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5064 Background: Immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that the HDAC inhibitor entinostat has synergistic antitumor effect in combination with immunotherapies in preclinical models by inhibiting Tregs and MDSCs function. The combination of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) is active in renal cell carcinoma (RCC). Thus, we have conducted a Phase I study with entinostat, atezolizumab and bevacizumab in patients (pts) with metastatic RCC. Methods: The primary objective was to evaluate safety and tolerability. The phase I portion included 3 dose levels of entinostat (1 mg, 3 mg or 5 mg, PO weekly) and fixed, standard doses of atezolizumab (1200 mg IV every 21 days) and bevacizumab (15 mg/Kg IV every 21 days). Pts with any histological type and prior therapies were included. Results: Dose levels were completed with up to 1 DLT/dose level. 5 mg was the Phase II recommended dose for entinostat. DLTs included hypertension, encephalopathy, hyponatremia and pruritus. The most common resolved grade 3/4 toxicities were hypophosphatemia (33%), hypertension (17%), and pneumonitis (11%). We have enrolled 18 pts (17 evaluable for ORR by RECIST). 5 pts continue on treatment. 3 pts discontinued treatment because of adverse events, 9 pts for disease progression, and one pt for physician decision. Good risk and intermediate risk pts were 61% and 39%, respectively. Overall ORR was 47.1% (95% CI 23.0-72.2) and median PFS was 7.6 months (95% CI 1.6-16.3). In pts with no prior therapies (12) the ORR was 58.3% (95% CI 27.7-84.8) and median PFS was 13.4 months (95% CI 1.5-28.9). One additional PR was observed by ir-RC but was not confirmed within the data cut-off date of 11/11/19. In pts with prior immune checkpoint inhibitors (ICIs) (5) ORR was 20% (95% CI 0.5-71.6) and median PFS was 7.6 months (95% CI 1.3-NR). Preliminary data show a statistically significant lower % of circulating monocytic MDSC (HLADR−1CD11b+CD33highCD14+CD15−) and exhausted T cells (CD45+CD3+CD8+TIM3+) following treatment in pts (4) with objective responses as compared to pts (4) with progressive disease. Conclusions: The results from this phase I suggest that the combination of entinostat, atezolizumab and bevacizumab is relatively well tolerated and is active in renal cell carcinoma patients, in both ICIs naïve and resistant disease. A phase II portion of this study is currently accruing patients. Clinical trial information: NCT03024437 .

5019 Background: Patients (pts) with laUC who are C-ineligible have inferior survival compared to counterparts who receive C based N-therapy and have a pathologic response at radical cystectomy (RC). Cohort 2 (C2) of the GU14-188 trial is designed to assess the tolerability and efficacy of N- G and P in laUC pts who are C-ineligible. Methods: Eligible pts for C2 were surgical candidates and C-ineligible with cT2-4aN0M0 bladder UC or mixed histology. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Pts were treated with N- G (1000mg/m2) on days 1, 8, and 15 of a 28 day cycle (cy) for a total of 3 cy, and overlapped with P 200mg every 3wks starting on cy 1 day 8 x 5 doses. Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of pathologic muscle invasive response rate (PaIR, ≤pT1N0) was assessed at RC and designed for 86% power, 4% significance to detect PaIR difference from 18 to 40%. Molecular subtyping is planned. Results: 37 pts were enrolled to C2 with a median (mdn) age of 72, 70% male, 55% > cT2. C-ineligibility was due to renal function (49%), hearing (30%), neuropathy (12%). Mdn per-pt doses given (intended) for P:5(5) and G:9(9). The PaIR was 51.6% (95%CI 0.35, 0.68), P0 (ypT0N0) rate of 45.2%, and neither correlated with baseline PD-L1 score. Downstage to PaIR occurred in 57% of pts with cT2, and 47% of > cT2. Mdn time to RC from last dose was 5.6wks. Six were not included in the primary analysis: 3 (8.1%) did not have RC due to progression (RFS censored), 2 did not receive required protocol therapy, and 1 withdrew consent. At mdn follow up of 10.8mo (4-24), the estimated 12mo RFS, OS, and DSS is 74.9%, 93.8%, and 100%, respectively. Treatment related AE included grade (gr) 3/4 neutropenia (24%), anemia (13%), and platelets (5%). There were no gr 4 non-heme AE, and of 14 (36%) pts with gr 3, 12 did not preclude RC. Of these, there were 4 gr 3 investigator assessed immune related adverse events (IAirAE) of pneumonitis (5%), colitis (3%), and AST elevation (3%). Though IAirAE improved, protocol therapy was discontinued in 3 pts: 2 did not have RC due to progression. Conclusion: N- G with P in C-ineligible pts with laUC is feasible with manageable toxicity, and has a pathologic downstage rate comparable to standard of care in the C-eligible population. G and P warrants further study with component contribution as a C- free N- option in laUC. Clinical trial information: NCT02365766 .

407 Background: A large number of metastatic germ cell tumors (GCTs) are cured with platinum-based chemotherapy. Patients that have relapsed or refractory disease can be cured with salvage therapy including salvage surgery, standard dose or high-dose chemotherapy with stem-cell transplant. However, 15-20% of patients with metastatic GCT are incurable with current therapeutic options. We sought to perform a genetic analysis on a cohort of these incurable patients to determine the presence of therapeutically targetable genetic mutations. Methods: After obtaining IRB approval, patients treated at Indiana University for refractory or relapsed GCT from 2016-2019 were analyzed with a next-generation sequencing (NGS) platform. Clinically relevant genomic alterations were reviewed to determine the potential for targeted therapies. Results: 10 patients with testicular (9) or ovarian (1) GCT underwent an analysis of tissue (7), blood (1), or both (2) with a mean 2.9 potential targetable mutations per patient. Four patients had NGS from preserved gonadal tissue removed prior to chemotherapy while 6/10 sample specimens were obtained post standard (1) or high-dose (5) chemotherapy. Potential known therapeutic targets were found in 80% (8/10). Of the platforms that tested biomarkers, high microsatellite instability (MSI) (1/5), intermediate tumor mutational burden (1/4), and high PD-L1 expression of 90% (1/3) was appreciated. The MSI-high patient did not respond to pembrolizumab. A patient with a KIT only mutation did not achieve a response to imatinib. One patient with KRAS, KIT, RAF1, CCND2, MET, AR, CDK6, PDGFRA, EGFR, and BRAF mutations was treated with brentuximab and was progression free for 2.5 months. Common mutations were CCND2 (4/10), RAF1 (2/10), KIT (2/10), and KRAS (2/10). Other mutations actionable in non-GCT tumors included ERCC1, TUBB3, RRMI, PIK3CA, TOPO1 and TP53. Conclusions: NGS identifies potential clinically relevant genomic alterations. Genetic mutations may enable future effective therapies as our understanding of platinum-resistant disease evolves. To our knowledge, this is among the first reports utilizing next-generation sequencing in GCT to direct potential therapeutic agents.

403 Background: Rate of serum TM decline is prognostic in patients (pts) with GCT receiving first-line chemotherapy. We investigated the prognostic value of TM decline in rGCT treated with HDCT+peripheral-blood stem-cell transplant (PBSCT). Methods: 462 consecutive pts with rGCT treated with HDCT+PBSCT at Indiana University between 1/2004-1/2019. All pts were planned for 2 consecutive HDCT courses with carboplatin+etoposide per protocol (N Engl J Med 2007;357:340-8). Pts with elevated AFP and/or hCG were included (N=347). Slope and half-life (T1/2) were calculated for weekly AFP+hCG during HDCT starting with peak value at days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized satisfactory (SAT). Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier. Uni- and multivariable analysis using Cox regression model was performed. Results: 347 pts had elevated TM: 312 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (292), mediastinum (26), retroperitoneum/other (29). Metastatic sites included retroperitoneum (277), lung (233), liver (83), brain (77), and bone (21). At initiation of HDCT, 77 pts had elevated AFP, 222 elevated hCG, and 48 elevated both AFP+hCG. Median AFP 9 (1-21,347) and hCG 113 (1-178,140). 314 pts (91%) completed 2 planned cycles of HDCT. Overall, 46/347 pts had SAT decline (13 for AFP; 30 for hCG; 3 for both). Pts with SAT TM decline had superior outcomes compared to UNSAT: 2-yr PFS 69% vs 45% (p=0.006) and 2-yr OS 75% vs 51% (p=0.006). When evaluating each TM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 74% vs 47% (p=0.002). There was statistically non-significant difference for AFP: 2-yr PFS 48% vs 42% (p=0.65). In univariable analysis, UNSAT decline of hCG, but not AFP, was an adverse prognostic factor for PFS: HR=2.51 (95% CI, 1.40-4.51); p=0.002. Multivariable analysis will be presented. Conclusions: SAT rate of TM decline, particularly in hCG, predicts superior outcomes in rGCT undergoing HDCT+PBSCT. Pts with UNSAT TM decline are at higher risk for relapse and death.

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

TPS587 Background: Patients (pts) with cisplatin ineligible metastatic urothelial carcinoma (mUC) who progress after first-line PD1/PDL1 inhibition have limited treatment options. The concept of maintenance therapy with targeted agents and adding onto it at time of progression is a proven effective strategy. Preclinical data indicate that carboplatin+gemcitabine have immunomodulatory effect to potentially augment immune response. We hypothesize that in pts with cisplatin ineligible mUC, the use of atezolizumab+chemotherapy after progression on single-agent PD1/PDL1 inhibitor will result in clinical benefit. Methods: Multi-center, single arm, open label phase 2 trial of atezolizumab+carboplatin+gemcitabine in pts with cisplatin ineligible mUC. Eligible pts are adults with mUC (mixed histology allowed) who progressed after first line PD1/PDL1 inhibitor. Pts should be cisplatin ineligible based on consensus criteria. Neoadjuvant/adjuvant chemotherapy completed ≥12 months prior to enrollment is allowed. Treatment with atezolizumab will continue until disease progression or unacceptable toxicity while carboplatin+gemcitabine can be stopped after 4-6 cycles. Primary objective is progression-free survival per RECIST and secondary objectives are overall response rate, clinical benefit rate, and overall survival (OS). Exploratory endpoints include to compare OS of atezolizumab+carboplatin+gemcitabine in this trial compared to a virtual control arm of carboplatin+gemcitabine in mUC after progression on first-line PD1/PDL1 inhibitors. Other exploratory endpoints include to compare PD-L1 status at time of diagnosis and at time of enrollment (after progression on PD1/PDL1 inhibitor). Using an alternate hypothesis that atezolizumab+carboplatin+gemcitabine will have a median PFS of 9 months compared to historical control of 5 months with a platinum regimen in 2nd line setting, we plan to enroll 33 patients. This study is currently enrolling pts. A protocol amendment is under way that will allow pts with prior platinum-based chemotherapy to enroll on this trial. Clinical trial information: NCT03737123.

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.

413 Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme which detoxifies quinones and reduces oxidative stress. NQO1 is expressed in multiple tumor types at levels up to 200-fold above normal tissue, including in breast, pancreatic, and non-small cell lung cancers. NQO1 bioactivatable drugs have the potential to deliver tumor-selective DNA damage and cell death by exploiting the elevation of NQO1. Alterations in catalase expression can cause marked cytoprotection. The ratio of NQO1:catalase activities is presumed to be a predictive marker for therapeutic activity of NQO1 bioactivatable drugs. There is no data available on NQO1 and catalase expression in germ cell tumors. Methods: Patients with germ cell tumor who underwent orchiectomy/tumor resection between January 2016 and December 2018 were identified from the Indiana University Melvin and Bren Simon Cancer Center database. Patients with non-seminomatous germ cell tumor of testis or primary mediastinal non-seminomatous germ cell tumor were selected. Immunohistochemistry staining for NQO1 and catalase was performed on tumor tissue. Results: NQO1 and catalase expression were assessed in 16 patients. Fifteen of 16 tumors stained positive for NQO1, 13 of which were moderately to strongly positive. Conversely, the majority of tumors were catalase deficient or only mildly positive for catalase. The details of the Immunostaining is summarized in the table below. Conclusions: Non-seminomatous germ cell tumors appear to have overexpression of NQO1 and deficiency of catalase. NQO1 bioactivatable agents could be beneficial in treating patients with refractory non-seminomatous germ cell tumors.[Table: see text]

TPS424 Background: Testicular cancer (TC) is the most common solid malignancy in men aged 15-35 yrs; germ cell tumors (GCTs) account for 95% of TC. Claudin 6 (CLDN6) is a tight junction membrane protein whose expression in normal tissue is confined to embryonic cells but is frequently aberrantly expressed in GCTs. ASP1650 (also known as IMAB027) is a monoclonal antibody targeted against CLDN6 that can induce antibody-dependent cell-mediated and complement-dependent cytotoxicity in CLDN6-expressing cells and has demonstrated potent antitumor effects in preclinical models of TC. Methods: This phase 2 study with a safety run-in (NCT03760081) will enroll ≤46 male patients (pts) with advanced GCTs who have had prior cisplatin-based combination chemotherapy and ≥1 salvage regimen. In the safety run-in, an initial ASP1650 dose level will be evaluated in 3 pts. If tolerated, a new cohort of 3 pts will begin at the next dose level per the Bayesian Optimal Interval Design. A Dose Evaluation Committee will assess tolerability and determine maximum tolerated dose. Once the recommended phase 2 dose (RP2D) has been established, ≤34 pts will be enrolled in phase 2 and will receive ASP1650 in 2-week cycles for up to 12 cycles or until study discontinuation criteria is met. Phase 2 of the study will utilize a Simon’s 2-stage design to allow for early termination. In stage I, 13 pts, including pts from the RP2D cohort of the safety run-in, will be evaluated for response. If there is ≤1 response among these 13 pts, the study will be stopped, otherwise an additional 21 pts will be enrolled in stage II. Primary endpoints of the study include establishment of the RP2D and confirmation of overall response rate, as assessed by modified RECIST v1.1 response criteria (RECIST v1.1 + serum tumor markers [βhCG and AFP]). Secondary endpoints include the determination of safety/tolerability and pharmacokinetic profiles as well as other efficacy measures (eg, clinical benefit rate; progression-free survival; change in serum tumor biomarkers). Enrollment is currently ongoing; as of Sept 12, 2019, 6 pts have enrolled and 2 are still on active treatment. Clinical trial information: NCT03760081.

414 Background: Viable germ cell tumors (vGCT) express high levels of certain circulating microRNAs, including miR-371a-3p (miR371) that has shown high specificity and sensitivity. However, neither tissue nor serum/plasma from patients with only teratoma are miR371 positive. miR375 is overexpressed in teratoma tissue, but detectability in blood is unknown. Methods: miR371 and miR375 expression was analyzed in 100 patients with various stages and histology of GCT. miR375 expression in teratoma was validated in patients with post-chemotherapy pathologically confirmed teratoma (PCPCT). The miRNAs expression was assessed by RT-PCR and quantified by ΔΔCT method. The optimal cut-off for miR375 expression was estimated by Youden index ( > 20). Spike-in cel-miR-39-3p, miR-451 and miR-30b-5p were used as internal controls. Sensitivity, specificity, AUC of the ROC of miR375 in detecting teratoma was analyzed. Results: In the discovery cohort miR371 and miR375 were measured in 62 pts: 27 CSI NED, 15 chemo-naïve metastatic seminoma and 20 with PCPCT. miR375 was over-expressed in pts with teratoma compared to CSI and seminoma pts (p = 0.002), while miR371 was expressed in the seminoma pts and undetectable in the PCPCT and CSI pts (p < 0.001). In the post-chemotherapy setting, 38 pts were analyzed: 21 PCPCT, 6 vGCT and 11 complete remission (CR). Also in this cohort, miR375 was over-expressed in pts with teratoma compared to the pts presenting vGCT and post-chemotherapy CR (p = 0.01), while miR371 was detectable only in the pts with vGCT (p < 0.001). Overall, sensitivity and specificity of miR375 in identifying teratoma were 78% and 80%, respectively; the AUC was 0.7 (95% CI: 0.5490-0.8186; p < 0.01). Conclusions: Pts with residual post-chemotherapy teratoma present higher plasma levels of miR375 compared to pts with vGCT in whom miR375 is low but miR371 is expressed at high levels. The simultaneous evaluation of miR371 and miR375 may be clinically useful to predict the histology of the GCT components in pts with post-chemotherapy residual disease to inform the best therapeutic options (surgery or chemotherapy). Further validation within larger studies is warranted.

421 Background: Most metastatic GCTs are cured with cisplatin-based chemotherapy. Clinical factors of adverse GCT-specific survival have been identified, however patterns of death are not well-defined and would inform clinical care and biological investigation. Methods: This multi-institutional study pooled data of male pts with death related to GCT from high-volume adult GCT academic centers (Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Indiana University) over 20 years (1997-2017). Pts were annotated for site, stage, IGCCC risk, histology, primary therapy and relapse variables (including relapse histology, metastatic (met) burden, salvage and palliative therapies), and detailed cause of GCT death. Cox regression assessed associations with survival. Results: The pooled cohort of 620 pts comprised 90% non-seminoma, 21% mediastinal primary and at diagnosis, 59% were stage III, 64% poor risk; 48% received high-dose chemotherapy plus transplantation. Median survival (OS) from first relapse after metastasis was 12.0 mos. Leading causes of death were chemorefractory GCT (83.1%), secondary somatic malignancy (SSM) arising from teratoma (9.4%), acute toxicity (4.5%), late toxicity (2.3%) and progressive untransformed pure teratoma (0.8%). Late relapse (relapse >2 years after 1st-line therapy) occurred in 11.3% at a median of 5.9 yrs. Of these pts, 1/3 were stage I at initial diagnosis and 75% were good or intermediate risk at met diagnosis, and were more likely to have SSM histology/death vs early relapse. Late relapsing disease (HR 0.48, p

Background Although once considered a homologous recombination DNA repair gene, CDK12 is now thought to have a distinct role in maintaining genomic stability. In prostate cancer, inactivating CDK12 mutations lead to gene fusion-induced neoantigens and possibly sensitivity to PD1 inhibitors. Methods We conducted a retrospective multicenter study to identify advanced prostate cancer patients with loss-of-function CDK12 mutations. We characterized their clinical features and therapeutic outcomes, including sensitivity to PARP and PD1 inhibitors. Results 58 men with at least monoallelic CDK12 alterations were identified from 9 academic centers; 28 (48%) had biallelic inactivation. Tissue for genomics was from primary tumors in 45 cases (77%) and from metastatic sites in 13 cases (23%). All CDK12 mutations were somatic-only. Median age at diagnosis was 60 y (41–78 y), 71%/29% were white/nonwhite, 79% had Gleason sum 9-10, 10% had ductal/intraductal histology, 76% had stage T3/T4 disease, 47% had metastases at diagnosis, and the median PSA was 24 ng/mL. Of those undergoing primary ADT (± Abi, ± Doce) for advanced disease (n = 54), only 85% had a PSA50 response, with median PFS of 11.8 (95% CI 8.3–15.4) mo; OS from ADT initiation was 40.8 (95% CI 18.7–53) mo. Of those receiving first-line Abi/Enza for mCRPC (n = 34), only 47% had a PSA50 response, with median PFS of 4.3 (95% CI 2.6–6.0) mo. Of those receiving a first Taxane agent for mCRPC (n = 20), only 35% had a PSA50 response, with median PFS of 4.0 (95% CI 2.6–5.3) mo. Eleven men received a PARP inhibitor (10 Olaparib, 1 Rucaparib): none had a PSA50 response, and median PFS was 3.6 (95% CI 3.0–4.2) mo. Eight men received a PD1 inhibitor as 4th to 6th-line mCRPC therapy (5 Pembro, 3 Nivo): 38% had a PSA50 response, and median PFS was 6.6 (95% CI 2.3–10.8) mo. Conclusions CDK12-altered prostate cancer is an aggressive subtype presenting at young age, with high Gleason grade, and often with de novo M1 disease at diagnosis. Outcomes to hormonal and taxane therapies are poor, and PARP inhibitors are also ineffective. A proportion of these patients respond favorably to PD1 inhibitors, implicating CDK12 deficiency in immunotherapy responsiveness. Legal entity responsible for the study Emmanuel S. Antonarakis. Funding Has not received any funding. Disclosure E.S. Antonarakis: Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy: ESSA; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Johnson & Johnson; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Licensing / Royalties: Qiagen. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Celldex. B.L. Maughan: Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Tempus; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas. M. Hussain: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): Genentech; Honoraria (self): Sanofi Genzyme; Honoraria (self): Research To Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics. All other authors have declared no conflicts of interest.

The advances seen in the treatment of testicular cancer are among the great achievements in modern medicine. These advances were made possible by the collaborative efforts of cancer researchers around the world. Investigators have been able to address many questions regarding the treatment of patients with disease limited to the testis, those with metastasis to the retroperitoneum only, and those with advanced metastatic disease. Questions answered include the chemotherapeutic agents to be used and in what combinations, the proper intensity of treatment and appropriate dosing, the optimal number of cycles of chemotherapy according to validated risk stratification, appropriate surgical approaches that preserve sexual function, the treatment of relapsed disease, what supportive care measures to take, and survivorship issues following treatment of testicular cancer. Today, cure is achievable in 95% of all patients with testicular cancer and 80% of those who have metastatic disease. Despite remarkable results with frontline and salvage combination chemotherapy, metastatic testicular cancer remains incurable in approximately 10% of patients, and novel treatment approaches are warranted. This review highlights past and recent discoveries in the treatment of patients with testicular cancer.

Background: For patients with metastatic urothelial carcinoma (mUC) that has progressed on or after platinum-based chemotherapy (cisplatin or carboplatin) and/or immune checkpoint inhibitors, there are currently no standard treatments, emphasizing the urgent unmet need for additional treatment options. Based on analysis of The Cancer Genome Atlas bladder cancer dataset, ≈60% of muscle invasive bladder tumors have homologous recombination (HR) deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a DNA repair pathway gene. Poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib exert their antitumor activity through synthetic lethality in cancer cells with HRD. Tumors with HRD have been shown to be sensitive to PARP inhibitors in breast, ovarian, and prostate cancers, and PARP inhibitors are approved for the treatment of patients with breast or ovarian cancer. Although there are little data on their activity in mUC, we hypothesize that PARP inhibition may have antitumor activity in this tumor type. The ATLAS (NCT03397394) trial is evaluating the efficacy and safety of the PARP inhibitor rucaparib as monotherapy for patients with locally advanced (unresectable) urothelial carcinoma or mUC previously treated with 1-2 anticancer treatments for advanced/metastatic disease. Methods: Eligible patients must have received 1-2 prior treatments (eg, platinum-based chemotherapy, immune checkpoint inhibitor, and/or clinical trial agent) and have radiographic progression, measurable disease (RECIST version 1.1), and adequate organ function. Tumor HRD is not required as rucaparib may potentially benefit patients with HR-proficient or HR-deficient tumors; however, fresh tumor or recently obtained archival tissue is mandatory for central HRD profiling. Prior PARP inhibitor treatment is an exclusion criterion. All patients will receive rucaparib monotherapy (600 mg BID) until disease progression or other reason for discontinuation. The primary endpoint is confirmed objective response rate (investigator assessed per RECIST version 1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluating plasma and tumor samples for biomarkers associated with response and resistance to rucaparib. The study has >90% power to reject the null hypothesis (P=0.10) at a one-sided 5% significance level if the true response rate for rucaparib is 20%. ATLAS is currently enrolling at ≈65 sites in 6 countries (France, Germany, Italy, Spain, United Kingdom, and United States), with a target enrollment of 200 patients. Citation Format: Petros Grivas, Min Yuen Teo, Nicholas Vogelzang, Ajjai Alva, Yousef Zakharia, Nabil Adra, Alexandra Drakaki, Arif Hussain, Rafael Morales-Barrera, Andrea Necchi, Alejo Rodriguez-Vida, Susan Feyerabend, Sumati Gupta, Debra H. Josephs, Yohann Loriot, Sandy Srinivas, Kenton Wride, Daleen Thomas, Rachel Dusek, Andrew D. Simmons, Dale Nepert, Simon Chowdhury. ATLAS: A Phase II, open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT179.

e16044 Background: Rate of STM decline is prognostic in patients (pts) with metastatic GCT receiving first-line chemotherapy. We investigated the prognostic value of STM decline in pts with rGCT treated with HDCT and PBSCT. Methods: 444 consecutive pts with rGCT were treated with HDCT and PBSCT at Indiana University between 2004-2018. All pts were planned for 2 consecutive HDCT courses. Pts with elevated STM (AFP > 25 and/or hCG > 4.9) were included in this analysis. Slope and half-life (T1/2) were calculated for weekly AFP and hCG values during HDCT starting with peak value during days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized as satisfactory (SAT); normalization within 7 days was also considered SAT regardless of T1/2. Pts with elevated AFP and hCG must have adequate decline in both to be SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier methods. Results: 2-yr PFS for pts with elevated STM at initiation of HDCT (N = 335) was inferior to pts with normal STM (N = 109) [49% vs. 89%; p < 0.001]. Among the 335 pts with elevated STM, 300 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (285), mediastinum (25), and retroperitoneum/other (25). Metastatic sites included retroperitoneum (267), lung (226), liver (81), brain (76), and bone (21). At initiation of HDCT, 73 pts had elevated AFP only, 215 had elevated hCG only, and 47 had elevated both AFP and hCG. Median AFP 9 (1-21,347) and hCG 115 (1-178,140). 307 pts (92%) completed 2 planned cycles of HDCT. Overall, 45/335 pts had SAT decline (13 for AFP; 29 for hCG; 3 for both). Pts with SAT STM decline had superior outcomes compared to UNSAT: 2-yr PFS 71% vs 46% (p = 0.004) and 2-yr OS 77% vs 52% (p = 0.004). When evaluating each STM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 76% vs 47% (p = 0.002). There was statistically non-significant difference in outcomes for AFP: 2-yr PFS 50% vs 43% (p = 0.55). Conclusions: SAT rate of STM decline predicts superior outcomes in pts with rGCT undergoing HDCT and PBSCT. Although UNSAT STM decline does not preclude long-term remissions, these pts are at higher risk of relapse and death.

e23085 Background: Patients given cisplatin-based chemotherapy (CBC) experience HL and tinnitus. However, the impact of these toxicities on psychosocial and physical functioning in cancer survivors has not been systematically evaluated. Methods: Eligible testicular cancer survivors (TCS) aged ≤ 55 y at diagnosis and given first-line CBC at Indiana U., completed comprehensive questionnaires. The validated 25-item Hearing Handicap Inventory for Adults (HHIA) quantified emotional (13 items) and social difficulties (12 items) related to HL. The validated 20-item Tinnitus Primary Function Questionnaire (TPFQ) assessed domains affected by tinnitus, i.e., concentration, emotion, hearing, sleep (5 items each). For each HHIA scale, TCS were grouped into 3 standard handicap levels: 0–16% (none/minimal), 18-42% (mild/moderate), and 44-100% (significant). Proportions of social vs. emotional handicap were compared with a McNemar’s test. For TPFQ, each scale score is continuous (0: [no interference] to 100% [total interference by tinnitus]) and computed as the mean of 5 items. TPFQ measures were compared by signed-rank tests (P < 0.05 was significant). Results: Of 43 TCS (median age: 35 y, range 20–74 y; median time since chemotherapy completion: 7 y, range 2-27 y), 95% were white, and 70% had at least a college degree. Median cumulative cisplatin dose was 300 (range 200-600 mg/m2). The most commonly administered regimen was bleomycin, etoposide and cisplatin; 23 (53.5%) reported HL, and 25 (58%) had tinnitus. Of TCS with HL, 25% had some degree of related handicap (total HHIA scale: 20% and 5% for mild/moderate and significant handicap, respectively). More TCS had social vs. emotional handicap (33.3% vs. 14.3%, P = 0.13). Tinnitus had significantly greater interference with emotion (median: 14, range 0-84) compared to concentration [(median 6, range 0-41), p = 0.04)], and sleep [(median: 0, range (0-78), p = 0.001)]. Other comparisons were not significant. Conclusions: Cisplatin-related HL has a considerably greater negative impact on social vs. emotional measures, and affected TCS may benefit from hearing aids. TCS experiencing significant issues related to emotion due to tinnitus may benefit from interventions to lessen their impact.

e16042 Background: Pts with rGCT can be cured with salvage chemotherapy (CT). We evaluated risk factors and outcomes of pts who developed RF during HDCT for rGCT. Methods: All pts were planned to receive 2 consecutive courses of HDCT per protocol (N Engl J Med 2007;357:340-8). Characteristics and outcomes of pts sustaining grade ≥3 RF were analyzed and compared with those not sustaining grade ≥3 RF. Results: 21 (4%) of 473 pts had grade ≥3 RF: median age 38 (range 25-70), median creatinine 1.2 (0.6-1.8), median creatinine clearance (CrCl) 94 (48-216), median body mass index 27.1 (19.9-34.2). Median # prior standard-dose cisplatin-based CT cycles 5 (4-8) and median total dose of cisplatin 1000mg (600-1976). 10/21 pts had history of renal disease prior to HDCT, 4 had hypertension, 2 had diabetes, 2 had solitary kidney and 5 had stent or nephrostomy tube for obstruction. 20/21 pts developed neutropenic fever. 5 required total parenteral nutrition and 18 required hemodialysis (HD) during HDCT. 6 of 21 died during HDCT. 10 of 15 pts who survived HDCT had renal function recover to baseline, 2 came off HD but renal function was not restored to baseline, and 3 continued to be on HD at most recent f/u. In comparison to pts (n = 452) who did not experience grade ≥3 RF, pts (n = 21) who did experience grade ≥3 RF were more likely treated with HDCT ≥ 3rd line setting (38% vs 15%), had ECOG PS 1/2 (53% vs 18%), less likely to receive both courses of HDCT (33% vs 94%), more likely to experience GI (62% vs 11%), hepatic (43% vs 3%), pulmonary (38% vs 2%), and infectious (95% vs 1%) grade ≥ 3 toxicities; treatment-related death was also higher in this group (29% vs 2%). With a median f/u of 10 months after HDCT, 5 pts had no evidence of disease (NED), 3 were alive with disease, 6 died of disease, 6 died from complications of HDCT, and 1 lost to follow up. Conclusions: Irreversible RF during HDCT for rGCT is uncommon, but is associated with higher rates of infectious, GI, hepatic, pulmonary complications and treatment-related death. These pts are more heavily pre-treated, have lower baseline PS, and are likely to have history of renal disease prior to HDCT. However, most surviving pts recovered their renal function and 5/21 remain alive with NED.

2572 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that HDAC inhibitors have synergistic antitumor effects in combination with PD-1 inhibition in tumor models by inhibiting the function of Tregs and MDSCs. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial, renal and prostate carcinoma. Methods: The primary objective was to evaluate the safety and tolerability of this combination strategy. The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and one week OFF) and a fixed, standard dose of pembrolizumab (200 mg IV every 21 days). Patients were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve urothelial and renal cancer pts = 15), Cohort B (previously treated, anti-PD1/PD-L1 resistant urothelial and renal cancer pts = 14), and Cohort C (prostate cancer pts = 14). Results: Dose levels 1 (4 enrolled, 3 evaluable) and 2 (4 enrolled, 3 evaluable) were completed without DLTs and 200 mg was the Phase II recommended dose for vorinostat. The most common resolved grade 3/4 toxicities were acute kidney injury (n = 1), anemia (n = 1), diarrhea (n = 1), and hypothyroidism (n = 1) in the dose expansion cohorts. We have enrolled 43 pts (37 evaluable) in the dose expansion cohorts. For Cohort A, B, and C the median PFS were 2.8 months, 5.2 months, and 3.5 months. Two PR were observed including the dose escalation phase. Two PCA pts have achieved undetectable PSA. We have performed several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells, PDL-1 staining and PSMA PET scans in a subset of pts. Conclusions: The results from this phase Ib suggest that the combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC/RCC pts and immune checkpoint naïve PCA pts. Clinical trial information: NCT02619253.

522 Background: HDCT plus PBSCT is effective salvage therapy for relapsed mGCT but has potential toxicity which can be more pronounced in older patients. We report survival and toxicity outcomes in pts with relapsed mGCT age ≥ 40 at time of HDCT. Methods: 440 consecutive pts with relapsed mGCT were treated with HDCT and PBSCT with tandem cycles at Indiana University (IU) between 2004-2017 per our previous reported regimen (N Engl J Med 2007; 357: 340-8). Kaplan-Meier methods were used for progression free survival (PFS) analysis. Results: 110 pts were age ≥ 40 while 330 pts were age < 40. Among pts age ≥ 40, median AFP was 6.6 (range, 1-2,709) and median hCG was 5.3 (range, 1-42, 453). Of the 110 pts age ≥ 40, 75 had complete remission without relapse during a median follow-up of 23 months. There were 3 treatment-related deaths. Conclusions: HDCT plus PBSCT is safe and effective salvage therapy in pts age ≥ 40 with relapsed mGCT. [Table: see text]

Motivation Cancer is a complex disease that involves rapidly evolving cells, often forming multiple distinct clones. In order to effectively understand progression of a patient-specific tumor, one needs to comprehensively sample tumor DNA at multiple time points, ideally obtained through inexpensive and minimally invasive techniques. Current sequencing technologies make the ‘liquid biopsy’ possible, which involves sampling a patient’s blood or urine and sequencing the circulating cell free DNA (cfDNA). A certain percentage of this DNA originates from the tumor, known as circulating tumor DNA (ctDNA). The ratio of ctDNA may be extremely low in the sample, and the ctDNA may originate from multiple tumors or clones. These factors present unique challenges for applying existing tools and workflows to the analysis of ctDNA, especially in the detection of structural variations which rely on sufficient read coverage to be detectable. Results Here we introduce SViCT , a structural variation (SV) detection tool designed to handle the challenges associated with cfDNA analysis. SViCT can detect breakpoints and sequences of various structural variations including deletions, insertions, inversions, duplications and translocations. SViCT extracts discordant read pairs, one-end anchors and soft-clipped/split reads, assembles them into contigs, and re-maps contig intervals to a reference genome using an efficient k-mer indexing approach. The intervals are then joined using a combination of graph and greedy algorithms to identify specific structural variant signatures. We assessed the performance of SViCT and compared it to state-of-the-art tools using simulated cfDNA datasets with properties matching those of real cfDNA samples. The positive predictive value and sensitivity of our tool was superior to all the tested tools and reasonable performance was maintained down to the lowest dilution of 0.01% tumor DNA in simulated datasets. Additionally, SViCT was able to detect all known SVs in two real cfDNA reference datasets (at 0.6–5% ctDNA) and predict a novel structural variant in a prostate cancer cohort. Availability SViCT is available at https://github.com/vpc-ccg/svict. Contact:faraz.hach@ubc.ca

In a large series of intermediate and poor risk nonseminomatous germ-cell tumors we were able to identify new prognostic factors and to construct an improved risk classification system. Fewer cycles of cisplatin, etoposide, and bleomycin chemotherapy might be necessary in most cases to attain a cure. Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) classification has been used since 1997 to allocate metastatic germ cell tumors (GCTs), but its applicability needs an update. We aimed to revisit the outcomes of intermediate and poor risk nonseminomatous GCTs (NSGCTs). Patients and Methods: Individual patient-level data from the databases of 2 institutions were collected. Outcomes of consecutive patients who received first-line chemotherapy from 1990 to 2014 were used. The Kaplan Meier method was used to estimate relapse -free (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS univariably. Forward stepwise selection was used to construct a multivariable model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). Results: A total of 647 patients were identified. Four RFs for OS in the multivariable model were identified: primary mediastinal NSGCT (P

BACKGROUND Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. PATIENTS AND METHODS We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. RESULTS We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic β-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). CONCLUSIONS Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

4553Background: A retrospective study using an institutional database from MSKCC [ASCO 2017, abstract # 4555] on 231 patients, showed that the presence of teratoma (T) in the primary testicular can...

4551Background: Four cycles of etoposide and cisplatin (EP × 4) or 3 cycles of bleomycin, etoposide, and cisplatin (BEP × 3) is the current standard of care for patients with good-risk testicular c...

e16525Background: Plasmacytoid urothelial carcinoma (PUC) is a rare variant histology where malignant cells resemble those of plasmacytoma. Majority of the patients (pts) are upstaged at the time o...

e22068Background: Few studies comprehensively examine AHO in uniformly treated TCS after modern cisplatin-based CHEM compared to surgery-only (SURG). We evaluated AHO in an ongoing North American s...

A phase III study adding aprepitant to a 5HT3 receptor antagonist (5HT3-RA) plus dexamethasone in germ cell tumor (GCT) patients treated with 5-day cisplatin combination chemotherapy demonstrated a significant improvement in complete response (CR) (J Clin Onc 30:3998-4003, 2012). Fosaprepitant has demonstrated non-inferiority compared to aprepitant in single-day cisplatin chemotherapy and is approved as a single-dose alternative. This single-arm phase II study is the first clinical trial evaluating fosaprepitant in patients receiving multi-day cisplatin regimen. GCT patients receiving a 5-day cisplatin combination chemotherapy were enrolled. Fosaprepitant 150 mg was given IV on days 3 and 5. A 5HT3-RA days 1–5 (days 1, 3, and 5, if palonosetron) plus dexamethasone 20 mg days 1 and 2 and 4 mg po bid days 6, 7, and 8 was administered. Rescue antiemetics were allowed. The primary objective was to determine the CR rate—no emetic episodes or use of rescue medications. Accrual of 64 patients was planned with expected CR > 27 %. Sixty-five patients were enrolled of whom 54 were eligible for analysis. Median age was 33. Fifty-one patients received bleomycin, etoposide, and cisplatin (BEP) chemotherapy. CR was observed in 13 (24.1 %) patients (95 % Agresti-Coull binomial C.I. 14.5 %, 37.1 %). The data in this phase II study, in contrast to our prior phase III study, appears to indicate a lower CR rate with the substitution of fosaprepitant for aprepitant. It is unknown whether the substitution of fosaprepitant for aprepitant provides the same benefit in multi-day cisplatin that was achieved with single-day cisplatin. Trial registration Clinical trial information NCT01736917

4558 Background: The optimal management of progressive brain mets in pts with GCT remains unsettled. Treatment options include chemotherapy, stereotactic or whole brain radiation (XRT), surgery, or a combination thereof. Global germ cell cancer group analysis suggested multimodality therapy improves survival probabilities in pts with brain mets at relapse (JCO.2016;1;34(4):345-51). We report our experience on managing 25 consecutive pts with relapsed GCT and progressive brain mets undergoing HDCT with PBSCT at Indiana University from 2006-2016. Methods: All pts received HDCT consisting of carboplatin 700 mg/m2 days 1-3 and etoposide 750 mg/m2 i.v. days 1-3 followed by PBSCT on day 5 for upto 2 cycles. Pts were treated with craniotomy, XRT, chemotherapy alone, or a combination of modalities. Patient and disease characteristics, management of brain mets, and outcomes were measured. Platelet transfusions were given to maintain platelet counts > 30,000 and goal of > 50,000 in those with signs of hemorrhage. Results: Patient characteristics and outcomes are summarized in Table 1. Median age was 27.7 years (range, 16-48). All pts had progressive brain mets at time of starting HDCT. AFP ranged 1.6 to 1130, hCG 0.5 to 25601. At median follow-up of 24.8 months (range 2.5 to 118.5 months), 11 pts (44%) were alive with NED, 2 pts were alive with relapsed disease, and 12 pts died of disease progression. 17/18 patients developed progressive CNS mets despite radiation and/or craniotomy and of those, 8 are alive with NED. Toxicity was as previously published with this regimen (N Engl J Med 2007;357:340-8). Conclusions: Patients with relapsed GCT with progressing brain mets, including those with prior locoregional therapy, are curable with HDCT. [Table: see text]

4546Background: IGCCCG risk classification is used since 1997 to allocate metastatic GCT patients (pts). Recently, its applicability and survival estimates have been called into question. Guidelines recommend 4 cycles of BEP or VIP for both intermediate (int) and poor risk disease. We sought to revisit the outcomes and treatments in a population of int and poor risk NSGCT from Indiana and INT Milano. Methods: Data on consecutive pts receiving first-line chemotherapy (CT) from 1990 to 2014 were collected. Kaplan-Meier method was used to estimate relapse-free survival (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS in an univariable model. Forward stepwise selection was used to construct a multivariable (MV) model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). Results: 647 pts were identified; median age was 27 years (range 13-60), 115 had a mediastinal pri...

TPS4579Background: Initial cisplatin-based combination chemotherapy will cure 80% of pts with metastatic GCT. Pts who relapse after initial chemotherapy can still be cured with second and even thir...

4505Background: Patients (pts) with mGCT who relapse after initial chemotherapy (CT) can still be cured with second-line and even third-line regimens. We previously reported series of 184 pts treat...

491 Background: Patients with mGCT’s treated between 1975-1990 were classified by the International Germ Cell Cancer Collaborative Group (IGCCCG) into good, intermediate, and poor risk. This study attempts to identify prognostic factors in a contemporary cohort of patients with mGCT treated at IU. Methods: Retrospective analysis of all patients with GCT seen at IU from 1998-2012. 1,341 consecutive patients with mGCT were identified of whom 615 patients received initial chemotherapy at IU and were eligible for analysis. All patients in this cohort were treated with cisplatin-based combination chemotherapy. Kaplan-Meier methods were used for analysis of 5 year progression free survival (PFS) and overall survival (OS). Results: Median age was 29. Median follow up time 5 years. Good, intermediate, and poor risk disease had median AFP of 8, 1822, 291 and median hCG of 8, 5000, 12837 respectively. 89 (14%) patients had seminoma and 526 (86%) had non-seminomatous GCT (NSGCT). Primary site was testis/retroperitoneal in 565 (92%) and mediastinum in 48 (8%). The 5 year PFS and OS for patients with poor risk excluding primary mediastinal NSGCT (PMNSGCT) was 52% and 78% respectively. In contrast, 5 year PFS and OS for patients with PMNSGCT was 49% and 58% respectively. The results comparing outcomes of patients in IGCCCG versus patients at IU are depicted in the table below. Conclusions: In this contemporary retrospective dataset from Indiana University there was improvement in OS for men with poor risk mGCT, possibly due to improved salvage chemotherapy. Only patients with PMNSGCT continue to have poor outcomes and pose a therapeutic challenge due to lack of effective salvage therapy. [Table: see text]

4539 Background: Metastatic GCT’s have been classified by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997 into good, intermediate, and poor risk with 5-year progression free...

4557 Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP > 10,000 or hCG > 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP>20,000, and 25% hCG>200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. [Table: see text]