatic disease or visceral involvement. Patients receive continuous androgen deprivation therapy (ADT) and have completed upfront docetaxel chemotherapy. Patients begin treatment with Prostvac-VF in combination with ipilimumab (1 mg/kg every 3 weeks for 2 doses), and nivolumab (3 mg/kg every 3 weeks for 6 doses) within 60 days of the last dose of docetaxel. Subsequently, patients receive nivolumab 480 mg IV every 4 weeks in conjunction with a personalized neoantigen DNA vaccine administered monthly via intramuscular electroporation. The primary objective of this exploratory study is to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure-free survival and milestone survival at 2 years, PSA response, and radiographic progression-free survival. Clinical trial information: NCT03532217.

413 Background: Limited data exists on the role of local therapy for metastatic urothelial carcinoma of the bladder (mUC). Large database analysis have inherent limitations but can shed light on survival outcomes in a real-world population and in scenarios not easily studied in a randomized fashion. We hypothesized that in the NCDB, radiotherapy (RT) to the bladder plus chemotherapy (CT) would be associated with improved overall survival (OS) vs CT alone. Methods: We queried the NCDB for newly diagnosed mUC cases (cT1-4 N0-3 M1) from 2004-2015 treated with CT alone vs CT plus RT to ≥ 45 Gy to the bladder. Cystectomy patients were excluded. To account for lead time bias, we excluded patients with < 2 months of follow-up. Variables for multivariable analysis (MVA) and matching included: age, sex, Charlson-Deyo comorbidity index (CCI), cT/N stage, facility type/location, insurance, year of diagnosis, and number of CT agents. Overall survival (OS) was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards analyses was performed. Propensity score matching (all variables) and exact matching (CCI score, age +/- 5 years, cT stage) was performed. Results: 4,459 patients with newly diagnosed mUC received either CT+ RT (n = 337) or CT alone (n = 4,122). Median follow-up was 10.7 months (range 2-144). Median RT dose was 57.6 Gy (IQR, 50.0– 63.0 Gy). Median OS for CT+RT was 13.8 (95% CI, 12.1-15.5) vs. 8.4 months (95% CI, 7.5-9.4) for CT (P < 0.0001). In MVA, RT was associated with improved OS (HR, 0.70; 95% CI, 0.62-0.79; P < 0.0001). Increasing age, comorbidity score, and cT-stage were associated with worse OS (P < 0.001). In subgroup analysis of patients without other comorbidities (CCI of 0), median OS for CT+RT was 14.4 (95% CI, 12.1-16.7) vs 11.1 months (95% CI, 10.7-11.5) for CT (P = 0.001). For patients with cT2-3N0 disease, median OS for CT+RT was 14.0 months (95% CI, 6.8-21.3) vs 10.9 months (95% CI, 10.1-11.7) for CT (P = 0.001). On propensity matched analysis (337 CT+RT and 337 CT patients), CT+RT was associated with improved OS (median 13.8 vs 8.5 months; P < 0.0001; MVA HR 0.59, 95% CI 0.50-0.69, P < 0.0001). On exact matched analysis (205 CT+RT and 205 CT patients), CT+RT was associated with improved OS (median 13.5 vs 9.9 months; P = 0.002; MVA HR 0.67, 95% CI 0.57-0.79, P = 0.002). Landmark analysis for patients living ≥6 months (median OS 16.3 vs 13.6 months, P = 0.004) and ≥12 months (median OS 22.2 vs 19.1 months, P = 0.029) demonstrated improved OS for CT+RT. Conclusions: In this large contemporary series, mUC patients treated with local RT plus CT had improved OS compared to CT alone. The magnitude of the effect persisted with matching and landmark analysis to try to mitigate the effect of selection bias, though we could not control for extent of metastatic disease. These findings are hypothesis-generating; a prospective trial evaluating the impact of bladder RT in mUC is warranted.

490 Background: Integrating molecular subtypes, gene transcripts associated with disease recurrence (DR), and clinicopathologic features may help risk stratify muscle-invasive bladder cancer (MIBC) patients & guide therapy selection. We hypothesized that combined transcriptomic & clinical data would improve risk stratification for DR (local or distant) after cystectomy +/- adjuvant chemotherapy. Methods: We identified 401 MIBC patients (pT2-4 N0-N3 M0) in The Cancer Genome Atlas with detailed demographic, clinical, pathologic, and treatment-related data. We split the data into training (60%) & testing (40%) sets. We produced RNA gene expression scores for molecular subtype using 48 established, relevant genes (PMID 28988769). In the training set, we performed feature selection by conducting random forest modeling of an additional 108 genes associated with DR. We kept genes of highest importance based on the evaluation of increasing mean-squared error & node purity. We excluded highly correlated genes & used the false discovery rate method for multiple hypotheses testing. We performed univariable analyses on genes of highest importance, molecular subtype, & clinicopathologic variables. Using adjusted multivariable analyses (MVA), we built two models: with & without transcriptomic data. Using the testing set, we compared the final models' performance to predict DR, using receiver operating characteristics & area under the curve (AUC). Results: Median follow-up was 18 months (range 1-168). 104 patients recurred with a 5-yr cumulative incidence of 34.6%[28.6-40.5%]. Using the training set, we identified 6 genes significantly associated with DR (VEGFA, TRMT1, FGFR2B, ERBB2, MMP14, PDGFC). The final MVA showed that the new 6-gene signature (HR 1.61, 95% CI 1.27-2.05, p < 0.001); immune molecular subtype [increased expression of PD-L1, PD-1, IDO1, CXCL11, L1CAM, SAA1] (HR 0.52, 95% CI 0.29-0.94, p = 0.03); smoking status (HR 1.17 per 10 pack-years, 95% CI 1.05-1.29, p = 0.005); and local failure risk factors [≥pT3 with negative margins & ≥10 nodes removed (HR 1.63, 95% CI 1.15-2.32, p = 0.006); ≥pT3 and positive margins OR < 10 nodes removed (HR 3.26, 95%CI 2.43 to 4.09, p = 0.007)], were all significantly associated with DR. This combined model outperformed a stand-alone clinicopathologic model (AUC 0.75 vs. 0.66) in the testing set. The combined model stratified patients based on DR risk into 3 groups with 5-yr cumulative incidences of 19.8%[7.7-31.9%] (low-risk); 34.5%[26.1-42.8%] (intermediate); and 49.8%[37.7-61.9%] (high), Gray’s Test p < 0.0001. Conclusions: To our knowledge, this study is the first to integrate clinicopathologic & transcriptomic information (including molecular subtype) to better stratify MIBC patients by risk of recurrence. This stratification may help guide decision-making for adjuvant treatment. Further validation is warranted.

Summary Background Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. Methods We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445. Findings Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8–11·4] vs 5·6 months [5·5–6·0]; hazard ratio 1·41 [80% CI 1·03–1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3–4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none). Interpretation In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. Funding Novartis and Pfizer.

Background: Liquid biopsy analysis of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) have emerged as potential tools to predict response to androgen receptor (AR)-directed therapy in metastatic prostate cancer (mPCa). However, current clinically available assays (e.g. CTC AR-V7) focus on one AR variant, demonstrate low sensitivity, and remain underutilized. The recent discovery of AR enhancer amplification in 81% of metastatic patients and its association with disease resistance opens opportunities to improve upon current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would more sensitively detect resistance with higher accuracy than the CTC AR-V7 assay used in clinical practice. Methods: We developed a targeted sequencing assay and analysis method called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with mPCa treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). In parallel, the Oncotype DX AR-V7 Nucleus Detect CTC assay was performed in peripheral blood from a subset of patients. Results: The most frequent genomic events detected were AR/enhancer alterations (copy number variation, tandem duplication or missense mutations) in 18 patients (45%), of which 16 patients (40%) had AR enhancer copy number gain or tandem duplication. Three patients (8%) were found to have independent AR enhancer amplification without AR gene body amplification. TP53 (8 patients, 20%) and PTEN (6 patients, 15%) were the other most frequently altered genes, subject to nonsynonymous mutations and copy number alterations. We also detected the TMPRSS2-ERG gene fusion in 5 cases (13%). cfDNA-detected alterations in the full AR locus including the AR enhancer were highly significant for overall survival (P=0.0015; HR=11.5) by Kaplan-Meier analysis, as well as progression-free survival by Kaplan-Meier analysis (P=0.0002; HR=6.8) and multivariate Cox proportional hazards regression (P=0.001; HR=12.7). While AR/enhancer alterations in plasma cfDNA identified 18 out of 23 treatment-resistant cases with 100% positive predictive value and 78% sensitivity (Fisher's P0.99). Conclusions: cfDNA based AR locus alterations including the enhancer are strongly associated with resistance to AR-directed therapy and significantly worse survival outcomes. EnhanceAR-Seq significantly outperformed the CTC AR-V7 assay used in standard clinical practice. Citation Format: Pradeep S. Chauhan, Ha X. Dang, Haley Ellis, Wenjia Feng, Peter K. Harris, Grace Smith, Mark Qiao, Katherine Dienstbach, Rachel Beck, Andrew Atkocius, Faridi Qaium, Jingqin Luo, Jeff M. Michalski, Joel Picus, Russell K. Pachynski, Christopher A. Maher, Aadel A. Chaudhuri. Detection of cell-free DNA alterations in AR and its enhancer significantly outperformed CTC AR-V7 detection for identifying treatment resistance in patients with metastatic prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-269.

5529 Background: Predicting primary resistance to androgen receptor (AR)-directed therapies is critical for personalizing treatment of metastatic prostate cancer (mPCa). Analyses of liquid biopsies are potential tools but remained underutilized due to limited sensitivity. We developed a cell-free DNA (cfDNA) assay (EnhanceAR-Seq) to monitor genomic alterations in mPCa including AR enhancer duplication, a resistance marker recently discovered in ~81% of mPCa patients. Here we show that applying EnhanceAR-Seq to plasma cfDNA to monitor alterations of AR gene and enhancer ( AR/enhancer) predicted primary resistance with high sensitivity and outperformed the clinically validated CTC AR-V7 assay. Methods: Forty mPCa patients were prospectively enrolled at the Washington University School of Medicine Siteman Cancer Center with plasma cfDNA analyzed by EnhanceAR-Seq. Twenty-five of them also had the Oncotype DX AR-V7 Nucleus Detect CTC assay performed at a similar timepoint at the discretion of the treating oncologist. All patients received AR-directed therapy (eg. abiraterone, enzalutamide) and underwent standard-of-care clinical and laboratory follow-up. Primary resistance was defined as PSA progression, change of treatment or death within 4 months of treatment initiation, or radiographic progression within 6 months. Results: Median clinical follow up after diagnosis was 50 months. EnhanceAR-Seq detected alterations targeting AR/enhancer in 18 patients (45%), TP53 in 8 patients (20%), and PTEN in 6 patients (15%). We found that AR/enhancer alterations (copy gain, tandem duplication, and point mutation) in cfDNA were strongly predictive of primary resistance to AR-directed therapy (PPV = 100%, Sens. = 89%). Our assay outperformed the CTC AR-V7 assay, which was positive in only two patients (PPV = 50%, Sens. = 6%). Furthermore, patients with AR/enhancer alterations had significantly worse progression-free survival (P = 0.0015; HR = 11.5) and overall survival (P = 0.0002; HR = 6.8). Finally, serial cell-free DNA analysis of 10 patients showed that AR/enhancer copy number gain was maintained or acquired in 5 of 6 AR-resistant cases, and neutrality maintained in 4 of 4 AR-sensitive cases. Conclusions: cfDNA-based AR/enhancer locus genomic alterations could potentially be used to predict primary resistance to AR-directed therapy with higher sensitivity than the clinically validated CTC AR-V7 assay, be used for serial timepoint monitoring and guiding personalized clinical decision-making.