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ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .

229 Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis, progression, and metastasis in preclinical models. While studies have identified recurrent molecular alterations in the Wnt signaling components in about 20% of aPC pts, the clinical significance of these alterations has been incompletely characterized. Methods: PROMISE is a multi-institutional, retrospective, clinical-genomic database - inclusive of aPC pts who had tissue and/or blood-based genomic testing by commercially available CLIA-certified platforms. We evaluated outcomes in pts with alterations leading to the activation of the canonical Wnt pathway, specifically activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 (Wnt altered), compared to those lacking such alterations (Wnt wild type). Multiple endpoints were evaluated, including the frequency of metastatic disease to different sites and co-occurring alterations. Results: 1596 pts with aPC were included with a median age of 63 years at diagnosis. Wnt pathway alterations were identified in 12.4% (198/1596). Wnt altered pts had a statistically significant increase in liver and lung metastases compared with Wnt wild type pts at diagnosis (4.5% vs 2.1%, p=0.0438; 6.1% vs 2.9%, p=0.0292), at first metastatic disease (11.6% vs 5.4%, p= 0.0015; 14.8% vs 6.6%, p

5002 Background: In the phase 3 VISION study, gallium (68Ga) gozetotide (68Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617). Given that 177Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68Ga-PSMA-11 PET/CT scans of pts in the 177Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUVmean), maximum SUV (SUVmax), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUVmean). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUVmean was associated with improved clinical outcomes; pts in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (< 6.0; < 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]

5013 Background: Black men have been underrepresented in large-scale molecular prostate cancer (PC) surveys, despite having higher PC incidence and mortality. Since molecular profiling to guide the use of targeted agents is increasingly important in mCRPC, we compared precision medicine data and utilization in a cohort of black and white men with mCRPC. Methods: The PROMISE precision medicine database is an academic collaboration to compile clinical and genomic data from men with PC. All patients have had germline and/or somatic genetic testing performed. Eligibility criteria for this analysis included a diagnosis of mCRPC with available race and biomarker data. The primary outcome was the proportion of non-Hispanic black (NHB) and non-Hispanic white (NHW) men with actionable molecular data, defined as the presence of mismatch repair deficiency (MMRd/MSI-H), homologous recombination repair deficiency (HRRd), tumor mutational burden (TMB) ≥ 10 mut/MB, or AR-V7. Secondary outcomes included the proportion of NHB and NHW men with other alterations, the type and timing of genomic testing performed, and the use of targeted therapy. Results: A total of 962 mCRPC patients (21.2% NHB; 78.8% NHW) met inclusion criteria of 1619 in the overall database. Median age (NHB/NHW) was 61/63; 77.5/68.8% had Gleason 8-10; 52.5/56.7% presented with de novo metastatic disease (33.8/29.9% LN, 36.2/32.2% bone and 8.3/6.1% viscera). The median time from diagnosis to first molecular result was 56.3 mo for NHB v 58.7 mo for NHW (p = 0.45). Use of blood-based molecular testing was more common in NHB men (48.7% v 36.4%, p < 0.001). Overall, 32.8% of NHB men harbored actionable molecular data compared to 30.3% of NHW men (Table). MMRd/MSI-H was more common in NHB men (9.1 v 4.9%, p = 0.04). Other than PTEN (12.7/23.8% NHB/NHW, p = 0.0001), no significant differences were seen in the 15 most frequently mutated genes, including TP53, AR, CDK12, RB1, and PIK3CA. Tumor suppressor co-mutations (PTEN/TP53/RB1) were found in 13.1% of NHB and 18.0% NHW (p = 0.13). Delivery of targeted therapy was reported in 19.6% of NHB and 23.7% of NHW men (p = 0.25) after a median of 2 CRPC lines. Median OS from development of mCRPC was 41.5 mo (95% CI, 34.7-51.3) and 44.7 mo (95% CI, 41.1-51.5) for NHB and NHW men, respectively (p = 0.14). Conclusions: In a real-world mCRPC molecular profiling cohort, we found similar overall rates of actionable molecular alterations in NHB and NHW men, but higher rates of MMRd/MSI-H and lower frequency of PTEN alterations in NHB men. We did not find differences in delivery of targeted therapy. [Table: see text]

129 Background: Pathogenic HRR gene mutations may confer sensitivity to PARP inhibitors (PARPi) and/or platinum chemotherapy (chemo). While pts harboring mutations in BRCA1/2 appear to benefit from these DNA damaging therapeutics, outcomes data for those with non- BRCA1/2 mutations are less robust. We evaluated outcomes in men with HRR gene-mutated PC who received treatment with PARPi and/or platinum-based chemo stratified by type of HRR alteration. Methods: Retrospective data from the PROMISE Consortium was utilized (PMID: 34363009). PC pts with pathogenic HRR mutations who received PARPi and/or platinum-based chemo were included. Differences in PSA progression-free survival (PFS), clinical/radiographic PFS (rPFS), and overall survival (OS) between those with BRCA1/ 2 mutations (Cohort A) and those with mutations in HRR genes that do not directly interact with the BRCA complex (Cohort B: ATM, CDK12, CHEK1, CHEK2, FANCL) were evaluated. We also evaluated outcomes in pts with HRR gene mutations known to interact with the BRCA complex aside from BRCA1/2 (Cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, BRIP1). Results: Of 361 pts identified with HRR gene alterations, 89 received PARPi and 70 received platinum-based chemo. Prior therapy and metastatic disease sites were similar between cohorts. PSA PFS, rPFS, and OS were significantly improved in Cohort A vs. Cohort B with PARPi but not platinum-based chemo (Table). Sample size in cohort C was too small to allow for statistical comparison, although PSA PFS, PFS and OS were reasonably long. Conclusions: PC pts with BRCA1/2 mutations had improved outcomes to PARPi compared to those with mutations in HRR genes not directly interacting with the BRCA complex. Platinum-based chemo appeared effective regardless of which HRR gene was affected. [Table: see text]

503 Background: Metastatic urothelial cancer is aggressive and associated with dismal 5-yr overall survival. Platinum-based chemotherapy and checkpoint inhibitors are standard first-line options with enfortumab vedotin, sacituzumab govitecan, and erdafitinib (in select FGFR altered tumors) subsequently utilized upon disease progression. However, despite these options, long-term outcomes remain poor, and novel strategies are needed to improve oncologic outcomes. We hypothesized that combining avelumab (anti-PD-L1 immunotherapy) with docetaxel is safe and will enhance cancer cell death by releasing neoantigens and potentiating anti-tumor immune-mediated cytotoxicity. Methods: This is a phase 1b, single-arm, open-label prospective clinical trial evaluating the combination of avelumab with docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. There are two phases. In Phase 1b, dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) aimed to establish the phase 2 dose in a standard 3+3 design. In dose-expansion, avelumab with the RP2D of docetaxel was evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles, and then avelumab alone is continued every 2 weeks. The primary endpoint is safety. Efficacy endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: At the cutoff date of 10/8/2021, 21 patients were enrolled in the study. Only one of the 6 patients treated with level 0 dose of docetaxel had dose-limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. An additional 15 patients were enrolled in the dose-expansion cohort. Of the 20 evaluable patients, ORR (CR+PR) was seen in 70% of subjects. (CR: 30%, PR: 40%, SD: 5%, PD: 25%, and 1 patient was not evaluable). The median PFS was 9.2 months (range: 1.5 – 25.8 months), and median OS was not reached. The most common Grade 3 or 4 AEs were febrile neutropenia, transaminitis, diarrhea, anemia, and neutropenia. No treatment-related deaths were noted. Conclusions: The combination of avelumab with docetaxel is safe with promising efficacy that is worth further studying in patients with platinum-refractory or ineligible metastatic urothelial cancer. Clinical trial information: NCT03575013.

138 Background: AR alterations such as ligand binding domain mutations and amplification evolve under the selective pressure of testosterone suppression and AR targeted agents (ARTA) such as abiraterone or enzalutamide, but their relevance to ARTA treatment outcomes remain unclear. Methods: PROMISE is a multi-institutional retrospective clinical-genomic database inclusive of aPC pts who had tissue and/or blood based genomic testing by commercially available CLIA-certified platforms. We analyzed men who received second generation ARTA and stratified patients according to genomic testing timing (pre-/post-ARTA), castration resistance, type of AR alteration, and PSA decline ≥50% on first ARTA. Time to progression (TTP) from first ARTA initiation was estimated using the Kaplan-Meier method and differences between subgroups defined by AR alteration status were assessed using the log-rank test. Results: 854 pts who received ARTA and had tissue-based (n = 600) or blood-based (n = 335) genomic testing were included. Median age was 62 (range, 33-93). Pre- and post-ARTA genomic testing was available in 387 and 467 pts, respectively. AR alterations were identified in 16% (61/387) of pre-ARTA and 48% (226/467) of post-ARTA pts with AR amplifications in 10% (38/387) and 35% (161/467) of the pts, respectively. 15/52 pts who had pre- and post-ARTA testing developed a new AR alteration. In pre-ARTA cohort; castration status, median TTP, and PSA response for 1st ARTA according to alteration status are summarized in the table. In the post-ARTA group, the most common AR mutations were L702H (53%), followed by T878A (33%); whereas, in the pre-ARTA group, the H875Y (26%) mutation was most common. AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). Conclusions: AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.[Table: see text]

344 Background: IROC is an expanding multi-institution collaborative database which includes socioeconomic, genomic, pathologic, clinical and laboratory data in metastatic RCC patients (pts), primarily in the modern setting. Elevated baseline NLR is now an established poor prognostic factor in renal cell carcinoma (RCC) but currently has limited practical use. We hypothesized that an increase in NLR of 3 or more (NLR Failure) at 2 months on therapy could be a predictor of eventual treatment failure and shorter overall survival and thus augment the utility of this marker. Methods: Patients with complete data on NLR at time = 0 and +2 months of therapy were analyzed. Information on comorbidities, previous therapy, demographics were collected for adjusted analysis. NLR failure was defined as an increase of 3 or more compared to baseline NLR. Cox proportional hazard models were used to analyze the risk of progression and death with NLR failure at 2 months (+/- 2 weeks). Kaplan Meier graphs were constructed to trace survival functions for PFS and OS by NLR. Results: Among 165 pts; 121 were eligible (Table). NLR failure at 2 months was associated with a highly statistically significant increase in the risk of death in < 1 year (HR 6.82, 95% CI [3.16-14.70], p

328 Background: Anti-PD1/PDL1 immune checkpoint inhibition (CPI) is active in advanced clear cell RCC, but not all patients benefit. Preclinical studies with the combination of hypomethylating agents and CPI resulted in reversal of immune evasion and tumor regression. We examined the combination of the hypomethylating agent guadecitabine (subcutaneously on Days 1-5), with the anti-PDL1 antibody durvalumab (intravenously at flat dose of 1500 mg on Day 8) in 28 day cycles in advanced RCC in a single arm trial. Methods: In the phase Ib portion (n=6; presented previously), guadecitabine dosing of 45 mg/m2/day was selected as maximum tolerated dose. For the phase II portion of Cohort 1 (36 pts with no prior CPIs), eligible patients had metastatic RCC with clear cell component, ECOG PS of 0-1, and measurable disease by RECIST 1.1. We present pooled efficacy and toxicity data for the 42 CPI-naive pts from the phase Ib and phase II portions. An exploratory Cohort 2 (N=16) consisting of CPI-refractory pts is enrolling. Results: Of the 42 pts, 71% were men, median age was 67 years, ECOG PS was 0 in 57%, IMDC risk group was intermediate in 83% and poor in 17%, and histology was mixed in 21%. At a median follow-up of 20.1 m, best RECIST 1.1 response was PR in 9 pts (22%); SD in 25 pts (61%); PD in 7 pts (17%); and non-evaluable in 1 pt. Response categories were identical by irRECIST. Clinical benefit defined as either PR or SD ≥6 months was seen in 66%. Median OS had not been reached and median PFS was 17 m. Treatment was generally well tolerated with asymptomatic neutropenia the most frequent AE attributed to guadecitabine (38.1%), and asymptomatic lipase elevation the most common AE from durvalumab (11.9%). Grade 4 AEs were noted in 50.0% pts, grade 3 59.5%. Immune-mediated AEs were generally mild (all ≤ grade 3), included pruritus (14.3%), rash (14.3%), asymptomatic amylase or lipase elevations (16.7%), hypothyroidism (11.9%), diarrhea (16.7%), dyspnea (16.7%), pneumonitis (4.8%), myalgia (4.8%), and transaminitis (9.6%). Laboratory peripheral blood profiling (done at baseline, C1D8, C2D8) was associated on univariate unadjusted analysis at baseline with response in two major PBMC subsets - MDSCs (negative) and ILCs (positive). Further functional analysis revealed that increased expression of IL-22 in both CD4 and CD8 positive T cells positively correlated with response. Associations were noted for toxicity with IL-22 expressed by CD8-CD4- T cells, and CTLs T-bet level. Baseline archival tumor tissue next generation sequencing results will be presented. Conclusions: Guadecitabine in combination with durvalumab was well tolerated and had reasonable activity in first-line advanced ccRCC. MDSCs and regulatory T lymphocytes decreased in responders, increased Th17 subpopulations of T cells were associated with immune-mediated toxicities. Further study of this combination in CPI-refractory RCC pts is ongoing. Clinical trial information: NCT03308396 .

5 Background: HPV is associated with 30 - 50% of penile cancers, with some studies showing improved outcomes in these patients. This study evaluated the effect of HPV infection on penile cancer outcomes. Methods: The national cancer database (NCDB) was utilized to identify HPV tested penile cancer patients at the time of diagnosis from 2004 – 2016. Chi-squared tests and Cox regression models were used in analysis. Results: Out of 486 patients with penile squamous cell cancer, 139 (29%) were HPV +ve, and 347 (71%) were HPV -ve. Greater than 50% of HPV +ve were < 65 years old, Caucasian, from low-income areas ( < $48,000), and had public or no insurance. Similar incidence patterns were noted in HPV- ve patients. 77% pts who were HPV +ve had a moderate to poorly differentiated tumor. Most HPV +ve presented with early-stage cancer, and 12% were stage IV at diagnosis. 5-year overall survival (OS) was better among HPV +ve 62% vs. 50% in HPV -ve patients. Multivariable analysis (MVA) shows superior survival among patients with age < 65 years, low comorbidity score (0-1), and earlier stage at diagnosis. Patients with HPV +ve adjusted for age, comorbidities, stage, and treatment showed significantly improved survival. HPV -ve patients had 1.49 times increased risk of death compared to HPV +ve. Conclusions: HPV positive penile cancer is associated with significantly improved survival independent of age, comorbidities, stage, and treatment modality. This study reiterates the prognostic significance of HPV status and testing for HPV status at diagnosis should be a standard practice. [Table: see text]

322 Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .

256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, & from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]

TPS5590 Background: Prostate-specific membrane antigen (PSMA) is a clinically validated therapeutic target for the imaging and treatment of mCRPC. AMG 160 is an HLE BiTE immune therapy designed to redirect T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells. BiTE immune therapy leads to direct tumor cell killing, T-cell activation and expansion, and the creation of a pro-inflammatory tumor microenvironment. Combining AMG 160 with a PD-1 inhibitor may enhance antitumor activity by enabling sustained T-cell-dependent killing of tumor cells in the inflamed tumor microenvironment. Methods: NCT03792841 is a phase I study of AMG 160 as monotherapy (part 1) and in combination with pembrolizumab (part 2) in men with histologically/cytologically confirmed mCRPC who are refractory to a novel hormonal therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed 1–2 taxane regimens (or are medically unsuitable or have refused taxanes), who have ongoing castration with total serum testosterone ≤ 50 ng/dL, and have evidence of progressive disease. Patients who received prior PSMA radionuclide therapy may be eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease will be excluded. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of AMG 160 given as monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Exploratory objectives include evaluation of potential pharmacodynamic and patient selection biomarkers, immunogenicity, and patient-reported pain and functional outcomes. The part 1 dose exploration will determine the MTD/RP2D of AMG 160. The part 1 dose expansion will confirm the safety and tolerability of the MTD/RP2D. The part 2 dose exploration will estimate the MTD/RP2D of AMG 160 in combination with pembrolizumab. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be used for evaluation of exploratory objectives. The study opened in February 2019 and is currently recruiting patients into both part 1 and part 2. Clinical trial information: NCT03792841 .

497 Background: Neoadjuvant chemotherapy followed by cystectomy in MIBC is associated with improved survival compared to cystectomy alone. Recent retrospective studies indicated that secondary MIBC (non-MIBC progressed to MIBC) had worse outcome with cisplatin based neoadjuvant chemotherapy when compared to primary MIBC. To further evaluate this observation, we queried our database to assess the differential response and determine if prior use of intravesical therapy diminishes the effect of cisplatin based neoadjuvant chemotherapy. Methods: A total of 387 patients diagnosed with T2-4 or N0-3 and M0 from 2000-2018 and underwent cystectomy were retrospectively chart reviewed for demographics, treatment and outcomes at University of Iowa Holden Comprehensive Cancer Center. Cox regression models were utilized to assess differences in recurrence-free survival (RFS) and overall survival (OS). Time was calculated from cystectomy to recurrence or death due to any cause for RFS and OS, respectively. Results: Of the 387 patients, 324 patients had primary MIBC and 63 had secondary MIBC. Median follow up was 25.8 months. Intravesical therapy was administered to 98% (62/63) of secondary MIBC patients. Neoadjuvant chemotherapy was administered to 38% (122/324) of primary MIBC patients and 21% (13/63) of secondary MIBC patients. NAC had no difference in response rates (CR and PR) for primary vs secondary MIBC (p=0.73). Additionally, there was no difference between the primary and secondary MIBC with regards to RFS (p=0.54) and OS (p=0.12) on univariate analysis. The effect of neoadjuvant chemotherapy did not differ based on prior use of intravesical therapy in terms of RFS (p=0.61) or OS (p=0.40). Additionally, neoadjuvant chemotherapy irrespective of prior use of intravesical therapy was not associated with RFS (p=0.66) or OS (p=0.15). Conclusions: Prior intravesical therapy was not associated with differential efficacy of neoadjuvant chemotherapy in secondary MIBC when compared to primary MIBC.

634 Background: Response to checkpoint inhibitors (CPIs) for renal cell cancer (RCC) remains variable, with markers like PDL1 proving unreliable. Preclinical models suggest that obesity could affect CPI outcomes. We conducted a retrospective study on the effect of obesity on outcomes in RCC patients treated with CPIs. Methods: RCC patients treated with nivolumab +/- Ipilimumab at university of Alabama at Birmingham (UAB) and University of Iowa (UIOWA) from 2015 - 2018 were classified according to WHO standard definition of BMI as non-obese (NOB-30Kg/m2). Overall survival (OS) was defined as the interval from the first CPI dose to date of death or to last follow up date if patients were still alive. Progression free survival (PFS) was defined as the interval from the first dose of CPI to date of progression or date of death and censored at last follow-up date if patients were still alive without progression. Multivariable Cox proportional hazard regression model was used to evaluate the association between OS/PFS and obesity status, controlling for age, sex, race and number of prior therapies. All analyses were performed using SAS 9.4. Results: 84 patients with at least 6 months follow-up received a median of 9 doses of CPI with median follow of 72 weeks. 48 patients were NOB while 36 patients were OB, with 40 patients deceased at time of analysis. The most common response was stable disease in 45%, with CR in 5% and PR in 10% for a disease control rate of 63%. The median OS was 30 months in NOB patients and 20 months in the OB group. The 2 yr survival was 59% in the NOB group vs 28 % in the OB group with a HR of 0.60 (0.32-1.14; p=0.12). Median PFS was 13 months in the NOB group vs 7.3 months in the OB group with 2 yr PFS of 28% in the NOB group vs 5.5% in the OB group (HR 0.58 {0.35-0.98}; p=0.04). Conclusions: In this analysis of RCC patients treated with CPI, BMI < 30 predicts better OS and PFS. Further studies are required to better understand the effect of BMI on CPI outcomes in RCC.[Table: see text]

487 Background: Advanced bladder cancer is the most common malignancy of the urinary system with 5-year OS rates of 5-7%. Platinum based chemotherapy and checkpoint inhibitors are currently available treatment options but with limited benefit. We hypothesize that combining Avelumab (anti-PD-L1 immunotherapy) with Docetaxel is safe and will lead to cancer cell death releasing neoantigens with enhanced anti-tumor immune mediated cytotoxicity. Methods: This is a phase 1b, single arm, non-randomized, open label prospective clinical trial to evaluate the combination of Avelumab and Docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. It has two phases: Phase 1b dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) to establish phase 2 dose in the standard 3+3 design. In the dose expansion phase, the phase 2 dose of docetaxel with avelumab will be evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles and then avelumab alone is continued every 2 weeks. Primary endpoint is safety. Efficacy endpoints include objective response rate, progression free survival and overall survival. Results: At the cutoff date of 10/21/2019, 10 eligible patients were enrolled in the study. Only one of the six patients treated with level 0 dose of docetaxel had a dose limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. Additional 4 patients were enrolled in the dose expansion cohort. Efficacy data is preliminary with 1 patient achieving CR, 2 pts had PR, 2 pts had SD, 1 pt PD and 4 pts are not yet evaluable. The most common Grade 3 or 4 AEs were febrile neutropenia, urinary tract infection and confusion. No treatment related deaths were noted. Conclusions: The combination of docetaxel in combination with avelumab is safe and the preliminary data showed promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT03575013.

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.

e12544Background: Recent studies indicated that aryl-hydrocarbon receptor (AHR) modulators - such as omeprazole - decrease breast cancer cell invasion among mice with estrogen receptor negative (ER...

e15084Background: Checkpoint inhibitors are approved as effective therapy in a number of malignancies. The response rates range between 20-40% in various cancers. Predictive as well as prognostic c...

630 Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.

543 Background: ER+ breast cancer (BC) by virtue of tumor dormancy can present with delayed recurrences, frequently years after initial diagnosis. Methods: Over 2,500 charts of ER+/HER2 negative BC...

e15537 Background: The GPA is a commonly used prognostic index based on RTOG protocols in patients with brain metastases (BM). The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of renal cell carcinoma with brain metastases (RCCBM) at a larger tertiary care center to predict overall survival. Methods: IRB approval was obtained and the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify RCCBM patients (pts) treated in the recent era (2000-12). A proportional hazards model was used to assess OS, which was measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 136 RCCBM (100 males), median age 60 years (range 32-79), were evaluated. Pts had a median of 2 (range 1-15) BM; Karnofsky Performance Scale (KPS) was 90-100 in 57%, 70-80 in 38% and 3).GPA was not prognostic for survival (p=.40), and neither GPA coding of KPS nor BM (1, 2-3, >3) was associated with outcome (p=.90 and .26, respectively). In contrast, diagnosis of RCC to BM >5 years, p=.004, brain as an initial site of metastasis, p=.005, normal hemoglobin, p=.01, a single BM, p=.02, controlled primary, p=.02, and age≤65 were found to be independently prognostic for improved OS. Using these factors, an alternative index can be formed. Conclusions: RCCBM specific GPA was notprognostic for OS in this study (p=.40), however a new index was developed based on a revised set of independent prognostic factors that was significant (p

e15023 Background: Small cell carcinoma (SCCB) is an aggressive tumor and presents in an advanced stage. In this retrospective study we analyze the patterns of treatment and survival among elderly patients (age>75 years). Methods: We identified 38 patients who were diagnosed with primary SCCB at our institution and its affiliated hospitals between 1995-2010. Out of which 15 patients were above the age of 75 years. For each patient histological, demographic and clinical data were obtained by chart review. Deaths of all patients were confirmed by social security death index (SSDI). Staging of all patients were categorized as limited (T1-4N0-1M0) or extensive stage (TxNxM1 or TxN2-3M0). Results: 15 patients were identified with pure small cell carcinoma of bladder. Mean age of patients was 80 years ( ranged from 76 years to 90 years). Male to female ratio was 5:1. 86% were caucasians. Among patients with available clinical information, 5 out of 15 patients (33.3%) had extensive stage and remaining 10 had limited stage SCCB. Around 73% (11/15) of the patients underwent transurethral resection of bladder tumor (TURBT). One patient had partial cystectomy and three patients had radical cystectomy. All three pateints who underwent radical cystectomy had limited disease and had an overall median survival (OMS) of 27 months. Patients with TURBT had a OMS of 6 months. Conclusions: Prognosis for patients with SCCB remains poor. Careful selection of patients for radical cystectomy with limited disease may improve overall median survival among elderly population with SCCB.