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PURPOSE The long-term toxicities of chemotherapy and radiotherapy can represent a significant burden to testicular cancer survivors. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors with minimal late morbidity although little data exist on its efficacy in early metastatic seminoma. Surgery in early metastatic seminoma is a prospective phase II single-arm, multi-institutional trial of RPLND as first-line treatment for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy. PATIENTS AND METHODS Twelve sites in the United States and Canada prospectively enrolled adult patients with testicular seminoma and isolated retroperitoneal lymphadenopathy (1-3 cm). Open RPLND was performed by certified surgeons with a primary end point of 2-year recurrence-free survival (RFS). Complication rates, pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. RESULTS A total of 55 patients were enrolled, with a median (IQR) largest clinical lymph node size of 1.6 cm (1.3-1.9). RPLND pathology demonstrated a median (IQR) largest lymph node size of 2.3 cm (0.9-3.5); nine patients (16%) were pN0, 12 (22%) pN1, 31 (56%) pN2, and 3 (5%) pN3. One patient received adjuvant chemotherapy. With a median (IQR) follow-up of 33 months (12.0-61.6), 12 patients experienced recurrence, with a 2-year RFS of 81% and a recurrence rate of 22%. Of the patients who experienced recurrence, 10 were treated with chemotherapy and two underwent additional surgery. At last follow-up, all patients who experienced a recurrence were disease-free and the 2-year overall survival was 100%. Four patients (7%) experienced short-term complications, and four patients experienced long-term complications including incisional hernia (1) and anejaculation (3). CONCLUSION RPLND is a treatment option for testicular seminoma with clinically low-volume retroperitoneal lymphadenopathy and is associated with low long-term morbidity.

Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy.Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off).No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment.The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

Many advanced cancer patients struggle with anxiety, depressive symptoms, and anger toward God and illness-related stressors. Patients may perceive their illness as an injustice (i.e., appraise their illness as unfair, severe, and irreparable or blame others for their illness), which may be a risk factor for poor psychological and spiritual outcomes. This study examined relations between cancer-related perceived injustice and psycho-spiritual outcomes as well as potential mediators of these relationships.Advanced lung (n = 102) and prostate (n = 99) cancer patients completed a one-time survey. Using path analyses, we examined a parallel mediation model including the direct effects of perceived injustice on psycho-spiritual outcomes (i.e., anxiety, depressive symptoms, anger about cancer, anger towards God) and the indirect effects of perceived injustice on psycho-spiritual outcomes through two parallel mediators: meaning making and acceptance of cancer. We then explored whether these relations differed by cancer type.Path analyses indicated that perceived injustice was directly and indirectly-through acceptance of cancer but not meaning making-associated with psycho-spiritual outcomes. Results did not differ between lung and prostate cancer patients.Advanced cancer patients with greater perceived injustice are at higher risk for poor psycho-spiritual outcomes. Acceptance of cancer, but not meaning making, explained relationships between cancer-related perceived injustice and psycho-spiritual outcomes. Findings support testing acceptance-based interventions to address perceived injustice in advanced cancer patients.

PURPOSE According to National Comprehensive Cancer Network guidelines, adjuvant chemotherapy (AC) has been advocated after primary retroperitoneal lymph node dissection (RPLND) to reduce the risk of relapse in pathologic nodal (pN) stage pN2 or pN3, whereas surveillance is preferred for pN1. We sought to explore the oncologic efficacy of primary RPLND alone for pathologic stage II in nonseminomatous germ cell tumors (NSGCTs) to reduce overtreatment with chemotherapy. METHODS Patients with pathologic stage II NSGCT after primary RPLND between 2007 and 2017 were identified. Patients were excluded for elevated preoperative serum tumor markers, receipt of AC, or if pure teratoma or primitive neuroectodermal tumor elements were found in the retroperitoneal pathology. RESULTS We identified 117 patients with active NSGCT in the retroperitoneum after primary RPLND. We excluded seven patients who lacked meaningful follow-up and 13 patients who received AC. There were 97 patients treated with RPLND alone: 41 pN1, 46 pN2, and 10 pN3. In total, 77 of 97 patients had not recurred after a median follow-up time of 52 months. The 2-year recurrence-free survival (RFS) was 80.3%, and the 5-year RFS was 79%. No differences in RFS were noted among nodal stage—pN1, pN2, and pN3—on Kaplan-Meier analysis. Lymphovascular invasion in the orchiectomy specimen, a high-risk pathologic feature, was also predictive of recurrence after primary RPLND. All 20 patients who recurred were treated with first-line chemotherapy and remained continuously disease free. CONCLUSION Most men with pathologic stage II disease treated with surgery alone in our series never experienced a recurrence. We did not observe a difference in recurrences between patients with pN1 and pN2. The recommendation for AC for pN2 disease may be overtreatment in most patients.

We aim to discuss the history of high-dose chemotherapy with autologous stem-cell transplant in testicular germ cell tumors, prognostic factors to consider prior to transplant, and issues both during and after transplant while also touching on the use of conventional-dose vs. high-dose chemotherapy for initial salvage treatment in patients with relapsed disease.The advancements in the treatment of testicular cancer have led to the majority of patients even with distant metastases being cured of their malignancy. Despite this, around 20% of patients with metastatic disease will relapse after first-line therapy, and the majority of these patients will go on to need further salvage chemotherapy, either with conventional-dose chemotherapy or high-dose chemotherapy. High-dose chemotherapy with autologous stem-cell transplant is an effective salvage therapy and will still remarkably result in cures for the majority of patients with relapsed disease. While patients receiving it as even third-line salvage therapy may achieve cures, earlier administration likely results in greater efficacy.

PURPOSE The majority of patients with advanced nonseminomatous germ-cell tumor are cured with combination chemotherapy and surgical resection of residual disease when appropriate. In patients with both retroperitoneal (RP) and non-RP postchemotherapy residual disease, management of the non-RP disease is typically guided by pathologic findings at the time of RP resection. There are limited data to help guide management decisions in patients with non-RP postchemotherapy residual disease alone. MATERIALS AND METHODS The prospectively maintained Indiana University testicular cancer database was queried for patients with metastatic nonseminomatous germ-cell tumor treated between 1990 and 2021 who had residual non-RP disease in the absence of residual RP disease after completing either first-line or salvage chemotherapy. RESULTS One hundred twenty-nine patients met eligibility and were included in this analysis. Seventy-five patients had teratoma in the primary tumor site, while 54 did not. Of those with teratoma in the primary, 55% had at least one postchemotherapy non-RP surgical specimen with teratomatous elements compared with 17% of those without teratoma in the primary ( P < .001). Of those without teratoma in the primary site, 56% had at least one postchemotherapy non-RP surgical specimen with active germ-cell tumor compared with 31% of those with teratoma in the primary ( P = .0046). CONCLUSION The presence of teratoma in the primary tumor site is associated with a higher rate of teratoma in postchemotherapy residual non-RP disease. Patients without teratoma in the primary tumor should still be considered for resection of residual postchemotherapy disease that could harbor teratoma or active germ-cell tumor.

PURPOSE On the basis of National Comprehensive Cancer Network guidelines, clinical stage (CS) II seminoma is treated with radiotherapy or chemotherapy. Primary retroperitoneal lymph node dissection (RPLND) demonstrated recent success as first-line therapy for RP-only disease. Our aim was to confirm surgical efficacy and evaluate recurrences after primary RPLND for CS IIA/IIB seminoma to determine if various clinical factors could predict recurrences. PATIENTS AND METHODS Patients who underwent primary RPLND for seminoma from 2014 to 2021 were identified. All patients had at least 6 months of follow-up. Nineteen patients were part of a clinical trial. Patients receiving adjuvant chemotherapy were excluded from Kaplan-Meier recurrence-free survival (RFS) analysis. RESULTS We identified 67 patients who underwent RPLND for RP-only seminoma. One patient had pN0 disease. Median follow-up time after RPLND was 22.4 months (interquartile range, 12.3-36.1 months) and 11 patients were found to have a recurrence. The 2-year RFS for RPLND-only patients without adjuvant chemotherapy was 80.2%. Patients who developed RP disease for a period > 12 months had the lowest chance of recurrence, with a 2-year RFS of 92.2%. Seven initial CS II patients were on surveillance for 3-12 months before surgery and no patients experienced recurrence. Pathologic nodal stage and high-risk factors such as tumor size > 4 cm or rete testis invasion of the orchiectomy specimen did not affect recurrence. CONCLUSION CS II seminoma can be treated with surgery to avoid rigors of chemotherapy or radiotherapy. Patients with delayed development of CS II disease (> 12 months) had the best surgical results. Patients may present with borderline CS II disease, and careful surveillance may avoid overtreatment. Further study on patient selection and extent of dissection remains uncertain and warrants further investigation.

PURPOSE Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/ 2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively ( P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Relapsed testicular germ cell tumours (GCTs) might be cured with salvage chemotherapy. Accepted salvage treatment is conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT). HDCT with peripheral blood stem cell transplant might produce a higher number of durable responses than CDCT. We discuss studies reporting on outcomes of salvage HDCT in relapsed GCTs. The most reproducible results were achieved with HDCT with two cycles of etoposide and carboplatin or three cycles of the paclitaxel, ifosfamide, carboplatin and etoposide regime. Using these two regimens, sustained cure rates of 50-66% were reported in phase I, phase II and retrospective studies published in the past two decades. Cure rates in patients with cisplatin-resistant disease are between 30% and 45%. Two phase III randomized studies were conducted with certain limitations and were unsuccessful in showing a survival benefit of HDCT. Thus, salvage treatment remains a controversial topic. Salvage HDCT with peripheral blood stem cell transplant and CDCT are two recommended treatment options for relapsed GCTs. Consistently reported cure rates from phase I, phase II and large retrospective studies support the use of HDCT in the hands of an experienced team of oncologists.

BACKGROUND High-dose chemotherapy (HDCT) plus peripheral blood stem cell transplantation (PBSCT) is effective salvage therapy for relapsed metastatic germ cell tumors (GCTs) but has potential toxicity. Historically, an age of ≥40 years has been associated with greater toxicity and worse outcomes. METHODS This is a retrospective analysis of 445 consecutive patients with relapsed GCT treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen. Kaplan-Meier methods and log-rank tests were used for progression-free survival (PFS) and overall survival (OS) analysis. RESULTS A total of 329 patients were

Purpose of review Research and innovation over the past half century have rendered testicular cancer a highly curable malignancy. Challenges and uncertainty remain in several aspects related to the management and surveillance of patients with germ cell tumors (GCT). Long-term effects of treatment on survivors of testicular cancer remain as continued areas of interest. This review aims to highlight pearls and perils in the management of patients with GCT. Recent findings Uncertainty remain regarding complex aspects of first-line and salvage treatments of GCT, interpretation of tumor markers in cases of α-fetoprotein levels less than 25 ng/ml, plateau of β-human chorionic gonadotropin (hCG) levels in patients with initial hCG greater than 50 000 mIU/ml, supportive therapies throughout chemotherapy regimens, and long-term survivorship of patients who underwent surgery or received platinum-based chemotherapy. This review aims to highlight challenges that remain in GCT, review the emerging data in these areas, and provide our institutional opinion on the management in several aspects of GCT. Summary Testicular cancer continues to present challenging clinical scenarios with respect to treatment, surveillance, and long-term management of patients. We review the data and share our institutional knowledge in several challenging areas related to the management of GCT.

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease. info:eu-repo/semantics/publishedVersion

Background Genomic biomarkers that predict response to anti‐PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti‐PD1 therapy in prostate cancer. Methods To enrich for response to anti‐PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair‐deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti‐PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort. Results Nineteen of 65 patients with dMMR metastatic castration‐resistant prostate cancer were treated with anti‐PD1 therapy. The PSA50 response rate was 65%, and the median progression‐free survival (PFS) was 24 (95% confidence interval 16–54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti‐PD1 treatment and with density of CD8+ tumor‐infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti‐PD1 therapy in a validation cohort. Conclusion Tumor FSP correlated with prolonged efficacy of anti‐PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity. Implications for Practice Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair‐deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti‐PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti‐PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti‐PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts., Biomarkers of immune checkpoint inhibition sensitivity are needed. This article reports on genomic biomarkers that may predict response to anti‐PD1 therapy in prostate cancer.

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

Testicular germ cell tumours (TGCTs) respond well to cisplatin-based therapy. However, cisplatin resistance and poor outcomes do occur. It has been suggested that a shift towards DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin-resistant cell models and observed a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analyses showed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumour suppressor genes. These data support the hypothesis that global remodelling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.

We analyzed the oncologic outcomes of men undergoing primary retroperitoneal lymph node dissection and characterized the use of adjuvant chemotherapy and template dissections.Retrospective review of the Indiana University testis cancer database identified patients who underwent primary retroperitoneal lymph node dissection between January 2007 and December 2017. Patients and providers were contacted to obtain information regarding adjuvant therapy, recurrence and survival. The primary outcome was recurrence-free survival. Kaplan-Meier curves assessed survival differences stratified by pathological stage, template of dissection and use of adjuvant chemotherapy.A total of 274 patients were included in the study. Most men presented with clinical stage I disease (214, 78%). A modified unilateral template was performed in 257 (94%) and bilateral template in 17 (6%). Overall 148 (54%) and 126 (46%) men had pathological stage (PS) I and PS-II disease, respectively. Thirteen patients (10%) with PS-II disease were treated with adjuvant chemotherapy. With a median followup of 55 months only 33 (12%) patients had recurrence. Of the 113 patients with PS-II disease who did not receive chemotherapy 21 (19%) had disease relapse and 81% were cured with surgery alone and never had recurrence. No difference in recurrence-free survival was noted between modified and bilateral template dissections.The use of adjuvant chemotherapy has been minimal during the last decade. The majority (81%) of men with PS-II disease were cured with retroperitoneal lymph node dissection alone and were able to avoid chemotherapy. Modified unilateral template dissection provided excellent oncologic control while minimizing morbidity.

PURPOSE Presence of teratoma in patients with metastatic testicular germ cell tumor (GCT) is of unknown prognostic significance. We report survival outcomes of patients with or without teratoma in primary tumor and postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and assess impact on prognosis. PATIENTS AND METHODS Patients with metastatic nonseminomatous GCT (NSGCT) who were evaluated at Indiana University between 1990 and 2016 and had primary testicular tumor specimen from orchiectomy (ORCH) were included. All patients were treated with cisplatin-based combination chemotherapy. The cohort was divided into 2 groups according to presence or absence of teratoma in ORCH specimen. Survival data were correlated with histopathologic findings. Differences in progression-free (PFS) and overall survival (OS) were evaluated using log-rank tests and Cox proportional hazards models to adjust for known adverse prognostic factors. RESULTS We identified 1,224 consecutive patients evaluated at Indiana University between 1990 and 2016 who met inclusion criteria. Median age was 27 years (range, 13-71 years); 689 patients had teratoma in ORCH specimen, and 535 did not. With median follow-up of 2.3 years, 5-year PFS was 61.9% (95% CI, 57.1% to 66.2%) for those with teratoma versus 63.1% (95% CI, 58.0% to 67.8%) for those without ( P = .66); 5-year OS was 82.2% (95% CI, 77.9% to 85.8%) versus 81.4% (95% CI, 76.5% to 85.3%; P = .91), respectively. A total of 473 patients underwent PC-RPLND; 5-year PFS for patients with pure teratoma in PC-RPLND specimen versus necrosis only was 65.9% versus 79.1% ( P = .06), and 5-year OS was 90.3% versus 93.4% ( P = .21), respectively. CONCLUSION Presence of teratoma in ORCH and PC-RPLND specimens was not a prognostic factor in this large retrospective study of patients with NSGCT.

Claudin6(CLDN6) is a tight junction protein of claudin-tetraspanin family and is of the earliest molecules expressed in embryonic epithelium. CLDN6 is frequently aberrantly expressed in testicular germ-cell tumors(GCT). ASP1650 is a chimeric-mouse/human-IgG1 antibody directed against CLDN6. Two-part, open-label, phase-II trial investigating ASP1650 in patients with relapsed/refractory GCT and no curable options. Part1 was a safety lead-in to establish the recommended-phase-II-dose(RP2D). Part2 was a phase-II study designed to evaluate the antitumor effects of ASP1650. CLDN6 expression was centrally assessed on archival tumor tissue using immunohistochemistry. The primary objectives were to establish the RP2D(safety lead-in) and the antitumor activity(phase-II) of ASP1650. Nineteen male patients were enrolled: 6 patients in 1000 mg/m

Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in numerous rare solid cancers is yet to be established. This study presents the first results of ipilimumab and nivolumab in the non-epithelial ovarian tumor cohort (#13) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). This cohort included several histologies grouped for statistical analysis. The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Seventeen evaluable patients (median age, 64 years) were analyzed. The subtypes of non-epithelial ovarian cancer were: granulosa cell (47%, n=8), carcinosarcoma or malignant mixed Mullerian tumor (MMMT; 35%, n=6), one each for Wolffian duct, yolk sac, and Sertoli-Leydig cell. There were 2 responses in the 8 patients with granulosa cell (ORR of 25% in the granulosa cell tumors): 1CR (79% regression [due to lymph node < 1.0cm], 59 month PFS, juvenile type) and 1 PR (79% regression, 51+ month PFS, adult type). 6/8 patients remain alive (PFS 52-1774 days). In contrast, carcinosarcomas showed no responses. One patient with Sertoli-Leydig cell tumor had a 22% response and 341 day PFS. Overall ORR was 12% (2/17), clinical benefit rate (CBR; no progression > 6months) of 29.4%. The median PFS was 3.5 months, median OS was 42.5 months. The most common adverse events were fatigue (52.9%, n=9) and hypothyroidism (35.3%, n=6). Grade 3-4 adverse events occurred in 47.1% of patients (n=8). There were 3 adverse events (17.6%) that led to discontinuation, of which 2 (11.8%) were grade 3-4. There were no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in non-epithelial ovarian cancer resulted in an ORR of 12% (with 2 of 8 patients with granulosa ovarian tumors showing a durable CR and PR [both, >4 years)) and CBR of 29.4%, with durable responses seen. In contrast there were no responses in the carcinosarcoma group. One patient with Sertoli Leydig cell tumor suggested a possible benefit. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in granulosa tumor but not carcinosarcoma are warranted. Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Kelly J. Wilkinson, Emily M. Whitman-Purves, Jayanthi Lea, John M. Schallenkamp, Nabil Adra, Leonard J. Appleman, Mitchell Alden, Jessica Thomes Pepin, John A. Ellerton, Andrew Poklepovic, Adam Walter, Murtuza M. Rampurwala, William R. Robinson, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the non-epithelial ovarian tumor cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT161.

Background: Targeted therapies against prostate-specific membrane antigen (PSMA) have exhibited promising antitumor activity in prostate cancer. With the FDA’s approval of (177) Lu-PSMA-617, PSMA has been validated as a target to treat metastatic castration-resistant prostate cancer (mCRPC). ARX517 is an antibody-drug conjugates (ADC) composed of a fully humanized anti-PSMA mAb site-specifically conjugated to AS269, a potent tubulin inhibitor, yielding a drug-to-antibody (DAR) ratio of 2. After binding to PSMA on the surface of cancer cells, ARX517 is internalized and delivers a cytotoxic payload which inhibits tubulin polymerization and induces cellular apoptosis. ARX517’s site-specific linkage, stable conjugation chemistry, and non-cleavable linker exhibit a homogenous drug-antibody-ratio, mAb-like biophysical properties, and exceptional stability. Therefore, ARX517 promotes highly specific tumor cell apoptosis with minimal off-target bystander activity. Trial Design: The Phase 1 study’s dose escalation and dose expansion evaluates the safety, pharmacokinetics, and preliminary evidence of anti-tumor activity of ARX517 in adults with mCRPC. Patients must have mCRPC which is resistant or refractory to standard therapies, including androgen receptor signaling inhibitors, and show disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria. All patients must have adequate organ function and brain metastases must be radiographically stable. Ascending dose levels of ARX517 administered as a single agent will use an i3+3 design in the dose escalation phase. During the dose expansion phase, ARX517 will be administered at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging. The total number of subjects is dependent on the number of ascending doses and cohort size before dose expansion. Status: ARX517-2011 began enrolling patients in July 2021. With no dose limiting toxicities through dose level 6 (2.0 mg/kg Q3W), dose escalation remains ongoing. As of January 2023, the APEX-01 study is currently enrolling in cohort 7 (2.4 mg/kg) of dose-escalation. Dose expansion will start after RP2D or MTD. Citation Format: John Shen, Richard Pachynski, Luke Nordquist, Nabil Adra, Mehmet Bilen, Rahul Aggarwal, Zachary Reichert, Michael Schweizer, Dong Xu, Manan Patel, Jin Zhang, Wenge Shi, Darryl Z. L'Heureux, Scott Tagawa. ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT121.

668 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we opened a Phase II clinical study with the HDAC inhibitor entinostat and the immune check point inhibitors nivolumab (nivo) and ipilimumab (ipi) in clear cell RCC pts previously treated with nivo + ipi or nivo alone. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a dose de-escalation, two stage, phase II clinical trial with a safety lead-in. Due to a funder decision, enrollment was halted after completion of accrual to the safety lead in group. Pts received oral entinostat at a dose of 5 mg (dose level 1) or 3 mg (dose level 2) every 7 days, continuously, with nivo at a dose of 3 mg/kg mg IV every three weeks in combination with ipi at a dose of 1 mg/kg every 3 weeks X 4 doses. Then, nivo 480 mg was continued every 4 weeks. Results: A total of 12 pts with prior nivo+ipi or nivo treatments was enrolled. Dose level 1 (5 pts enrolled) was completed with the following DLTs: thrombocytopenia, nausea and vomiting, pneumonitis. Seven pts were enrolled on dose level 2 which was established as the recommended phase II dose. The most common treatment-related toxicities were fatigue, hypophosphatemia, neutropenia and thrombocytopenia. All were transient. Most of the pts had 2 or more prior treatments. Four pts achieved a partial response, with 3 out 4 pts previously treated with nivo alone (ORR 33%; 95% CI 9.9-65.1). The median PFS was 11.1 months (CI 1.3-26.4). We collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and nivo+ ipi is relatively well tolerated and may be active in pts with RCC. Clinical trial information: NCT03552380 .

422 Background: Primary mediastinal pure seminoma is a rare entity and there is no clear consensus for optimal management. We report treatment and survival outcomes of patients with primary mediastinal seminoma evaluated at our institution. Methods: The Indiana University (IU) testicular cancer database was queried for patients with primary mediastinal seminoma. 21 patients evaluated at IU between 1994-2022 were included in this analysis. Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age at diagnosis was 40.7 (range, 19.4-54.2). 18 (85.7%) patients were IGCCCG good risk and 3 (14.3%) were intermediate risk. Median pre-chemotherapy hCG was 10.3 (range, 0.6-1500). 12 (57.1%) patients had metastatic disease. Metastatic sites included mediastinal/supraclavicular lymph nodes in 9 patients (42.9%), lungs in 3 (14.3%), retroperitoneal lymph nodes in 3 (14.3%), brain in 1 (4.8%), liver in 1 (4.8%), adrenal gland in 1 (4.8%), kidney in 1 (4.8%) and bone in 1 (4.8%). First-line chemotherapy was BEPx3 in 9 (42.9%) patients, EPx4 in 4 (19.0%), BEPx4 in 3 (14.3%), BEPx3 + EPx1 in 2 (9.5%), VIPx4 in 2 (9.5%), and VIPx1 + BEPx3 in 1 (4.8%). With a median follow-up of 4.65 years from first-line chemotherapy start date, 3 (14.3%) patients progressed after first-line chemotherapy. Among patients who progressed, salvage 2nd line therapy was high-dose chemotherapy in 1 patient. 1 patient received more than 2 lines of therapy. 1 patient underwent surgical resection of residual mediastinal mass due to concern for local progression, with pathology revealing necrosis only. The 5-year progression-free survival (PFS) from first-line chemotherapy was 82.4% (95% CI 54.7-93.9). The 5-year overall survival (OS) was 94.1% (95% CI 65.0-99.1). At last follow-up, 20 (95.2%) patients had no evidence of disease, and 1 (4.8%) was dead of disease. Conclusions: Patients with primary mediastinal pure seminoma have high cure rates with risk adapted cisplatin-based combination chemotherapy. Despite residual masses, further surgical resection or radiation is not required in the vast majority of these patients and these residual masses can be safely monitored with surveillance.

LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177Lu prolongs 18-month (mo) met-free survival (MFS) more than 111In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT < 8 mo and/or absolute PSA > 20 ng/mL and serum testosterone < 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177Lu (70 mCi/m2) or 111In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177Lu vs 76% with 111In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177Lu in analyses censoring start of new treatment. Confirmed >50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade >3 heme AEs were more common with 177Lu vs 111In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr >3 non-heme AEs were less common with 177Lu vs 111In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177Lu leads to improved 18-month met-free survival vs 111In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .

TPS292 Background: PT-112 is a novel small I-O molecule currently in development for several cancers. Preclinical studies have shown the robust induction of immunogenic cell death by PT-112, leading to an anti-cancer adaptive immune response. Biodistribution experiments in mice showed PT-112’s partial bone affinity. In two prior phase I studies, late-line metastatic castration-resistant prostate cancer patients (mCRPC pts) were treated with evidence of anti-cancer activity, including tumor volume reductions, improvements in PET and bone scans, PSA and alkaline phosphatase (ALP) reductions, and anecdotal cases of improvement in disease-related pain. This, taken together with the immunogenic and osteotropic properties observed in preclinical work, provided a strong rationale to further explore PT-112 in mCRPC, an immunologically “cold” disease with a high prevalence of bone metastases. Moreover, in an analysis of >6,000 mCRPC pts, circulating tumor cell (CTC) declines (CTC0 and CTC conversions) were correlated with improvements in survival to a greater extent than PSA declines (PSA50) (Heller et al., JCO, 36:6 2017), prompting incorporation of CTC changes as a secondary endpoint. Methods: The primary objective of the study is to define the dose regimen of PT-112 for pivotal study. Pts are randomized to one of three arms, receiving IV PT-112 on 28-day cycles via one hour infusions on (1) Days 1 and 15 at 250 mg/m2, (2) Days 1 and 15 at 360 mg/m2, or (3) Days 1 and 15 of cycle 1 at 360 mg/m2 followed by 250 mg/m2 on Day 15 of subsequent cycles. Key eligibility criteria include radiographically progressive disease at study entry; ≥3 life-prolonging therapies for metastatic disease including 1-2 taxanes, ≥1 new generation anti-androgen therapies, and other drugs FDA approved on the basis of survival; and allowing bone-only metastatic disease. Efficacy assessments comprise disease control rate at 4 months (DCR4) using RECIST and PCWG3 criteria, objective response rate, CTC0 and CTC conversion, PSA50 and ALP reductions. Additionally, T cell receptor sequencing is conducted to characterize treatment-induced changes in T cell fraction and clonal expansions, as a means of generating meaningful supportive data on the immune mechanism of PT-112 monotherapy. A Fleming two-stage design will be used to assess each arm, with a 20% DCR4 as the null hypotheses, requiring ≥6 of 25 pts responding in stage one and ≥14 of 45 in total to reject the null. In addition, other efficacy measures, such as CTC responses, as well as exposure/response and exposure/safety analyses will be applied to characterize the risk/benefit ratio and select the optimal dose regimen for PT-112. As of October 11th, 2022, 38 pts have been enrolled out of a planned maximum of 135. Clinical trial information: NCT02266745 .

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

384 Background: Polo-Like Kinase-1(PLK1) is one of the key regulators in G2/M cell cycle. Preclinical studies have shown that PLK1 might be involved in treatment resistance in prostate cancer (PCa). PLK1 overexpression by immunohistochemistry is associated with higher Gleason grade and thus PLK1 could play a role in PCa tumorigenesis. In this study, we utilized a different methodology by using RNA-seq PLK1 expression and correlated with clinical outcomes. Methods: Patients with all stages of prostate adenocarcinoma diagnosed between 2014 and 2020 from nine participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Tumor RNA-seq was analyzed for PLK1 expression and associated with clinical data obtained from ORIEN AVATAR. PLK1 expression was stratified into high expression (defined as ≥75th percentile of PLK1 mRNA expression) vs. low expression (≤75th percentile). Univariate and multivariate Cox proportional hazard model were used to compare overall survival between patients with low vs high PLK1 expression adjusting for age, race, PSA and stage. Results: A total of 452 tumors were evaluated for PLK1 expression. Of those, 241 (53.3%) had high PLK1 and 211 (46.7%) had low PLK1 expression. Median age at diagnosis for high and low PLK1 expression was 64.5 and 63.2 years respectively. The majority of patients were Caucasian in both groups. In high PLK1 group, 93 (65%) had localized high risk/very high risk disease, 27 (19%) had localized intermediate risk, 20 (14%) had metastatic vs. 97 (63%), 38 (25%) and 18(12%) respectively in low PLK1 group. Gleason ≥ 8 and PSA

700 Background: Genomic alterations in RCC can serve as biomarkers for response to therapy. Wild type VHL has shown inferior response to VEGF inhibitors, while patients (pts) with mutated VHL have improved outcomes with immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapy. We describe the impact of genomic alterations on outcomes and response to front-line therapy. Methods: Pts with mRCC who underwent genomic sequencing between 2015-2022 at Indiana University and were treated with front-line therapy were included. Kaplan-Meier method was used to analyze progression free survival (mPFS) and overall survival (OS) using the log rank test to compare groups. Results: 141 pts were included. Median age was 58yrs (range, 24-81). Tumor histology was 68% clear cell, 10% papillary, 9% unclassified, 1% chromophobe, 1% poorly differentiated, and 9% other. 18% of pts had sarcomatoid features; 13% had rhabdoid. 47% pts had metastasis at diagnosis and 53% at relapse. Metastasis sites were lungs 60%, regional lymph nodes (LNs) 41%, bone 36%, distant LNs 21%, liver 17%, and brain 8%. IMDC risk was 18% good, 48% intermediate, 17% poor, and 17% unknown. Front-line therapy was IO/IO in 21%, IO/TKI in 18%, single-agent TKI in 29%, single-agent IO in 6%, and other in 26%. Genetic alterations included VHL in 50%, PBRM1 in 29%, SETD2 in 23%, BAP1 in 16%, and TP53 in 15%. Median follow-up was 2.74yrs (range 0.1-18.6). Overall mPFS with first line therapy was 1.2yrs (95%CI 0.9-1.5). 2-yr OS was 80% (95%CI: 71-86). For pts with a VHL mutation, mPFS was 1.4yrs (95% CI; 0.9-1.8) compared to 0.9yrs (0.5-1.4) for pts without (p=0.38). 2-yr OS for pts with a VHL mutation was 93% (95% CI: 82-97) vs. 68% (95%CI: 54-78) for pts without (p=0.01). No other mutations impacted overall mPFS or 2-yr OS. mPFS for pts treated with IO/IO was 0.6yrs (95%CI 0.3-0.9) vs. 0.9yrs (95%CI 0.5-1.4) for IO/TKI (p=0.09). 2-yr OS for pts treated with IO/IO was 70% (95% CI 44-85) compared to 94% (95% CI 65-99) for IO/TKI (p=0.29). For pts with SETD2 mutations treated with IO/IO, mPFS was 0.7yrs (95%CI 0.3-1.2) vs. 1.4yrs (95%CI 0.8-1.9) for IO/TKI (p=0.01). For pts with BAP1 mutations treated with IO/IO, mPFS was 0.4yrs (95%CI 0.2-1.2) vs. NE (95%CI 0.2-NE) for IO/TKI (p=0.04). The table outlines outcomes by genomic mutation and therapy. Conclusions: VHL mutation was associated with improved 2-yr OS. Pts with SETD2 and BAP1 mutations treated with IO/TKI had improved mPFS, though no differences in OS. [Table: see text]

407 Background: Active surveillance is routinely recommended to manage patients (pts) with clinical stage I (CSI) germ cell testicular tumors (GCT), the most common presentation of newly diagnosed GCT. Circulating plasma miR371a-3p (miR371) has shown high sensitivity and specificity in pts with metastatic non teratoma GCT or in pts with clinically detectable testicular GCT prior to orchiectomy. However, limited data are available about this biomarker accuracy to detect minimal residual disease post-orchiectomy in pts on active surveillance for early stage disease. Methods: CSI GCT pts with available plasma samples after radical orchiectomy enrolled in the British Columbia provincial biobank research program were selected for this study. RT-PCR was used for qualitative miR371 analysis. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated for miR371 and compared to the same operating characteristics of current gold standard diagnostic tests. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 (positive or negative) status. Fisher’s exact test was used to evaluate the sensitivity and specificity, unpaired t-test for comparison of miR371 expression. RFS was calculated using the Kaplan-Meier method, and differences between groups were estimated using the log rank test, 2-sided and with 5% significance threshold. Results: With a median follow-up of 41 months, 101 pts with CSI GTCwere included, of whom 35 (34.6%) experienced a disease relapse during the follow-up. miR371 was positive in 22/35 (62.8%) of the relapsed pts. miR371 positivity preceded clinical evident disease by a median of 3 months (range: 1-12 months).The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95% CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the pts with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to guide treatment selection after orchiectomy. Further studies, including the SWOG S1823 clinical trial, are ongoing or have been planned in this setting for validation of clinical utility.

The therapeutic benefit of performing a lymph node dissection (LND) in patients with renal cell carcinoma (RCC) has been controversial. In prior studies, it was thought that a low event rate for nodal metastases affected the ability to draw any conclusions. Here, we opted to select patients that had low burden 1 or 2 nodes positive to study survival outcomes and recurrence patterns based on limited LND or extended LND with a template retroperitoneal lymph node dissection (RPLND).We used our single institutional database from 2000 and 2019 and identified 45 patients that had only 1 or 2 nodes positive on final pathology without any other systemic disease. These patients all underwent nephrectomy with limited LND or a template RPLND on the ipsilateral side.We identified 23 patients in the limited LND and 22 in the template RPLND group. Thirty-one patients included in the study had 1 positive lymph node and 14 patients had 2 positive lymph nodes. For patients undergoing a limited LND, a median 4 (IQR 1-11) lymph nodes were resected and for those undergoing template RPLND, 18 (IQR: 13-23) lymph nodes were resected. On Kaplan-Meier analysis, a difference was noted in overall survival (P = 0.04) when comparing limited LND to template RPLND. We also mapped out patterns of recurrence and found that 6 patients had retroperitoneal lymph node recurrences after a limited LND in the ipsilateral node packet. On univariate analysis, pathologic stage was a major factor for survival, but did not remain as significant with the inclusion of template RPLND status and Charlson Comorbidity Index in multivariate analysis.We identified specific patients that had RCC with limited lymph node involvement. We found that a select number of patients had durable improvement in survival outcomes with template RPLND. In examining the recurrence patterns, a greater number of patients may have derived benefit for an initial template RPLND.

Studies evaluating outcomes in bladder cancer sub stratified into T2a and T2b pathologic staging have demonstrated inconsistent results. Survival outcomes in a cohort of pure urothelial carcinoma patient undergoing radical cystectomy were evaluated to determine the prognostic value of T2 sub staging.Using our prospectively maintained institutional cystectomy database, we identified patients with pure urothelial carcinoma of the bladder, either pT2aN0 or pT2bN0. We excluded any patients with variant histology, patients that underwent neoadjuvant chemotherapy, and patients that had margin positive disease. Demographic and clinicopathologic data were collected, and Cox proportional hazard regression assessed overall survival (OS), cancer specific survival (CSS), and recurrence free survival (RFS).From 2001 to 2019, we identified 1,929 patients that underwent radical cystectomy, 61 patients had pT2a and 65 had pT2b pure urothelial carcinoma that met inclusion criteria. Only age (P = 0.02) and the initial transurethral resection of bladder tumor pathology (P0.01) were notably different when comparing the clinical characteristics of patients with pT2a and pT2b. No differences were noted in OS, CSS, or RFS between the 2 groups on Kaplan-Meier analysis. On univariate Cox regression analysis, age, TURBT stage, cystectomy pathology stage, carcinoma in situ, and lymphovascular invasion status, and Bacillus Calmette-Guérin therapy status was not found to be significant factors for OS, CSS, or RFS between patients with pT2aN0 or pT2bN0 tumors.Prior studies have sub stratified pT2a and pT2b, studying survival outcomes with equivocal results. Many of these studies included variant histology or use of chemotherapy in the analysis. Here, we identified a pure urothelial cohort to compare survival outcomes between pT2a and pT2b and found no difference in OS, CSS, and RFS.

INTRODUCTION AND OBJECTIVE:Adjuvant chemotherapy (AC) has been advocated after primary retroperitoneal lymph node dissection (RPLND) to reduce the historical 50% risk of relapse in pN2/N3 patients,...

Background The optimal management of progressive brain metastases in patients with germ cell tumors (GCTs) remains unsettled. This study reports the management of 25 consecutive patients with relapsed GCTs and progressive brain metastases undergoing high-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBSCT) at Indiana University from 2006 to 2016. Methods All patients were planned to undergo HDCT, which consisted of carboplatin at 700 mg/m2 on days 1 to 3 plus etoposide at 750 mg/m2 on days 1 to 3, followed by PBSCT on day 5 for 2 cycles. Patients were treated with brain metastectomy, stereotactic radiotherapy or whole-brain radiotherapy, HDCT alone, or a combination thereof. All 25 patients had progressive brain metastases at the time of initiating HDCT. Patient and disease characteristics, management of brain metastases, and outcomes were measured. Platelet transfusions were given to maintain platelet counts > 30,000/µL; the goal was >50,000/µL when there were signs of prior or active hemorrhaging. Results Twenty-two of 25 patients completed both courses of HDCT. The median α-fetoprotein level was 7.5 ng/mL (range, 1.6-1130 ng/mL), and the human chorionic gonadotropin level was 31.3 IU/mL (range, 0.5-25,601 IU/mL). At a median follow-up of 24.5 months (range, 0.4-117 months), 11 patients (44%) were alive with no evidence of disease, 2 patients were alive with relapsed disease, and 12 patients had died of disease progression or complications from HDCT. Fifteen patients developed progressive brain metastases despite radiation and/or craniotomy before HDCT, and 8 of these patients were alive without evidence of disease. There were no intracranial hemorrhagic events leading to death. Conclusions Patients with relapsed GCTs and progressive brain metastases are curable with multimodality therapy that includes HDCT and peripheral blood stem cell transplantation.

Background Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5 mg PO daily and panobinostat 10 mg PO 3 times weekly (weeks 1 and 2) given in 21-day cycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1 months (95% confidence internal; 2.0-7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients' miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients' miR-605 levels increased (p = 0.0179). Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009.

Germ cell tumors (GCT) are the most common cancer in men between 15 and 35 years of age and the incidence has increased during the past several decades. This article reviews the current knowledge on high-dose chemotherapy (HDCT) and stem cell transplant for salvage treatment of patients with relapsed metastatic GCT. Furthermore, the authors attempt to dissect the controversy of using standard-dose versus high-dose therapy as initial salvage and identify patients who are most likely to benefit from HDCT and peripheral blood stem cell transplant.

Presence of teratoma in the orchiectomy and residual retroperitoneal mass size are known predictors of finding teratoma during postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). We sought to determine if the percentage of teratoma in the orchiectomy specimen could better stratify the risk of teratoma in the retroperitoneum.The Indiana University Testis Cancer Database was reviewed to identify patients who underwent PC-RPLND for nonseminomatous germ cell tumors from 2010 to 2018. A logistic regression model was fit to predict the presence of retroperitoneal teratoma using teratoma and yolk sac tumor in the orchiectomy, residual mass size and log transformed values of prechemotherapy alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin. The study cohort was split into 60% training and 40% validation sets using 200 bootstraps. A predictive nomogram was developed for predicting teratoma in the retroperitoneum.A total of 422 men were included. Presence of teratoma in the orchiectomy (OR 1.02, p0.001), residual mass size (OR 1.16, p0.001) and log transformed prechemotherapy AFP (OR 1.12, p=0.002) were predictive factors for having teratoma in the retroperitoneum. The C-statistic using this model demonstrated a predictive ability of 0.77. Training set C-statistic was 0.78 compared to 0.75 for the validation set. A nomogram was developed to aid in clinical utility.The model better predicts patients at higher risk for teratoma in the retroperitoneum following chemotherapy, which can aid in a more informed referral for surgical resection.

BackgroundATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).MethodsPatients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks.ResultsOf 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleteriousBRCA1orBRCA2alteration.ConclusionsRucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.Trial registrationThis trial was registered inClinicalTrials.gov(NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).